tag:blogger.com,1999:blog-54729213280782530362024-03-15T18:09:59.520-07:00Current Research into Cures for Type-1 DiabetesNews and updates on potential cures for type-1 diabetes, that are in human (or clinical) trials. Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.comBlogger331125tag:blogger.com,1999:blog-5472921328078253036.post-27293830371781223452024-03-08T10:12:00.000-08:002024-03-08T10:12:35.180-08:00Levicure's Combination Therapy<p>Levicure is a startup which is currently raising money to fund a phase-II trial for a combination therapy designed to prevent or delay T1D if given during the honeymoon period. This blog posting is reporting on the results of their retrospective phase-I clinical trial. That trial has already been completed and is motivating them to move forward with a larger phase-II trial. </p><p>The combination therapy used three medicines: GABA, Sitagliptin or Saxagliptin (which are dipeptidyl peptidase-4 inhibitors), and Omeprazole (a proton pump inhibitor). All three of these drugs are available now, and all have some evidence that they will help people with diabetes. They have all been tested (in some cases in combination with other medicines and each other). However, I think this is the first clinical trial that has reported on these three together. </p><h3 style="text-align: left;">The Study</h3><p>This was a retrospective study, where the researchers reviewed the medical records of people who had been treated with the three drugs. The people were given the three drugs because their doctors thought it was the right treatment for them, not because they were enrolled in a trial. There is no randomization process and no control group. The trial size is determined by how many people got all three treatments in the time period the researchers looked at. </p><p>The researchers ended up with 19 people. Ten of them had received the three drugs during the first year after diagnosis (their honeymoon period). Nine more had received the drugs after that, so they had established T1D. The two groups were analyzed separately.<br /></p><h3 style="text-align: left;">Results</h3><p>The group (ten people) that started therapy during their honeymoon phase, called "early therapy" below had a statistically significant rise in <a href="https://cureresearch4type1diabetes.blogspot.com/p/common-words-phrases-and-ideas-in-this.html#WhyMeasureCPeptides">C-Peptide</a> production. The average went from just over 200 pmol/L to just under 500. Since the average for a person without T1D is at least 365, this is an important difference, as the change is from an abnormal result to a normal one. (All of these are fasting numbers.) <br /></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEitHupOzkOK-RSZKJZOVujCyCNNjd-imgX50PeoG0QYv3z1aZ1-HyZtMAr6JTb6lr3FTKRSnUijMI6xwfa3yRrl4WebtJLzympZeFe1paIZwNyQqCPU3ABx9369BsRlSrajmEXm6baoumCeYqT7nokVZ0-xoB3fDxEefzh-kikuqNN6aN_EhlTlIMpyIIQ/s431/Levicure.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="431" data-original-width="367" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEitHupOzkOK-RSZKJZOVujCyCNNjd-imgX50PeoG0QYv3z1aZ1-HyZtMAr6JTb6lr3FTKRSnUijMI6xwfa3yRrl4WebtJLzympZeFe1paIZwNyQqCPU3ABx9369BsRlSrajmEXm6baoumCeYqT7nokVZ0-xoB3fDxEefzh-kikuqNN6aN_EhlTlIMpyIIQ/s16000/Levicure.jpg" /></a></div><br /><p></p><p>The group (nine people) that started the treatment more than a year after the onset of T1D did not show an improvement in their C-Peptide number, and none of them was able to stop injecting insulin. They did show improvements in treating T1D (using less insulin, having better A1c numbers, etc.) <br /></p><p>Company: <a href="https://www.levicure.com/">https://www.levicure.com/</a><br />History: <a href="https://healthtransformer.co/levicure-is-developing-a-breakthrough-triple-therapy-for-type-1-diabetes-b6c521e6b2c5">https://healthtransformer.co/levicure-is-developing-a-breakthrough-triple-therapy-for-type-1-diabetes-b6c521e6b2c5<br /></a>Clinical Trial Report: <a href="https://www.frontiersin.org/articles/10.3389/fendo.2023.1171886/full">https://www.frontiersin.org/articles/10.3389/fendo.2023.1171886/full<br /></a>Animal Testing: <a href="https://www.frontiersin.org/articles/10.3389/fendo.2022.1028114/full">https://www.frontiersin.org/articles/10.3389/fendo.2022.1028114/full</a></p><h2 style="text-align: left;">Discussion <br /></h2><h4 style="text-align: left;">LADA vs. Classic T1D</h4><p>Discussion of this study needs to start out with the question: Is it a LADA study, or is it a classic T1D study, and are they different? </p><p>The successful (early treatment) part of this study enrolled people between the ages of 17 and 58 (average age was 31 and standard deviation was 13 years), so about half of these people had LADA rather than classic type 1 diabetes. LADA stands for Latent Autoimmune Diabetes in Adults; you can think of it as classic T1D, but diagnosed in adults. A common cut off is 30 years old. People under that age are said to have classic T1D and after that age, LADA. LADA has a honeymoon, just as T1D does, but it is not the same. It is well known to be longer and stronger. This makes it easier for drugs that delay/extend the honeymoon to work better on LADA than on T1D. Therefore, we don't know if the good results seen here for many people with LADA are going to be as good in people with classic T1D.</p><h4 style="text-align: left;">Prospective vs. Retrospective Studies<br /></h4><p>I usually report on prospective studies, which are inherently more reliable than retrospective studies, and this study was retrospective. In this case, these researchers are already raising money for another study and that new study will be prospective, so it will provide a better signal as to the success of the treatment. In the meantime, there is nothing to do but wait, and hope they can raise the money quickly.</p><h4 style="text-align: left;">Similar Studies With Semaglutide <br /></h4><p>The obvious clinical trial to compare this to is the Semaglutide study which I blogged on here:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2023/09/strong-results-from-pilot-study-of.html">https://cureresearch4type1diabetes.blogspot.com/2023/09/strong-results-from-pilot-study-of.html</a><br />That study was in many ways very similar, both in study design and result. They were both retrospective studies based on clinical practice, and they both had many people off insulin for a year in the honeymoon phase.</p><p>Interestingly, Semaglutide has a similar mechanism of effect to Sitagliptin or Saxagliptin. They all end up impacting glucagon-like peptide-1 (GLP-1). However, Semaglutide is an injected drug while Sitagliptin and Saxagliptin (tested here) are pills. </p><h4 style="text-align: left;">Availability Now <br /></h4><p>The three drugs tested here are all commonly available. GABA is a dietary supplement, Omeprazole is sold both over the counter and by prescription. Only the second component: Sitagliptin or Saxagliptin is a prescription drug and both have been approved for use since the late 2000s. They each have a generally good safety profile. If you want to have an "<a href="https://cureresearch4type1diabetes.blogspot.com/p/common-words-phrases-and-ideas-in-this.html#OffLabelUse">off label</a>" discussion with your doctor, the exact dosing information is in the clinical trial report (link above). </p><p> </p><div style="text-align: center;"><span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div><div style="text-align: left;">
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<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><span style="font-size: x-small;">
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<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-24051740333472191312024-01-29T21:06:00.000-08:002024-01-29T21:06:04.644-08:00Results from a Phase-IIΔ Trial of Pleconaril and Ribavirin<p>This clinical trial represents an attack on T1D slightly different than anything I've blogged on before.</p><p>Pleconaril and Ribavirin are both antiviral drugs. The idea here is that viruses either cause T1D or contribute to it, and that attacking viruses during the early honeymoon period will do something good. Maybe delay the onset, extend the honeymoon, or even allow the long term survival of more beta cells to lower long term complications of T1D. </p><p>I want to stress that this "virus causes T1D" hypothesis is just that: a hypothesis. It is held by some researchers, but is not the consensus cause of T1D. However, these researchers are moving forward assuming it is true, and therefore testing a prevention technique that is likely to work if it is true. They had previously found low grade enteroviral infection in the pancreas of people recently diagnosed with T1D, and that motivated them to run this study. <br /></p><p style="text-align: left;">The study participants were between 6 and 15 years old and<span style="font-size: small; font-weight: normal;"> within 3 weeks of diagnosis. These were early honeymooners. The drug combination was in liquid form and drunk daily for six months, and then the people were followed for an additional six months, which is reported here. Although they reported results in October, the study will continue for two more years and so we should get more results in the future.</span></p><p>The key finding was "During the 12-month study period, the relative decrease in C-peptide was 11% in the Pleconaril and Ribavirin group and 24% in the placebo group" (paraphrased). So both groups dropped, but the treated group dropped much less. <a href="https://cureresearch4type1diabetes.blogspot.com/p/common-words-phrases-and-ideas-in-this.html#CPeptideChanges">See here for more discussion of why these sorts of results do not excite me</a>.<br /></p><p><img height="434" src="data:image/png;base64,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" width="640" /></p><p>This study was supported by JDRF, INNODIA and others.<br /></p><div>News Coverage: <a href="https://www.medscape.com/viewarticle/997094?form=fpf">https://www.medscape.com/viewarticle/997094?form=fpf<br /></a>Journal Article: <a href="https://www.nature.com/articles/s41591-023-02576-1">https://www.nature.com/articles/s41591-023-02576-1</a></div><div>Clinical Trial Registry: <a href="https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003350-41">https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003350-41</a></div><div>Earlier Report of Enteroviruses: <a href="https://www.frontiersin.org/articles/10.3389/fendo.2022.881997/full">https://www.frontiersin.org/articles/10.3389/fendo.2022.881997/full</a> <br /></div><div> </div><div>Wikipedia Pleconaril: <a href="https://en.wikipedia.org/wiki/Pleconaril">https://en.wikipedia.org/wiki/Pleconaril</a><br />Wikipedia Ribavirin: <a href="https://en.wikipedia.org/wiki/Ribavirin">https://en.wikipedia.org/wiki/Ribavirin</a><br /></div><h2 style="text-align: left;">Discussion</h2><p>The idea that a virus causes T1D, or triggers it, or make it worse, is widely held. Many parents remember that their kids were sick just before or as part of their T1D diagnosis. However, the causality part has not been proven. Viruses may cause T1D, or they might trigger it (i.e. the person was going to get T1D anyway, and the virus just caused it to manifest now rather than next month), or it may be that early T1D symptoms are similar enough to the flu so that people get them mixed up, or it might be that after a diagnosis of T1D, parents suddenly connect it to the last illness the child had.<br /></p><p>On the other hand, Coxsackie B viruses (a type of enterovirus) have been associated with T1D in previous population studies, and enteroviruses are known to target pancreatic islets. There is another clinical trial which attempts to use a Coxsackie B vaccine to lower the rate of T1D, and a third using flu vaccine on people in the honeymoon phase. So the causal part is certainly possible. </p><p>About these anti-virals specifically, I think it is important to note that Pleconaril was never approved for use by the FDA because of side effects. It was evaluated in the early 2000s. Ribavirin is approved, but use in T1D would be "off label" and its label includes two black box warnings.<br /></p><p>To me, these results seem similar to the Teplizumab in honeymooners results, although with the obvious caveat that this result is in a 100 person phase-IIΔ study, and the Teplizumab study was a 300 person phase-III study. The Teplizumab honeymoon trial reported a difference of 0.13 pmol/ml while this study reported 0.16 pmol/ml.</p><p>But also, this study only shows preservation of beta cells (and not even complete preservation), and I usually only get excited about beta cell regrowth in the honeymoon phase.<br /><br /> </p><div style="text-align: center;"><span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div><div style="text-align: left;">
<div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><span style="font-size: x-small;">
</span><div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p><p> </p><p> </p><p><br /></p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-23912226327736603232024-01-22T10:07:00.000-08:002024-01-22T10:07:08.244-08:00Results From A Phase-IIΔ Baricitinib (Olumiant)<p>Baricitinib (trade name Olumiant) is a drug which targets the immune system, and is already approved for Rheumatoid Arthritis (since 2018) and Alopecia Areata (since 2022). Since these two diseases are both autoimmune diseases, like T1D, it makes sense that this drug would be tried for T1D as well. This drug is called a JAK inhibitor, and it blocks both JAK variants: <span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE">JAK1 and JAK2. JAK inhibitors have been an active area of research because of some case studies where they seem to impact T1D when people took them for other conditions. I blogged on this once before:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2021/02/ruxolitinib-case-study.html">https://cureresearch4type1diabetes.blogspot.com/2021/02/ruxolitinib-case-study.html<br /></a></span></span></p><p><span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE"><b>About This Study</b></span></span></p><p><span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE">People were recruited in their honeymoon phase, within 100 days of diagnosis. A total of 91 people participated, 60 got treatment and 31 were in a control group. The age range was 10 to 30, and about half were under 18 and half over. They took a 4mg pill of Baricitinib (or placebo) once a day for 48 weeks. The study was blinded for both participants and researchers.<br /></span></span></p><p><span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE">The study was funded by JDRF and JDRF Australia.<br /></span></span></p><p><span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE"><b>Results</b></span></span></p><p><span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE">The key results for me are C-Peptide numbers, which are shown in the graph below. The treated group (Baricitinib) actually rose in C-Peptide generation, going from 0.6 to 0.65, a rise of 8%. That is not huge, but it is in the right direction, and it is not just "preserving" beta cells, it is growing them. <br /></span></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgzVHmC1MmFoAhOEoPPZePpNtTlb0JoXNfhyphenhyphenYccFsnTfPFbyQSGpDGAPO3yZqR5f28JBWGzLWMKhayo7EsZyecpPb7r6Jlwr-0hrPx5LVgopIu93I_ZrI9Bs3Czg4758-xkfYlRIfupOmLJx67ztFsJLK8C6q2KXOj3NjOKrx51X_718xc6QnnYe71J2G8/s355/Capture.PNG" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="272" data-original-width="355" height="490" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgzVHmC1MmFoAhOEoPPZePpNtTlb0JoXNfhyphenhyphenYccFsnTfPFbyQSGpDGAPO3yZqR5f28JBWGzLWMKhayo7EsZyecpPb7r6Jlwr-0hrPx5LVgopIu93I_ZrI9Bs3Czg4758-xkfYlRIfupOmLJx67ztFsJLK8C6q2KXOj3NjOKrx51X_718xc6QnnYe71J2G8/w640-h490/Capture.PNG" width="640" /></a></div><p></p><h2 style="text-align: left;"><b>Discussion</b></h2><p>For me, these are good results in a first-in-T1D clinical trial, but it definitely needs follow-on work. At this point, I think it is pretty clear that any treatment that helps C-Peptide numbers in the honeymoon phase should be tried in at-risk people. To use TrialNet terminology, if it works in stage 3, it should work better in stage 2. <span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE"> </span></span></p><p><span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE">You can see </span></span>the <a href="https://cureresearch4type1diabetes.blogspot.com/p/common-words-phrases-and-ideas-in-this.html#ConfidenceBars">confidence bars</a> in<span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE"> the image above, they are the little horizontal bars above and below the measurements, and the same color. Confidence bars represent </span></span>the uncertainty in measurement,<span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE"> and the uncertainty in averaging a small number of data points. We talk about an average as though it were one, exact number. But an average is a statistical combination of many numbers. Each one of those numbers has a measurement error (was it really 0.6 or was it 0.62 or maybe 0.59)? Hopefully those errors cancel out as we measure more data points, but it is possible they combine to get worse. Also, the average of a small number of data points might be different than the average of a large number of data points even if they are measuring the same thing. Researchers summarize these uncertainties on their graphs with confidence bars. Two data points within each other's confidence bars might be the same, even if they appear different.<br /></span></span></p><p><span style="font-family: times;"><span id="ctl00_body_CXSTUDYTITLE">If you look at the diagram, </span><span id="ctl00_body_CXSTUDYTITLE">the placebo and treatment are
within confidence interval of each other, until the last measure. Even then, the treatment group is just barely outside the confidence interval of the placebo.</span></span> (And the placebo is clearly inside the confidence interval of the treatment.) All this means, to me, that a bigger study is needed to get a strong signal. I'm hoping that would also lead to more data on how much beta cell growth there is.<br /></p><p>Finally, it is important to remember that, although Baricitinib is approved for use already, it comes with black box warnings, which are the most serious warnings that the FDA has. These need to be considered before off-label use is considered, and right now, using Baricitinib on people with T1D is off label.<br /></p><p>There are two other JAK inhibitors approved for use in the US: Tofacitinib (sold as Xeljanz) and Upadacitinib (sold as Rinvoq).</p><p>JAK inhibitors are very different medicines than Tzield (Teplizumab), or Diamyd, or Verapamil, so it is entirely possible that two or more of these treatments could be used together in the future.</p><p>Trialnet is running a clinical trial on JAK inhibitors (Abrocitinib and Ritlecitinib) which I will blog on in the future. It is enrolling people between 12 and 35 year olds during the first 100 days of their honeymoon period. You can read more about it here: <a href="https://trialnet.org/our-research/newly-diagnosed-t1d/jakpot-t1d">https://trialnet.org/our-research/newly-diagnosed-t1d/jakpot-t1d</a><br /></p><p>News Coverage: <a href="https://www.medicalnewstoday.com/articles/rheumatoid-arthritis-drug-shows-promise-as-type-1-diabetes-treatment">https://www.medicalnewstoday.com/articles/rheumatoid-arthritis-drug-shows-promise-as-type-1-diabetes-treatment</a><br />Journal Article: <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2306691">https://www.nejm.org/doi/full/10.1056/NEJMoa2306691</a></p><p>Clinical Trial Registry: <a href="https://www.clinicaltrials.gov/study/NCT04774224">https://www.clinicaltrials.gov/study/NCT04774224</a><br />Wikipedia: <span style="font-family: times;"><a href="https://en.wikipedia.org/wiki/Baricitinib">https://en.wikipedia.org/wiki/Baricitinib</a></span></p><p><b>A Note About Naming Drugs<br /></b></p><p>In the medical world, it is common to capitalize the name brand of drugs, like Olumiant, but not capitalize the generic names for drugs, like baricitinib. I have never understood this. To me, they are both proper names of specific things, and both should be capitalized. Therefore, I do capitalize both. <br /></p><p><br /><br /> </p><div style="text-align: center;"><span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div><div style="text-align: left;">
<div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><span style="font-size: x-small;">
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<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p><p> </p><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-69060772129819311652024-01-06T09:56:00.000-08:002024-01-06T09:56:43.484-08:00What To Watch In 2024<p>At the start of a new year, some bloggers write a posting on the year that was, and a some write a posting on what they expect in the new year. This posting is a little of each. </p><h2 style="text-align: left;">The Big News From Last Year<br /></h2><p>Teplizumab! Which became the product Tzield. Getting a drug approved that actually changed the course of T1D is a big deal. I know it is for people at-risk, not people who have T1D. I know it only delays the onset of T1D. I know it is incredibly expensive. Those things matter, especially in the short term, but in the long term this is still a huge breakthrough. </p><p>And next year, it may well expand. I recently reported on a phase-III clinical trial done on honeymooners:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2023/11/teplizumabtzield-reports-results-from.html">https://cureresearch4type1diabetes.blogspot.com/2023/11/teplizumabtzield-reports-results-from.html</a><br />It is also being tested on younger kids, to expand the people who can benefit from it. I'm also hoping that more widespread use will lead to more knowledge about how it works, and maybe even a realization that it delays T1D even longer than we know now.</p><p>Also, we have seen a few more clinical trials running in 2023 than in previous years. I'm not sure if that is just a post-COVID bounce, or real and continuing growth in the human trial pipeline. We are a little higher than our pre-COVID numbers (more clinical trials), so I'm hoping this is actual growth. It is possible that previous research and Teplizumab's approval has laid a foundation that will accelerate future research. I'm an optimist.<br /></p><h2 style="text-align: left;">What I'm Watching In The New Year<br /></h2><p><b>Semaglutide</b> (sold as: Ozempic, Wegovy and Rybelsus) had very strong results in a very small study of honeymoon T1Ds:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2023/09/strong-results-from-pilot-study-of.html">https://cureresearch4type1diabetes.blogspot.com/2023/09/strong-results-from-pilot-study-of.html</a><br />People who took the drug sometimes did not need to inject insulin for a year. Other people had to inject long acting insulin, but did not need to inject at meal times (again, for the first year of their honeymoon). I'm hoping to read about more research starting up in 2024 to confirm these results. Because Semaglutide is widely used to treat T2D and for weight loss, I think just one or two confirmation studies will be required to enable widespread use. If that gets us a year or two delay starting injections, that would be a huge win (and even more so if it could be combined with Teplizumab or other treatments).<br /></p><p><b>Ladarixin</b> is a drug being developed by Dompé. Ladarixin targets two specific immune system chemicals: IL-8a and IL-8b. I think it is the only research aimed at those targets, so it is a little unique. I'm interested in this because it is a phase-III trial. Those are large trials done only after results from phase-II trials. This one is being funded by the same company that did the phase-II trial, so they are really (in American terminology) "putting their money where their mouth is". That is the good news.</p><p>The bad news is that it usually requires two phase-III studies to get approval, and (as far as I know) this is the only phase-III trial done so far. Also, the results from the previous phase-II trial were not that strong. And finally, this trial is not going to be quick. They are gathering data for two years, which means the study will last at least two years after they finish recruiting, and they are still recruiting now. Therefore, we should not expect results before the end of 2025. However, even with all that, the company thought it was worth funding a large (300+ person) clinical trial, and that means that they have a realistic hope that it will be successful.</p><p><a href="https://cureresearch4type1diabetes.blogspot.com/2023/05/dompe-starts-gladiator-phase-iii.html">https://cureresearch4type1diabetes.blogspot.com/2023/05/dompe-starts-gladiator-phase-iii.html</a><br /></p><p><b>Verapamil</b> is another interesting "off label" drug. This is a drug which is already approved (since 1981) and widely used (3 million prescriptions a year) for high blood pressure. It is being tested on honeymooners. Therefore, if clinical trials show that it helps, it should be available quickly, especially for aggressive doctors who are willing to prescribe it off label.</p><p>Unfortunately, the ongoing study which was going to finish in 2024 is now going to finish in either 2025 or 2026, so we'll be waiting longer for results. I blogged about the start of this study here:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2022/02/verapamil-sr-starts-phase-ii-trial-ver.html">https://cureresearch4type1diabetes.blogspot.com/2022/02/verapamil-sr-starts-phase-ii-trial-ver.html</a><br /></p><p><b>Diamyd</b> is another drug in phase-III trials. They hope to finish in 2025, but the news we can look for is that their clinical trial is fully enrolled in 2024. If that happens, it puts them on track for results in 2025 or maybe 2026 in the worst case. Diamyd has a long complex history, but in the end, all that matters is results, and the news from 2024 will tell us if results will be coming in 2025 or 2026.</p><p><a href="https://cureresearch4type1diabetes.blogspot.com/2023/12/diamyd-update.html">https://cureresearch4type1diabetes.blogspot.com/2023/12/diamyd-update.html</a><br /></p><h2 style="text-align: left;">My Biggest Hope (Over More Than A Year)</h2><p>All four of these treatments target honeymooners or pre-honeymooners, and they all seem to have different reasons they work. Therefore, it would be just wonderful if we could stack them. Use 2, 3, or even all 4 to delay the onset of T1D and then delay the need for injections, for many years.</p><p>Of course, success in established T1Ds would be even better, but I don't see that on the horizon for the next few years.<br /></p><div style="text-align: center;"><span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div><div style="text-align: left;">
<div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><span style="font-size: x-small;">
</span><div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p></p><p><br /></p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-40693878175764906782023-12-24T15:40:00.000-08:002023-12-24T15:40:17.942-08:00Diamyd Update<p>This is my first update on the Diamyd company in many, many years. It is focused on their DIAGNODE-3 clinical trial, but before I discuss that one study, I cover Diamyd's history, and after I discuss the study, I've included a list of all the studies the company has done (which is a lot: about 19 studies in about 20 years).</p><p>But that is not all that Diamyd is active with. In a future blog, probably in February, I'm going to discuss two more clinical trials which are important to applying Diamyd to at-risk people and people with LADA. DIAGNODE-3 is focused on honeymooners. That future blog will also include some interesting discussion of JDRF's funding of Diamyd.<br /></p><p>The drug Diamyd is a form of GAD65. GAD65 is an enzyme, which is common in the pancreas and is used to make GABA and it is also a target of the immune system which can cause type 1 diabetes. The company Diamyd believes that the drug Diamyd works by teaching immune cells not to attack beta cells and therefore beta cells will not be destroyed at the onset of T1D. The technical phrase for this is "antigen-specific tolerizing beta-cell preserving therapeutic". It is also sometimes called a reverse vaccine, because it teaches your immune system <u>not to attack</u> a specific kind of cell (your beta cells), while a standard vaccine teaches your immune system <u>to attack</u> a cell (the attacking virus).<br /></p><h2 style="text-align: left;">History</h2><p>When I first started this blog, in 2006, Diamyd was already one of the potential cures most advanced in the research pipeline. In 2008 they started two phase-III clinical trials in people in the honeymoon phase of T1D. If successful, these could have led to government approval. In January 2009, I considered the start of these clinical trials to be one of the "big-5" best news of the year. At that time they were also running several phase-II trials to test out Diamyd in other situations.</p><p>However, in 2011 one of the phase-III trials ended unsuccessfully ("did not meet the primary efficacy endpoint"), and in the next year, the other phase-III study was terminated. In the years after that, several of the previously started phase-II were unsuccessful, and the company started a few more studies, but again none of these were particularly successful.<br /></p><p>Later, in 2015 the company started the DIAGNODE clinical trial which involved injecting the Diamyd treatment directly into a person's lymph nodes. Previous studies injected Diamyd right under the skin, much like insulin. Results from that study were available in 2020 and the follow on DIAGNODE-2 had results in 2021. I took a quick look at them, and they did not look successful to me. (See the details below, the trial was unsuccessful, but also included some results that gave hope.) So I never blogged on them.</p><p>Meantime, the company ran some meta analysis which pooled data from more than one of their studies. They included some genetic subtyping and the results were successful and statistically significant for some genetic types. I go into the details below. This led Diamyd to a much more optimistic view of the results,
and so they started the DIAGNODE-3 clinical trial.</p><h2 style="text-align: left;">The DIAGNODE-3 Trial</h2><p>This phase-III trial will recruit 330 people in the honeymoon phase of T1D, within 6 months of diagnosis. They will be between 12 and 29 years old and will have a specific gene called HLA DR3-DQ2.<br /></p><p>Each patient will get three injections of Diamyd, one month apart, and also take vitamin-D for 2 months, and will be followed for 2 years. The primary end points are C-peptides and A1c. Secondary end points include time-in-range, insulin dose, and unexpected lows.<br /></p><p>This study started recruiting in Europe in 2022, but the recent news is
that in September 2023 it started recruiting in the United
States. This is a big study, with 60 recruiting locations all over Europe and the United States. The trial has it's own web page here:<br /><a href="https://www.diagnode-3.com/">https://www.diagnode-3.com/</a><br />which includes a cool interactive map to find a clinic near you:<br /><a href="https://www.diagnode-3.com/Clinics.aspx">https://www.diagnode-3.com/Clinics.aspx</a><br />(Remember to select your country, if it starts off displaying a different country.)</p><p>Diatribe has a good article on this clinical trial as well: <br /><a href="https://diatribe.org/trial-investigates-promising-new-beta-cell-treatment">https://diatribe.org/trial-investigates-promising-new-beta-cell-treatment</a></p><p>News Coverage: <a href="https://www.precisionmedicineonline.com/business-news/diamyd-medical-expand-phase-iii-diabetes-drug-trial-us">https://www.precisionmedicineonline.com/business-news/diamyd-medical-expand-phase-iii-diabetes-drug-trial-us</a><br />Clinical Trial Registry: <a href="https://clinicaltrials.gov/study/NCT05018585">https://clinicaltrials.gov/study/NCT05018585<br /></a>Corporate Web Site: <a href="https://www.diamyd.com/">https://www.diamyd.com/</a> <br /></p><p><b>Discussion</b></p><p>For me, there are two areas of discussion for this clinical trial: (a) will it work, when previous research didn't, and (b) will the FDA approve it, based on successful results from this one study, or will more research be needed?</p><p>The big question is: will the current clinical trials be successful when the previous ones were unsuccessful? As far as I can see, there are two differences. The first is that for the recent studies, Diamyd is injected into a lymph node, while in the older studies it was injected under the skin, far from lymph nodes. Because the lymph nodes are part of the system that educates immune cells to attack the foreign cells, getting more Diamyd closer to them could make it more effective. </p><p>The second difference is that they are only accepting people who have the HLA DR3-DQ2 gene (technically they must "carry the HLA DR3-DQ2 haplotype"). The gene is associated with autoimmune diseases, especially T1D, and it is involved in synthesizing GABA, so again, it makes sense that people with this gene would be more sensitive to the Diamyd treatment. About half the people with T1D have this gene.<br /></p><p>Are these differences enough to create success? The obvious way to measure this is to look at the phase-II DIAGNODE-2 study, which was published here: <a href="https://diabetesjournals.org/care/article/44/7/1604/138800/Intralymphatic-Glutamic-Acid-Decarboxylase-With"><br />https://diabetesjournals.org/care/article/44/7/1604/138800/Intralymphatic-Glutamic-Acid-Decarboxylase-With</a> <br /><a href="https://academic.oup.com/jcem/article/107/9/2644/6602344">https://academic.oup.com/jcem/article/107/9/2644/6602344</a></p><p>Unfortunately, the data is not clear. This study recruited enough people to run the analysis in a statistically significant way looking at the whole population, but when it was designed the impact of the HLA DR3-DQ2 gene was not known. After the study started a meta-analysis combining past studies suggested that people with the HLA DR3-DQ2 were much more likely to be helped by the treatment. So the researchers added a HLA DR3-DQ2 analysis to the study while it was underway and still blinded, but they did not enlarge the study. Once the study finished, they did their analysis separately: once for everyone and again for people with the HLA DR3-DQ2 gene. Sure enough, the study was unsuccessful when everyone was analyzed together. But when just the HLA DR3-DQ2 people were analyzed, the treated group did better than the untreated group. However, it was not statistically significant. There were not enough people with that gene in the study to get a statistically significant result. </p><p>In summary, we have three pieces of data:</p><ol style="text-align: left;"><li>The phase-II study as a whole was unsuccessful.</li><li>The phase-II study looking just at the one genetype suggests success, but is not big enough to be sure.</li><li>A meta analysis combining previous studies was successful for the genetype.<br /></li></ol><p>The phase-III trial is only enrolling people with the HLA DR3-DQ2 gene, and is enrolling more people. So I do expect a clear yes or no answer from this trial.<br /></p><p>As for the question of FDA approval, that is much simpler to answer: no one knows, but the company is optimistic and plans to submit for FDA approval if the clinical trial is successful. On paper, the FDA requires two phase-III clinical trials, and for T1D these trials involve about 300 people each. So normally, I would say they need to run another study before getting approval. </p><p>However, "in real life" (as opposed to the "on paper" requirements) the FDA did approve Teplizumab, which did not have two phase-III studies. Instead, it had one phase-III and several older studies. And Diamyd has a phase-III study and even more older studies than Teplizumab had. Diamyd has a long history of safety in previous clinical trials, something like 15 trials covering over 1000 people. Finally, Diamyd already has an orphan drug designation from the US FDA, and the company believes that will help get approval.</p><p>But no one except the FDA knows for sure what will happen if it were submitted for approval based on the phase-III trial currently underway. The path to approval is clear: Complete the clinical trial, get a successful result, submit for approval, and then it is in the hands of the US FDA.</p><h2 style="text-align: left;">Diamyd More Generally</h2><div><span style="background-color: white;">Diamyd has run 18 different clinical trials, which you can see here:</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/search?term=diamyd">https://clinicaltrials.gov/search?term=diamyd</a></span></div><div><span style="background-color: white;">Below, I've organized them into five groups:</span></div><div><span style="background-color: white;"> </span></div><div><span style="background-color: white;">The DIAGNODE trials </span><span style="background-color: white;">which enroll people with </span>the HLA DR3-DQ2 gene and Diamyd is injected into the Lymph node. These are aimed at getting government approval and turning Diamyd into a product for honeymooners. <br /></div><div>More info:<br /></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT05018585">https://clinicaltrials.gov/study/NCT05018585</a> "DIAGNODE-3" Recruiting honeymooners</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT05351879">https://clinicaltrials.gov/study/NCT05351879</a> "DIAGNODE-B" Extension to </span><span style="background-color: white;">DIAGNODE-2 <br /></span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT03345004">https://clinicaltrials.gov/study/NCT03345004</a> </span><span style="background-color: white;">"DIAGNODE-2"</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT02352974">https://clinicaltrials.gov/study/NCT02352974</a> "DIAGNODE-1" </span></div><div><span style="background-color: white;"><br /></span></div><div><span style="background-color: white;">DIAGNODE expansion trials. These are using the same DIAGNODE technique, but the first is aimed at people who are at-risk of T1D, not honeymooners, and the second is aimed at people with LADA. These are the studies I will discuss in a future blog posting.<br /></span></div><div><div>More info:<br /></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT05683990">https://clinicaltrials.gov/study/NCT05683990</a> "Diaprecise" Recruiting at-risk </span></div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT04262479">https://clinicaltrials.gov/study/NCT04262479</a> GADinLADA" Testing on LADA patients </span></div><div><span style="background-color: white;"><br /></span></div><div><span style="background-color: white;">The DIAPREVENT trials were supposed to get the data required for governmental approval, for what I would call "classic Diamyd", which is injected under the skin (not into the Lymph node), and given to any honeymooner (not just those with </span>HLA DR3-DQ2).</div><div>More info: <br /></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT00723411">https://clinicaltrials.gov/study/NCT00723411</a> Phase-III "DIAPREVENT-2" Unsuccessful </span></div><div><span style="background-color: white;">ended in 2011<br /></span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT00751842">https://clinicaltrials.gov/study/NCT00751842</a> Phase-III "DIAPREVENT" Terminated in 2012</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT01129232">https://clinicaltrials.gov/study/NCT01129232</a> Phase-II </span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT00435981">https://clinicaltrials.gov/study/NCT00435981</a> Phase-II<br /></span></div><div><span style="background-color: white;"><br /></span></div><div><span style="background-color: white;">These studies were "Diamyd And" studies, where the company Diamyd tested the Drug Diamyd and one or two other medicines, hoping for better results. these are all "classic Diamyd" style clinical trails:<br /></span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT02002130">https://clinicaltrials.gov/study/NCT02002130</a> </span><span style="background-color: white;">Diamyd and </span><span style="background-color: white;">GABA</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT02387164">https://clinicaltrials.gov/study/NCT02387164</a> Diamyd and Vitamin D</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT01785108">https://clinicaltrials.gov/study/NCT01785108</a> Diamyd, Vitamin D, and </span><span _ngcontent-ng-c2733006604="" class="study-overview-item-text">Ibuprofen<br /></span><a href="https://clinicaltrials.gov/study/NCT02464033">https://clinicaltrials.gov/study/NCT02464033</a> Diamyd, Vitamin D, Vitamin D, and <span _ngcontent-ng-c2733006604="" class="study-overview-item-text">Etanercept </span></div><div><span _ngcontent-ng-c2733006604="" class="study-overview-item-text"><br /></span></div><div><span style="background-color: white;">Other Old Studies:</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT00837759">https://clinicaltrials.gov/study/NCT00837759</a> NIDDK</span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT00529399">https://clinicaltrials.gov/study/NCT00529399</a> NIDDK (Trialnet?) <br /></span></div><div><span style="background-color: white;"><a href="https://clinicaltrials.gov/study/NCT00456027">https://clinicaltrials.gov/study/NCT00456027</a> Diamyd on LADA <br /><a href="https://clinicaltrials.gov/study/NCT01122446">https://clinicaltrials.gov/study/NCT01122446</a> For at-risk people, not honeymooners.</span></div><div><span style="background-color: white;"><a href="https://www.diamyd.com/docs/pressClips.aspx?ClipID=4665003">https://www.diamyd.com/docs/pressClips.aspx?ClipID=4665003</a> Reanalysis of two previous studies.<br /></span></div><div><span style="background-color: white;"><br /></span></div><div style="text-align: center;"><span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div><div style="text-align: left;">
<div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><span style="font-size: x-small;">
</span><div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p></p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-91112121148912830982023-12-16T11:26:00.000-08:002023-12-16T11:26:29.413-08:00Islet Cell Transplantation Clinical Trails<p>In this blog I'm going to report on three different clinical trials involving transplantation. The basic idea for all of these is to transplant beta cells into someone with T1D, and those new beta cells will produce insulin and cure the person. As I describe below, this idea has been around for 40 years, but it has not been successful in the past because of two problems: First, the body's immune system attacks the transplanted cells because it is working properly and they are foreign cells. Second, the body's immune system attacks the new cells because it is broken and mistakenly attacks beta cells. Some people think there is a third problem: beta cell supply, but personally, I'm less worried about that. These three trials all attack these problems in different ways.</p><h2 style="text-align: left;">VX-880 <br /></h2><p>A lot of people are excited about this trial because it is generating headlines like "Vertex VX-880 Clinical Results Lead To Insulin-Independence". This is not a lie, but it is highly misleading. I discuss the problems with transplants which require immune suppression below (and VX-880 requires immune suppression). However, it is important to understand that these are not recent improvements. Transplantation trials have been getting results like this for a long time.</p><p>Another reason people are excited about this study, is because the beta cells used here are created from stem cells, and therefore there is an unlimited supply available, and a lot of control over how they are made. Previous studies used beta cells harvested from cadavers or from pigs, each of which has its own problems of supply. <br /></p><p>For over 20 years islet transplantation have led to many people not needing to inject insulin for many years (search for "Edmonton Protocol" with Google). These are the same results seen in VX-880. They are not seen as a cure, because of the bad effects of immune suppression drugs, which are required, and which must be taken for the rest of the person's life, and because they only work for a few years. Typically, people do not need to inject insulin for 5 or 10 years, but then they do again. So headlines reporting on no injecting insulin a year after a transplant are nothing new.<br /></p><p>This trial is currently running, but I'm not covering it as a potential cure for T1D. It requires each person to take a full suite of immune suppression drugs to support the transplant. They will need to do this for their whole lives, even if the transplant only works for a few years. Furthermore, the drug combinations used for transplants have significant bad long term side effects, causing health problems in their own right.</p><p>Therefore, I view transplants that require life long immune suppression to be trading one drug treatment (T1D) for another (Immune Suppression), and not a cure. At this point, I'm not even sure which is more dangerous, more hassle, and has more side effects. </p><p>Of course, in medicine, things change over time. In the future immune suppression may become easier and safer and I might revisit this decision, but until then, for me transplants requiring immune suppression are not cures. </p><p>Clinical Trial Record: <a href="https://www.clinicaltrials.gov/study/NCT04786262">https://www.clinicaltrials.gov/study/NCT04786262</a><br /></p><h2 style="text-align: left;">VX-264 (Phase-I)<br /></h2><p>For me, VX-264 is much more interesting than VX-880, even though they both use the same cells, because it does not require life long immune suppression. In VX-264, the islet cells are encapsulated in a special, high tech membrane. The membrane allows nutrients and sugars in, and wastes and insulin out, but blocks immune cells. This is possible because nutrients, sugar, waste, and insulin are all relatively small, while immune cells are relatively large.</p><p>This study will enroll 17 adults and everyone will get the treatment (no control group), so I consider this a phase-I trial. Everyone will have established T1D for at least 5 years.<br /></p><p>The outcomes of this trial are a little complex. Early in the study they will focus on adverse events (side effects) for a total of 2 years after the transplants, but later they focus on C-peptides 3 months after the transplants. The secondary endpoints include C-peptides, insulin use, and A1c numbers for 2 years after transplant.<br /></p><p>They expect to finish in mid 2026.<br /></p><p>If successful, this would allow islet transplantation without immune suppression, and that would be a cure for T1D. </p><p>They are recruiting at several locations in the US and Europe. You can contact them at medicalinfo@vrtx.com or 617-341-6777, or look in the Trial Page or the "Contacts and Locations" section of the clinical trial record, which has an interactive map of the study locations.<br /></p><p>Trial Page: <a href="https://clinicaltrials.vrtx.com/safety-tolerability-and-efficacy-study-vx-264-participants-type-1-diabetes">https://clinicaltrials.vrtx.com/safety-tolerability-and-efficacy-study-vx-264-participants-type-1-diabetes</a><br />DiaTribe Article: <a href="https://diatribe.org/join-type-1-diabetes-trial-testing-encapsulated-insulin-producing-cells">https://diatribe.org/join-type-1-diabetes-trial-testing-encapsulated-insulin-producing-cells<br /></a>News Article: <a href="https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-fda-clearance-investigational-new-drug">https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-fda-clearance-investigational-new-drug</a><br />Clinical Trial Registry: <a href="https://www.clinicaltrials.gov/study/NCT05791201">https://www.clinicaltrials.gov/study/NCT05791201</a> </p><p><b>Discussion</b></p><p>This idea of filtering out immune cells, but letting the smaller stuff in and out of the islet has a long history. Research had already started in the 1980s, and the earliest clinical trials were running in the 1990s. Obviously, none of those were successful, which suggests to me that the idea is a lot easier to think of than to actually implement. The English language idiom is "The devil is in the details." I'm not sure how many transplantation with high tech membrane type clinical trials have been run in the last 30 years, maybe 5 or 10, but certainly none was successful, so it is a hard problem that Vertex is trying to solve.<br /></p><h2 style="text-align: left;">VCTX211 (Phase-I)</h2><h2 style="text-align: left;"> </h2><p>The VCTX211 clinical trial is also avoiding life long immune suppression. It is being run by <span _ngcontent-ng-c1344077723=""><span _ngcontent-ng-c1344077723="" class="padding-left-05">CRISPR Therapeutics AG, and combines technology from them with stem cells and encapsulation technology from </span></span>ViaCyte (since bought by Vertex). CRISPR is powerful gene editing technology which is too complex for me to discuss here, so I don't, but you can see a list of all the different things they hope to do with it, here: <a href="https://crisprtx.com/pipeline">https://crisprtx.com/pipeline</a>.<br /></p><p><span _ngcontent-ng-c1344077723=""><span _ngcontent-ng-c1344077723="" class="padding-left-05">This trial uses the CRISPR gene editing technique to modify the implanted cells so they are invisible to the immune system. Therefore, they do not trigger the natural immune system rejection of transplanted organs, nor can the autoimmune attack which triggers T1D affect them. No long-term immune </span></span>suppression drugs<span _ngcontent-ng-c1344077723=""><span _ngcontent-ng-c1344077723="" class="padding-left-05"> are required. <br /></span></span></p><p><span _ngcontent-ng-c1344077723=""><span _ngcontent-ng-c1344077723="" class="padding-left-05">ViaCyte is part of a line of companies that has been trying a transplantation cure since the 1990s, the historical line is Neocrin -> Novocell -> ViaCyte -> Vertex. </span></span> </p><p>This study will enroll 40 adults who have had T1D for 5 years or longer. They will be followed for 1 year. Everyone will get the treatment; there is no control group. The primary end points include side effects and C-peptide generation. Secondary end points include several of insulin, A1c, and side effect measurements.<br /></p><p>They expect to finish in mid 2025.</p><p>This trial is recruiting in two locations in Canada: Edmonton and Vancouver. You can contact them at +1-877-214-4634 or MedicalAffairs@crisprtx.com.<br /></p><p>Clinical Trial Registry: <a href="https://www.clinicaltrials.gov/study/NCT05565248">https://www.clinicaltrials.gov/study/NCT05565248</a></p><p><b>Discussion</b></p><p>This study is absolutely huge, both for T1D and for every other transplantation cure in the world. Right now, most organ transplantation is a big deal, because it requires immune suppression, which has a whole raft of problems and issues associated with it. If CRISPR can be used to avoid that, suddenly every form of transplantation is going to become a much better, much more common cure than it was before.</p><p>The idea that using CRISPR to make stem cells that could be transplanted to anyone has been an active area of research for years now, and here is an article that covers it from 2019:<br /><a href="https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system ">https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system </a><br />Although I don't believe that this research was exactly the same as what is being tested in VCTX211.<br /></p><p>Recent news on CRISPR based treatments of sickle cell disease:<br /><a href="https://www.statnews.com/2023/12/08/fda-approves-casgevy-crispr-based-medicine-for-treatment-of-sickle-cell-disease/">https://www.statnews.com/2023/12/08/fda-approves-casgevy-crispr-based-medicine-for-treatment-of-sickle-cell-disease/<br /></a>But it is important to note that for this disease, CRISPR is not used to make the cells invisible to the immunological system. That is why the VCTX211 clinical trial is so important. <br /></p><div style="text-align: center;"><span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div><div style="text-align: left;">
<div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><span style="font-size: x-small;">
</span><div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p></p> <br />Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-10929925336957475432023-11-28T20:57:00.000-08:002023-11-28T20:57:25.490-08:00Teplizumab/Tzield Reports Results From A Phase-III in Honeymooners (PROTECT)<div><p>Teplizumab (sold as Tzield) was recently approved for use in people at-risk of diagnosis for T1D. At risk meaning people who have two autoantibodies and abnormal blood glucose measurements, but not yet requiring insulin injections. However, this phase-III study was testing its effectiveness on people after diagnosis; people in the honeymoon stage. The goal is to get Tzield approved for honeymooners in addition to the current approval for at-risk people.</p><p>This was a large study: 328 people, 217 got the treatment and 111 were in the control group. The people were all between 8 and 17 years old, within 6 weeks of diagnosis. They got two treatments with each treatment being 12 days of Tzield infusions. One treatment is 6 months after the other.</p><h2 style="text-align: left;">Results <br /></h2><p>The results are good but not great. Perhaps a better way to say it, is that they are scientifically good, statistically significant and all that, but it is not clear how much they will matter to families with T1D.</p><p>The key result measured how much insulin a person was generating. During the honeymoon period, it normally drops a lot. In this trial, people who got the treatment did generate less insulin, but not as much less as people who were not treated. And the difference was significant. Untreated people insulin production dropped .21 (pmol/ml), while those who were treated dropped .09. However, the other question is, does this .12 difference really mean anything? They are still loosing the ability to generate their own insulin.<br /></p><p>They also measured slightly lower insulin use, and slightly lower A1c numbers, but these were not statistically significant, nor were they clinically significant. Clinically significant meaning important to the people with T1D or their families. For example, a person who injected 4.6 units of insulin with treatment might have injected 5.8 units without. That is a differences, but it is not clear how much it matters to the person doing the injection. The A1c differences were about 0.1%, which is well below the 0.5 difference that is generally considered important.<br /></p><p>Press Release: <a href="https://www.news.sanofi.us/2023-10-18-TZIELD-R-Phase-3-data-presented-at-ISPAD-shows-potential-to-slow-the-progression-of-Stage-3-type-1-diabetes-in-newly-diagnosed-children-and-adolescents-full-data-simultaneously-published-in-The-New-England-Journal-of-Medicine">https://www.news.sanofi.us/2023-10-18-TZIELD-R-Phase-3-data-presented-at-ISPAD-shows-potential-to-slow-the-progression-of-Stage-3-type-1-diabetes-in-newly-diagnosed-children-and-adolescents-full-data-simultaneously-published-in-The-New-England-Journal-of-Medicine<br /></a>Journal Article: <a href="https://www.nejm.org/doi/pdf/10.1056/nejmoa2308743">https://www.nejm.org/doi/pdf/10.1056/nejmoa2308743<br /></a>Clinical Trial Registry: <a href="https://classic.clinicaltrials.gov/ct2/show/NCT03875729">https://classic.clinicaltrials.gov/ct2/show/NCT03875729</a></p><h2 style="text-align: left;">Discussion <br /></h2><p>For the company, the big question is: Is this one phase-III trial enough to get approval for an additional population? I don't know the answer, but I suspect we will all find out in 2024. Either the FDA will approve it, or they won't. Once the FDA makes that decision, it will tell us a lot about how the FDA will make future decisions about similar treatments. However, I don't think it is worth guessing about the decision; better to just wait for it.<br /></p><p>For people living with T1D, the big question is: Is it worth it? That is a decision every person (or family) must make for themselves. It is a trade off of two 12 day series of infusions so that your body creates more of its own insulin for a longer period of time. However, it is not clear to me how much this will matter in the long term. You will still be injecting insulin, just a little less than otherwise. Many people believe that generating more insulin for longer periods of time will lower the long term bad effects of T1D, and this would be a clear benefit. However, this has never been measured and no one knows if the effect of this treatment is big enough to matter.</p>One question I'm sometimes asked is "will doctors be able to play around with the dosing to get better results?" My answer to that is yes they will be able to, but I don't think they will, at least not aggressively. Why not? It is an infusion treatment, which is not going to encourage experimentation. Also, the drug sometimes has side effects over the 14 days of infusion (things like rashes and decrease in white blood cells), which is not going to encourage experimentation with higher doses, either. More generally, since the benefit is basically a statistical delay in onset of T1D, if a doctor wanted to experiment, they would not see the results for years, and would only see them in a statistical sense after they had done the experiment on many patients. I just don't see that happening. <br /><br /> </div><div style="text-align: center;"><span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div><div style="text-align: left;">
<div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><span style="font-size: x-small;">
</span><div style="text-align: center;">
<span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p></p><p> <br /></p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-14934181295647625732023-11-11T14:09:00.000-08:002023-11-11T14:09:03.673-08:00JDRF Funding for a Cure 2023<p>In the US, we are in the "Walking Season" when JDRF (Juvenile Diabetes Research Foundation) asks us to walk
to raise money for a cure for type-1 diabetes. So I'd like to do my part, by reminding you
all of how important JDRF is to the human trials of potential cures for T1D, which I track.<br />
</p>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">Let
me give you the punch line up front: 65% of the treatments currently in
human trials have been funded by JDRF. This is a strong impact; one that any non-profit
should be proud of. Below is a list of all the treatments, grouped by
phase, and separated into trials that JDRF has funded, and those JDRF
has never funded. </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">As a reminder, last year I changed the way I counted treatments in two ways: First, treatments which are subsets of other treatments are counted only once. For example, if drug X is being tested, and there is a separate test of a combination of X and Y, these are only counted once. If a third test is testing X, Y, and Z, then it is still only counted once. Second, treatments being tested in two different phases of the disease (such as honeymoon and established) are only counted once.</div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b> </b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>The List, Divided by Phases</b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><p>Below
is the list of all treatments, divided into six phases: FDA Approved, In Process of Approval, Phase-III, Phase-II, Phase-IIΔ, and Phase-I. Phase-II
trials are "classic" phase-II trials, which are done after a Phase-I
trial. What I call Phase-IIΔ trials test treatments which never went through phase-I trials on people with
T1D. (I used to call those Phase-II? but I think using punctuation that way is confusing, so I'm using a delta instead: Phase-IIΔ.) They've been shown safe in other diseases, so have skipped phase-I
trials on people with T1D. These Phase-IIΔ trials
might be Phase-II from the point of view of size and safety, but they
are Phase-I in terms of effectiveness, so I'm putting them in their own
category.</p><p>For T1D research, phase-I studies are usually about 10 people and test for both safety and efficiency. In other diseases, phase-I trials are sometimes only done on healthy
people, or only test for safety issues, but this is not the way T1D research is usually done. Over 90% of phase-I studies are done on people with T1D, and
over 90% test for both safety and effectiveness.</p><p>Phase-II trials about about 100 people, and phase-III about 300. After two successful phase-III trials, the FDA considers approval for general use. These two studies can be run at the same time, and are often identical. Occasionally, only one phase-III trial is required for approval. <br /></p></div><p><b>Approved!</b></p><p>Summary: there is 1 drug approved by the US FDA to delay the onset of T1D symptoms, and it was funded by JDRF:</p><ul style="text-align: left;"><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab">Teplizumab</a> by Provention Bio (At Risk)</li></ul><p>This is big news! It is the first drug approved which changes the course of T1D, rather than just treating the symptoms, like insulin. I'm looking forward to reporting its progress to see how usage expands moving forward.<br /></p><p><b>In Process of FDA Approval</b></p><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">Nothing is in process of approval right now.<br /></div>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<b><br /></b><b>Phase-III Human Trials</b><br />
<div>
Summary:
currently there are 2 treatments in phase-III clinical trials. 1 is funded by JDRF:<br />
<ul><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/oral%20insulin">Oral Insulin</a> (Preventative) <br /></li></ul><p>Not funded by JDRF:</p><ul style="text-align: left;"><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Ladarixin">Ladarixin</a> by Dompé<span style="color: red;"><br /></span></li></ul>
<b>Phase-II Human Trials <br /></b></div>
Summary: there
are 17 trials in phase-II, and 13 of them have been funded by JDRF,
while 4 have not. Here are the treatments that have been funded by JDRF:<br /><ul style="margin: 0.5em 0px; padding: 0px 2.5em;"><li>ATG and GCSF by Haller at University of Florida (Established) </li><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Abatacept">Abatacept</a> in honeymooners and as a prevention by Orban at Joslin Diabetes Center and Skyler at University of Miami (Prevention) </li><li>Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK </li><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd">Diamyd</a> in several combinations by Ludvigsson at Linköping University and Larsson at Lund University (Honeymoon and Prevention) </li><li>Difluoromethylornithine (DFMO) by Panbela<br /></li><li>Gleevec by Gitelman at UCSF </li><li>Gluten Free Diet: Three Studies (Preventative)</li><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Stem%20Cell%20Educator">Stem Cell Educator</a> by Zhao (Established) </li><li>Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute </li><li>TOL-3021 by Bayhill Therapeutics (Honeymoon and Established) </li><li>Umbilical Cord Blood Infusion by Haller at University of Florida </li><li>Ustekinumab by University of British Columbia</li><li>Verapamil by Shalev/Ovalle at University of Alabama at Birmingham</li></ul>
Not funded by JDRF:<br />
<ul><li>ATG and autotransplant by several research groups: Burt, Snarski, and Li </li><li>Dual Stem Cell by Tan at Fuzhou General Hospital </li><li>Stem Cells of Arabia (Established)</li><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Vitamin%20D">Vitamin D</a> by Stephens at Nationwide Children's Hospital (Prevention)</li></ul>
<b>Phase-IIΔ Human Trials</b><br />
Summary: there are 14 trials in phase-IIΔ, and 8 of them have been funded
by JDRF, while 6 have not. Here are the treatments that have been funded
by JDRF:<br />
<ul><li>Alpha Difluoromethylornithine (DFMO) by DiMeglio</li><li>GABA by Diamyd </li><li>Golimumab by Janssen (Honeymoon and Established)</li><li>Hydroxychloroquine by Greenbaum (At Risk) </li><li>Intranasal Insulin by Harrison at Melbourne Health (Prevention)</li><li>Iscalimab (CFZ533) by Novartis <br /></li><li>Rituximab by Pescovitz at Indiana University</li><li>Influenza Vaccination at <span lang="EN-US"></span><span lang="EN-US">Aarhus University Hospital</span> </li></ul>
Not funded by JDRF:<br />
<ul><li>Azithromycin by Forsander</li><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Ixekizumab">Ixekizumab</a>/Taltz by Vastra Gotaland Region <br /></li><li>Liraglutid (At Risk)</li><li>NNC0114-0006 and Liraglutide by Novo-Norsk (Established)<br /></li><li>Rapamycin Vildagliptin Combo by IRCCS (Established)</li><li>Visbiome by Medical College of Wisconsin </li></ul>
<b>Phase-I Human Trials</b><br />
Summary: there are 25 trials in phase-I, and 16 of them are funded by JDRF, while 9 are not. Here is the list funded by JDRF:<br />
<ul><li>AG019 and Teplizumab by ActoGeniX</li><li>DIMID1 (Faecal Microbiota Transplantation) at AMC Hospital <br /></li><li>CGSF by Haller at University of Florida </li><li>Golimumab (At Risk)</li><li>MER3101 by Mercia (previously IBC-VS01 by Orban) </li><li>MonoPepT1De by Cardiff University</li><li>Mozobil by University of Alberta (Established)</li><li>MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London</li><li>Nasal insulin by Harrison at Melbourne Health (Prevention)</li><li>PRV-101 (Coxsackie B Vaccine) by Provention Bio (Prevention)</li><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Semaglutide">Semaglutide</a> by Dandona at University of Buffalo<br /></li><li>Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University</li><li>TOPPLE T1D by Novo Nordisk (Established) <br /></li><li>Pro insulin peptide by Dayan at Cardiff University </li><li>VC-01 by Viacyte (Established)</li><li>VCTX210A by Viacyte/CRISPR (Established) <br /></li></ul>
Not funded by JDRF:<br />
<ul><li><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/AVT001">AVT001</a> by Avotres<br /></li><li>Baby Teeth Stem Cells by CAR-T Biotechnology</li><li>Extracorporeal Photopheresis by ADSCC <br /></li><li>Gluten Free Diet by Carlsson at Lund University</li><li>Mesenchymal Stromal Cell by Carlsson at Uppsala University</li><li>NN1845 (Glucose Sensitive Insulin) by Novo Nordisk</li><li>OPT101 by Op-T (Established) </li><li>PIpepTolDC at City of Hope Medical Center</li><li>ProTrans by NextCell (Established)</li></ul>
<b>Summary of all Trials</b><br />
59 in total<br />
39 funded by JDRF<br />
So 66% of the human trials currently underway are funded (either directly
or indirectly) by JDRF. Everyone who donates to JDRF should be proud of
this huge impact; and everyone who works for JDRF or volunteers for it,
should be doubly proud.<br />
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<br /></div>
<b>Just Looking at Trials on Established Type-1 Diabetics</b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b> </b><br />
Of these treatments 12 (20%) are being tested on people with established T1D, of those, 9 are funded by JDRF. So 75% of the trials recruiting people with established T1D are funded by JDRF.<br /></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b><br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>Compared to Last Year</b><br />
In 2022 there were 53 treatments in clinical trials, in 2023 there are 59 (growth of 11%).</div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">In 2023, one treatment was approved by the FDA!<br />
In 2022 there was 2 treatments in Phase-III trials, in 2023 there are 3 (growth of 50%).<br />
In 2022 there were 16 treatments in Phase-II trials, in 2023 there are 17 (growth of 6%).<br />
In 2022 there were 13 treatments in Phase-II<b>Δ</b> trials, in 2023 there are 14 (growth of 7%).<br />
In<span style="color: red;"> </span>2022 there were 22 treatments in Phase-I trials, in 2023 there are 25 (growth of 14%).</div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<br />
<b>A Little Discussion</b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> <br />The money that we donate does many things:</div><ol style="text-align: left;"><li>It finances more clinical trials (especially early clinical trials).</li><li>It finances making clinical trials (especially early clinical trials) larger and better designed. <br /></li><li>It
helps push possible cures to the next level of trial. It finances
moving phase-I trials to phase-II, and phase-II to phase III.</li></ol><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">I
like to say that there are two reasons for donating money for research
into T1D. People who like the research being done should donate money
to move it forward, faster. People who don't like the research being
done should donate money to start up different research which
(presumably) they will like more. So no matter which group you are in,
you should donate. 😀 <br /></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> <b> </b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>Trial Populations<br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">The
list above uses the following marks to show the nature of the
treatments, and if one treatment is being tested in different
populations, then it will be listed more than once. <br />
<b>Honeymoon:</b> Most trials are done on people within the first year
of diagnosis. All the studies listed above which are not Established,
At Risk, or Prevention are in this Honeymoon category. <b><br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>Established:</b> One or more trials are open to people who have had type-1 diabetes for over a year. <br />
<b>At Risk:</b> One
or more trials are open to people who have 2 or more autoantibodies,
but have not yet started showing symptoms of type-1 diabetes.<br />
<b>Prevention:</b> This treatment is aimed at preventing type-1 diabetes, not curing it.<br />
If a trial is not marked, then it is for people in the honeymoon (first year) of T1D. <br />
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<br /></div>
I
give an organization credit for funding a treatment if they funded it
at any point in development; I don't limit it to the current trial. </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">I also give credit if
JDRF funds research indirectly, through another organization. For example, JDRF
funds both nPOD and Immune Tolerance Network and so I give JDRF credit
for clinical trials based on their work.<br /></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> <b><br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>How I Count Trials for This Comparison</b></div>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<ul><li>I don't count trials where the JDRF funded some basic research, but not the research which lead to a specific clinical trial. I'm sure this under estimates JDRF's impact. For example OPT101 is an anti CD154 drug. JDRF has funded many studies on CD154, but not the particular research that is being tested here. Similarly with Ixekizumab, JDRF has funded related research on that drug, but not the clinical trial or the research immediately leading to the clinical trial here.<br /></li><li>I mark the start of a research trial when the researchers start
recruiting patients (and if there is any uncertainty, when the first
patient is dosed). Some researchers talk about starting a trial when
they submit the paper work, which is usually months earlier. </li><li>For trials which use combinations of two or more different
treatments, I give funding credit, if the organization in the past
funded any component of a combination treatment, or if they are funding
the current combined treatment. </li><li>I have made no attempt to find out how much funding different
organizations gave to different research. This would be next to
impossible for long research programs, anyway. </li><li>Funding of research is not my primary interest, so I don't spend a
lot of time tracking down details in this area. I might be wrong on
details. </li><li>I only include intervention studies here, because those are the only
type of study that the FDA will accept for the eventual approval of a
new treatment. <br /></li></ul>
Some Specific Notes:<br />
<ul><li>Oral Insulin: This trial was a phase-III trial, meaning that it was
large and designed to provide enough information so that, if
successful, the treatment could be widely used. However, as it turned
out, only part was successful, and that part was phase-II sized, so I
don't think we will see widespread use based on this trial alone. You
can think of this as a phase-III trial with phase-II results.<span style="color: red;"><br /></span></li></ul>
This is an update and extension to blog postings that I've made for the previous fourteen years:<br />
<ul><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2022/10/jdrf-funding-for-cure-2022.html">https://cureresearch4type1diabetes.blogspot.com/2022/10/jdrf-funding-for-cure-2022.html</a> <br /></span></li><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2020/10/jdrf-funding-for-cure-2020.html">https://cureresearch4type1diabetes.blogspot.com/2020/10/jdrf-funding-for-cure-2020.html </a><br /></span></li><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2019/10/jdrf-funding-for-cure-2019.html">https://cureresearch4type1diabetes.blogspot.com/2019/10/jdrf-funding-for-cure-2019.html</a> <br /></span></li><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2018/10/jdrf-funding-for-cure-2018.html">https://cureresearch4type1diabetes.blogspot.com/2018/10/jdrf-funding-for-cure-2018.html</a> </span></li><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2017/10/jdrf-funding-for-cure-2017.html">https://cureresearch4type1diabetes.blogspot.com/2017/10/jdrf-funding-for-cure-2017.html</a></span></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2016/10/jdrf-funding-for-cure-2016.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2016/10/jdrf-funding-for-cure-2016.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2015/10/jdrf-funding-for-cure-2015.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2015/10/jdrf-funding-for-cure-2015.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html%20"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html</span></a></li></ul>
</div>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<div style="background-color: white;">
<span style="background-color: transparent;">Please
remember that my blog (and therefore this posting) covers research
aimed at curing, delaying, or preventing type-1 diabetes that is currently being
tested in humans. There is a lot more research going on than is counted
here.</span><br />
<span style="background-color: transparent;"><br /></span></div>
Please
think of this posting as being my personal "thank you" note to all the
JDRF staff, volunteers, and everyone who donates money to research a
cure for type-1 diabetes:<br />
<div style="background-color: white; color: #666666; font-family: "trebuchet ms", trebuchet, verdana, sans-serif; font-size: 13.2px; line-height: 1.4; text-align: right;">
<span style="font-size: large;"><i><span style="font-family: "times" , "times new roman" , serif;">Thank You!</span></i></span></div>
<br />Finally,
if you see any mistakes or oversights in this posting, please tell me!
There is a lot of information packed into this small posting, and I've
made mistakes in the past.
<div style="background-color: white;">
<br /></div>
</div><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My kid has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-56029138941983819072023-10-09T19:49:00.000-07:002023-10-09T19:49:36.835-07:00DFMO Starts A Phase-II Clinical Trial (TADPOL)<p></p><p>Difluoromethylornithine (DFMO), also known as <span>Eflornithine, is FDA approved since 1990 as an injection to treat African Sleeping Sickness (trypanosomiasis) and since 2000 as a cream to prevent excessive hair growth in women. DFMO has also been approved, for clinical trial use only, as an oral solution to treat certain cancers. <br /></span></p><p><span>I have blogged on a previous Phase-</span><span>IIº</span><span> study for this treatment here: <a href="https://cureresearch4type1diabetes.blogspot.com/2018/06/alpha-difluoromethylornithine-dfmo.html">https://cureresearch4type1diabetes.blogspot.com/2018/06/alpha-difluoromethylornithine-dfmo.html</a></span></p><p>This drug lowers polyamine synthesis in beta cells. Polyamines are a class of chemicals used in beta cells to regulate the production of insulin. The researchers believe that too many polyamines in beta cells that also have inflammation, is part of the process that leads to type-1 diabetes. They hope that lowering polyamine synthesis will preserve β-cell insulin production and delay the onset of type-1 diabetes.<span> </span></p><p><span></span></p><h2 style="text-align: left;">The New Study</h2><p>This study will enroll 70 people, aged 6 to 40, who are within 100 days of T1D diagnosis. They started in March 2023 and hope to finish in December 2027. The study chair is Emily K Sims, and funding comes from JDRF and Cancer Prevention Pharmaceuticals.</p><p>This is a randomized, placebo controlled study. About 2/3 of the people will get a dose of 1000mg/m2 (see dose note below) because this was the most successful dose from a previous, small study. This is two pills per day which they will take for 6 months. There are two primary end points: C-peptide in response to a meal and side effects. Secondary end points include more C-peptide numbers and measurements of beta cell stress.</p><p>If this study is successful at recruiting, it could be finished much more quickly than scheduled. They only need to gather data for a total of 12 months (6 while taking the drug, and then 6 more). That means if they can recruit 70 people in 2 years, the study would be done in 3 years, rather than the 4 years they expect, and even faster if they can recruit 70 people in a year.<br /></p><p></p><p>More information on the study:<br /></p><p><a href="https://medicine.iu.edu/research-centers/pediatrics/research/diabetes/clinical/tadpol ">https://medicine.iu.edu/research-centers/pediatrics/research/diabetes/clinical/tadpol https://finance.yahoo.com/news/first-patient-enrolled-jdrf-funded-121500059.html<br /></a>Clinical Trial Registry: <a href="https://clinicaltrials.gov/ct2/show/NCT05594563">https://clinicaltrials.gov/ct2/show/NCT05594563</a> </p><p><b>Dose Note</b></p><p>This drug is dosed as mg/m2, meaning milligrams per meter squared. The dose is based on the skin area of the person getting it. This is the first time I've seen a drug dosed like that. I suspect it has to do with the drug's use as a hair growth preventative.<br /></p><h2 style="text-align: left;">Recruiting</h2><p>They have already started recruiting in Indiana, and will soon be recruiting at the rest of these sites:</p><p>Overall Contacts:<br /> Maria L Spall 317-278-7034 malnicho@iu.edu <br /> Operations Manager 317-278-8879 tadpol@iu.edu<br /></p><p>Barbara Davis Center, Aurora, Colorado, United States, 80045<br />Contact: Lexie Chesshir 303-724-1755 lexie.chesshir@cuanschutz.edu <br /> <br />University of Chicago, Chicago, Illinois, United States, 60637<br />Contact: Triniece Pearson 773-359-7556 tpearson1@medicine.bsd.uchicago.edu <br /> <br />IU Health Riley Hospital for Children, Indianapolis, Indiana, United States, 46202<br />Contact: Ellie M Ryan 317-278-7037 elmryan@iu.edu <br />Contact: T1D Research 317-278-8879 tadpol@iu.edu <br /> <br />Children's Mercy Hospital, Kansas City, Kansas, United States, 64108<br />Contact: Heather Harding <br /> <br />University of Michigan, Ann Arbor, Michigan, United States, 48109<br />Contact: Sheree Nicholson 734-232-4213 nsheree@med.umich.edu <br /> <br />Medical College of Wisconsin, Milwaukee, Wisconsin, United States, 53226<br />Contact: Joanne Kramer 414-955-8486 jkramer@mcw.edu </p><h2 style="text-align: left;">Discussion / Previous Study <br /></h2><p></p><p>The same researcher had previous run a Phase-I clinical trial. the results of this were published as a poster at IDS 2023. The key quote on results was: </p><p style="margin-left: 40px; text-align: left;">An exploratory secondary analysis showed that at the two highest dose levels, treatment with CPP-1X stabilized C-peptide areas under the curve compared to placebo.</p><p style="text-align: left;">However, when I look at the poster results (especially Fig 4A) it looks to me like the placebo group dropped over time (as expected), and the treated group stayed flat. This does lead to a statistically significant difference at 6 months, but it is not clear to me that it will lead to a cure, treatment, or delay onset, especially when given during the honeymoon when patients are already injecting insulin. Even if the drug stops loss of beta cells, at that point, the people are already injecting insulin, so I'm not sure it will help much.<br /></p><p style="text-align: left;">On the other hand, for the 1000mg dose group only (the biggest dose given), there is a slight increase in C-peptide generation between 3 and 6 months. I don't think it is statistically significant, but if we are going to cure T1D, we are going to need to increase C-peptide generation, not just hold it constant in the honeymoon phase. These are the types of results we are going to need to see, and bigger, in the follow-on study if this line of research is to be successful.</p><p style="text-align: left;">This study also shows the problems we (as a society) face in terms of diversity in clinical trials. The study involved 41 people. 38 were White, 1 was Black, and 2 are listed as Multiple. None were listed as Asian, or Hispanic. They were recruiting in Indianapolis, Buffalo, and Wauwatosa, Wisconsin, and I would think they could do better than that.<br /></p><p></p><p>Press Release: <a href="https://www.biospace.com/article/releases/panbela-announces-poster-presentation-at-immunology-of-diabetes-society-meeting-evaluating-the-potential-of-cpp-1x-eflornithine-in-recent-onset-type-1-diabetes/">https://www.biospace.com/article/releases/panbela-announces-poster-presentation-at-immunology-of-diabetes-society-meeting-evaluating-the-potential-of-cpp-1x-eflornithine-in-recent-onset-type-1-diabetes/</a><br />The poster itself: <a href="https://panbela.com/wp-content/uploads/2023/06/ENDO2023poster.pdf">https://panbela.com/wp-content/uploads/2023/06/ENDO2023poster.pdf</a> <br /></p><p> More Information: <a href="https://en.wikipedia.org/wiki/Eflornithine">https://en.wikipedia.org/wiki/Eflornithine</a></p><h2 style="text-align: left;">Discussion / Compassionate Use (Right Now)</h2><p style="text-align: left;">In the past, I've often said there were two ways to get access to a drug in the USA. Either through FDA approval for your illness, or through "off label" use if the drug is approved for a different illness. However, since 2016, there is a third way, called "Compassionate Use". This is authorized by the 21st Century Cures Act. I bring it up here, because Orbus, the company developing DFMO has an official Compassionate Use policy, which you can read here:<br /><a href="https://www.orbustherapeutics.com/s/Orbus-Expanded-Access-Policy.pdf">https://www.orbustherapeutics.com/s/Orbus-Expanded-Access-Policy.pdf</a></p><p style="text-align: left;">It is quite limited, and completely at the discretion of the company to approve. Patients (and their parents) can not even request Compassionate Use. Instead, their doctors must request it. They will need to fill out an FDA form 3926.</p><p style="text-align: left;">I'm sure there are many rules and requirements for this, but the key ones are that the drug is in active clinical development (phase-II or phase-III), and the patient must have a serious or life-threatening disease or condition. </p><p style="text-align: left;">I expect to see more of this in the future, as companies (and even later, doctors) get more comfortable with this aspect of the 21st Century Cures Act. I want to stress, that I'm not mentioning it here because I think this particular drug is a good candidate to ask your doctor to ask the company for Compassionate Use. As I hope I made clear in the "Previous Study" section, the results so far are not so good that they suggest to me that pre-approval treatment with DFMO is worth the uncertainty and risk. However, I do think it is important for everyone to understand their options before the situation comes up where they might need to use those options. </p><div style="text-align: left;"><div style="text-align: center;">
<span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div>
<div style="text-align: center;">
<font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><font size="2">
</font><div style="text-align: center;">
<font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-23312902085669680952023-09-20T21:39:00.000-07:002023-09-20T21:39:26.140-07:00Strong Results from a Pilot Study of Semaglutide in Adult Honeymooners<p>I've been blogging on research aimed at curing type-1 diabetes for over 15 years, and in that entire time, rarely have I rushed to blog on a new piece of research. That is because research progresses slowly, and it rarely matters if findings become public this month or next month. However, the results of this research initially felt so good, that I started rushing. However, as I've worked more on the posting, I've become less sure of how important it is. I do think that adults who are in the early part of their honeymoon may want to discuss this with their endocrinology team and consider taking action quickly. The big, open, unknown question is, should teenagers and children do the same?<br /></p><p>The drug in question is Semaglutide, which is sold under several trade names: Ozempic, Wegovy and Rybelsus. It was approved for use by people with type-2 diabetes in 2017 and for overweight people in 2021. It is widely prescribed for both of these conditions. Semaglutide is an example of a class of drugs called Glucagon-like peptide-1 (GLP-1) <span style="background-color: white;">receptor agonists. As a receptor agonists it </span>attaches to the same part of the cell as glucagon. This class includes seven approved drugs, sold under at least twelve different brand names by several "big pharma" companies.</p><p>Semaglutide is thought to work in four different ways: beta cells generate more insulin in response to food, the liver releases less sugar, digestion is slowed down, and appetite is suppressed. The last three can be expected to help anyone with T1D, and the first one to help T1D honeymooners. Of course, Semaglutide could have <span style="background-color: white;">other actions in</span> addition to these.<br /></p><p>This was not a randomized, controlled, clinical trial. Rather several endocrinologists knew that Semaglutide had good results in causing beta cells to generate more insulin, and thought this would help their patients, especially those in the early honeymoon phase. So therefore, they chose to prescribe it "off label". After having done this for 10 patients for a year, they went back and reviewed their charts. The data was very positive and they published a correspondence in the New England Journal of Medicine. There was no external funding for this; they spent their own time. </p><p>This blog is long because the research has many implications, but also some weaknesses, all of which require discussion.</p><ul style="text-align: left;"><li>What Was Found: The Good News</li><li>What Are The Weaknesses: The Bad News</li><li>What Should Honeymooners Do Now</li><li>Next Research Steps <br /></li></ul><h2 style="text-align: left;">What Was Found: The Good News <br /></h2><p>Semaglutide was given to 10 adults (18 years or older: average age 27) during the first 100 days after they were diagnosed with T1D ("stage 3" in Trialnet terminology). This was a weekly injection. They also got standard treatment for T1D in the honeymoon phase. For this practice, that included daily injections of long acting insulin, short acting insulin with meals, and general advice to eat fewer carbs. The key results were (these are all quotes from their publication, which I have edited slightly):</p><ul style="text-align: left;"><li>Mealtime insulin was eliminated in all the patients within 3 months.</li><li>Long acting insulin was eliminated in 7 patients within 6 months. </li><li>These doses were maintained until the end of the 12-month follow-up period. </li><li>The mean A1c level fell to 5.9 at 6 months and to 5.7 at 12 months. [Normal for non-T1D is below 5.7] <br /></li><li>The fasting average C-peptide level increased from 0.65 at diagnosis to 1.05 [Normal for non-T1D is between 0.5 and 2.0.]</li><li>The time-in-range was 89% according to continuous glucose monitoring. </li></ul><p>Obviously, these are some big results. <br /></p><p>During the honeymoon phase, people with T1D continue to generate some insulin, so it is quite common to have fluctuating insulin requirements during this time. Some people go weeks, even months, without needing to inject insulin, and this is even more true of adults. The results above are much better than seen on average in teenage honeymoons, but I'm not sure how they compare to average adult honeymoons. I discuss this much more below, in the "weaknesses" section.<br /></p><p>I do think it is important that the fasting C-peptide numbers went up for the year of the honeymoon. (Remember that C-peptide is generated by the same process that generates natural insulin. So generating more is better because it means the body is also generating insulin.) In the past, I have seen honeymoon studies where treatments would stop the decline of C-peptide. The researchers would then compare them to the control group where the C-peptide number did decline, and see a statistically significant difference. They would say that their treatment "preserved beta cell function". That's true, but these people already had T1D, and so preserving that did not help them much, and these treatments have not entered widespread use.</p><p>But these C-peptide numbers show improvement, not just preservation. At the end, these people were generating 61% more fasting C-peptide than when they started, they went from 0.65 up to 1.05. For comparison, non-T1Ds are typically between 0.5 and 2.0.</p><p>This study was published as a correspondence in the New England Journal of Medicine (NEJM), which is an important medical research journal. The authors all work at the University of New York at Buffalo, and the authors have worked on dozens of clinical trials.<br /></p><p><b>What Are The Weaknesses: The Bad News</b></p><p>This study has several weaknesses. I want to stress that none of these show a mistake or invalidate the results. They do show the need to run a larger clinical trial, and also more/different clinical trials. Larger trials validate that this was not just an accidental result and more/different trials show more about who is likely to be helped and exactly what part of the treatment is helpful. </p><p></p><p><b>Small Study Size</b>: This study has 10 people, which is common for a phase-I or pilot study, but larger studies are needed to be sure of the results. Phase-II studies are often 100 people, phase-III studies for T1D cures are usually 300 people, and in other diseases, they are often even larger.<br /></p><p></p><p><b>No Control Group</b>: This study has no control group. That is common for a phase-I trial (especially the first phase-I trial, a "pilot" trial), but it is still a weakness. The researchers did compare their treatment group to the control groups from 5 recently completed clinical trials, 4 of which were done in adults. You could say they "borrowed" control groups from these other studies. </p><p>They compared A1c data from their treatment group to the other study's control groups. This technique is better than nothing, but it is not a true control group, and (for me) using A1c data is a second choice to using C-peptide data. (Because C-peptide means the body is making insulin, but A1c numbers are influenced by how much people eat and how careful they are in injecting insulin.) With all those limitations, basically they found that A1c numbers in all the groups dropped for the first 6 months, but then went up in the the control groups. However, in their treated group, it continued to go down (slightly) for the whole year.<br /></p><p><b>Retrospective</b>: This was a retrospective study, meaning the researchers gathered the data, and then realized there was something important in it, and created the study "backwards" while already holding the data. Most clinical trials that I follow are prospective. The researchers design the study, and then recruit the patients, gather the data, and analyze it according to the design done at the start. There are a <span style="background-color: white;">large number of potential problems which</span> can occur in a retrospective study that are avoided with a prospective design. It would take a book chapter, or maybe a whole book, to describe all the potential problems, so I can't even list them here. In any case, there is no way for me to know if this study actually encountered any of them, and therefore no reason to worry about them. But this is why a prospective study confirming these results is important. <br /></p><p><b>Impact of LADA</b>: This study enrolled people between the ages of 18 and 49 (average age was 27 and standard deviation was 6 years), so many of these people probably had LADA rather than classic type 1 diabetes. LADA stands for Latent Autoimmune Diabetes in Adults; you can think of it as juvenile diabetes diagnosed in adults, but we don't call it juvenile diabetes any more. LADA has a honeymoon, just as T1D does, but it is not the same. It is well known to be longer and stronger. Since there was no control group, the researchers compared their patients to patients in other studies of adults in their honeymoon phase of T1D. I think that is the best comparison available, but it is important that people not compare these results to standard T1D honeymoons seen in teenagers or younger kids. That is not a good comparison.<br /></p><p><b>Correspondence vs. Article</b>: This publication was not a journal article. Instead it was a correspondence, a shorter work. I don't know what the NEJM's review and editorial processes is for correspondence and how it differs from other articles. I don't know how much peer review NEJM correspondence get, if any.<br /></p><p><b>Only Fasting C-peptide Data</b>: I would have preferred to also have C-peptide data from after a meal, but this data was never collected because it is not part of standard care, and these patients were mostly getting standard care (just with Semaglutide in addition). I like to see both fasting and meal based C-peptide data, because the fasting number just measures the body's ability to make insulin "at rest". The meal number measures the body's ability to make insulin in response to eating food. They are both important in different ways, which is why I like to see both. <br /></p><p><b>No Clinical Trial Registration</b>: This study was not registered
with the FDA. That is normal for this kind of "chart review" /
retrospective style of research. But it still means I don't have as
much data on the study as I usually have before blogging. <br /></p><p><b>Restricted Carb Diet</b>: The letter stated "Carbohydrate intake was restricted in all the patients" which initially made me very nervous, because carb restrictions can significantly lower insulin requirements, especially if taken to extreme. However, in a discussion with one of the authors, I was told that this was simply part of "standard of care" for newly diagnosed T1Ds at their practice. That all such people are told not to eat excessive carbs. They were not told to limit carbs to X grams per day, or Y grams per meal, or anything like that. It was just suggested that they eat fewer carbs as part of a healthy T1D diet.</p><p><b>Inclusion Criteria</b>: The publication does not say how
these 10 people were selected to be included in this study. However, in discussion with one of the authors, I was told that the 10 people included everyone who had been treated with Semaglutide at the practice and followed for a year. There was no "selection" of people. Everyone who they had data for was included. Of course, it is still possible that something about the people who agreed to take Semaglutide or something about how the doctors decided to prescribe it, impacted the findings. <br /></p><h2 style="text-align: left;">What Should Honeymooners Do Now</h2><p>I think that adults (especially those with LADA) who are early in their honeymoon phase have two choices: <br /></p><p>The first is to do nothing. I think that is a reasonable thing to do in response to a 10 person, no control group, pilot study such as this one. I've gone over the pros and the cons of this treatment above, but it is also important to remember that most research is not successful. In fact, less than 1% of the successful phase-I clinical trials ever become successful treatments. So the long term odds of this being successful are low, and doing nothing is a reasonable course of action. There are some risks both because Semaglutide has known side effects, but also because it has not been fully tested in people with T1D.<br /></p><p>The second is to talk to your endocrinologist about it. Semaglutide is a prescription medicine, so if you want to use it, you will need a doctor to write you a prescription. For people in the early part of their honeymoon (the first 100 days) it is a very reasonable conversation to have with your doctor. New medicines and treatments are one of the reasons you have a doctor (and not only a pharmacist). Semaglutide has been widely used for many years, so there is a lot of safety data available. However, it is not approved for type-1 diabetes, so a discussion with your doctor about off label use is appropriate. Doctors have the discretion to use medicine off label. They have the knowledge of T1D in general and the information about their patients in particular to make good decisions even with uncertainty.</p><p>Obviously, one major question is: this study was done on adults, does it apply to teenagers or children? No one knows the answer to this with certainty, and that is why I would talk to your endocrinologist if you are considering it.</p><p>What about non-honeymooners? Semaglutide has been given to people with T1D for years, usually to treat being overweight. There is no question it helps lose weight, lowers the amount of insulin used, and generally improves A1c and time in range numbers for most people who use it. You can read about cases here:</p><p>https://t1dexchange.org/semaglutide-type-1-diabetes/<br />https://www.diabetes.co.uk/diabetes-medication/semaglutide.html<br />https://www.oatext.com/impact-of-adding-semaglutide-in-a-person-with-type-1-diabetes-a-case-report.php <br /></p><h2 style="text-align: left;">Next Research Steps</h2><p style="text-align: left;">For me, there are several different research programs that this study should motivate, and I think we (as a society) should work on all of them at the same time.</p><p style="text-align: left;"><b>Follow Those 10 People For Years</b></p><p style="text-align: left;">One of the big questions is, how long will these people avoid injecting insulin. Obviously a year delay is valuable to some people. The Teplizumab value proposition is based on a 2-3 year delay. By simply following these 10 people for years in the future, we can get some data on the longer term effects of this treatment. <br /></p><p style="text-align: left;">I was able to learn that a couple of the people in the study were no longer being followed because they had moved out of the area or out of the practice. Also, a few more had stopped taking Semaglutide because they had continually lost weight on it, to the point where they needed/wanted to stop. But even with this shrinking study size, I'm still interested in what happens to people in the coming years.</p><p style="text-align: left;">One of the worries of a treatment like this is that it is
somehow "burning out" beta cells early and that people who get it might
do better in the short term, but worse in the long term. That is the
kind of fear that can be removed (or confirmed) by following people for
more years. With less than 10 people, the data will be approximate, but I'm a
big believer that some data is better than none.</p><p style="text-align: left;"><b>Run A Larger Phase-II Study on Semaglutide In Honeymooners</b></p><p style="text-align: left;">I listed a bunch of weaknesses in this research, but the three biggest weaknesses are (a) small size, (b) no control group, and (c) only adults were included. All of these issues could be resolved by running a larger, randomized, controlled, clinical study which included younger people. The authors are looking into doing this. The first step is (always) getting the money.</p><p style="text-align: left;">JDRF: are you listening? Fund this larger study! 😁<br /></p><p style="text-align: left;"></p><p style="text-align: left;"><b>Run A Study On Semaglutide In People "At Risk" of T1D</b><br />(By "at risk" I mean "stage 2" in Trialnet terminology.)</p><p style="text-align: left;">One thing that came through very clearly is that C-peptide levels improved with this treatment. Therefore, it makes sense to try the treatment earlier, when people are still generating more C-peptide naturally. This is the same progression that Teplizumab went through, and TrialNet is perfectly set up to run a similar clinical trial for Semaglutide.</p><p style="text-align: left;">TrialNet: are you listening? Organize this longer, stage 2 study! 😁 <br /></p><p style="text-align: left;"><b>Survey Honeymooners Taking Semaglutide "Off Label" Now</b></p><p style="text-align: left;">Finally, I suspect that some younger people are going to get Semaglutide "off label" during their honeymoon in the hopes that they will see results like those seen in this study of adults. I have no idea if that will be successful or not, but I hope that the doctors who prescribe it in this situation publish the results. That would be very valuable no matter if it is successful or not. One of the things I'm worried about is that many people try it, it does not work, but no one publishes the negative results, so people continue to try it. </p><p style="text-align: left;">Of course, if someone runs the larger phase-II study discussed above, that would give better results than a survey, but a survey might be quicker to organize. Of course, we could do both, a quick survey and a slower but more definitive phase-II clinical trial.<br /></p><h2 style="text-align: left;">Lots More To Read<span style="color: red;"><br /></span></h2><p>https://www.cnn.com/2023/09/08/health/ozempic-diabetes-semaglutide-study/index.html<br />https://www.buffalo.edu/news/releases/2023/09/UB-research-semaglutide-Type-1-diabetes-insulin.html<br />https://www.nejm.org/doi/full/10.1056/NEJMc2302677<br />https://en.wikipedia.org/wiki/Semaglutide <br />https://www.novomedlink.com/semaglutide.html</p><p>...and you might want to read my previous blogging on Teplizumab, too.<br /></p><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px; text-align: center;"><span style="font-size: x-large;"><span style="font-family: "Dancing Script";"><i>Joshua Levy</i></span></span></div><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px;"><div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: "courier new", courier, monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></div><div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: "courier new", courier, monospace;">publicjoshualevy at gmail dot com</span></span></div></div><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px; text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p><p><br /></p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-72060789863308450052023-07-31T10:49:00.000-07:002023-07-31T10:49:14.127-07:00T1D Research News (Quick Bits for July)<p></p><p style="text-align: left;">This blog is a collection of smaller news items about T1D.<br /></p><h2 style="text-align: left;">COVID Not Likely to Increase T1D in Children<br /></h2><p>From the beginning of COVID there has been an expectation that T1D rates would go up because COVID would either "cause" or "trigger" T1D. </p><p>(I might be splitting hairs by separating "causing" and "triggering", but in my mind, these are two different things. If X causes Y, that means that if the person avoids X they will never get Y. That X takes a healthy person and they get Y. On the other hand, X triggers Y, means that the person was always likely to get Y, and X changed the timing so that the person got Y right then, but they still would have gotten Y eventually, even if X had not happened. I think there is widespread agreement that many illnesses "trigger" a diagnosis of T1D, but the question of weather they "cause" T1D is very much open.)<br /></p><p>In any case, this research suggests that T1D diagnosis rates did go up, but not because of COVID, but rather because of changes in behavior due to the lock down.<br /></p><p>Source: <a href="https://www.news-medical.net/news/20230322/SARS-CoV-2-not-likely-to-increase-the-incidence-of-type-1-diabetes-in-children.aspx">https://www.news-medical.net/news/20230322/SARS-CoV-2-not-likely-to-increase-the-incidence-of-type-1-diabetes-in-children.aspx</a></p><p>From the article:</p><p></p><blockquote><p>More children and adolescents than usual developed type 1 diabetes in Finland in the first 18 months of the coronavirus pandemic. According to a recently completed study, the cause was not the novel coronavirus, but altered environmental factors.</p><p>According to the study, the incidence of type 1 diabetes increased in children in Finland by 16% in the first 18 months of the pandemic. However, very few children or adolescents who developed type 1 diabetes had SARS-CoV-2 antibodies indicating a past infection.<br /><br />According to the researchers, the increase in the incidence of type 1 diabetes in the early stages of the pandemic is not likely to have been caused directly by coronavirus. Instead, it may be related to the society-wide lockdown in the pandemic period and the resulting social isolation.<br /><br />"According to what is known as the biodiversity hypothesis, microbial exposure and infections in early childhood can boost the protection against autoimmune diseases. The reduction in contacts in connection with the societal lockdown significantly reduced acute infections in children, which may have increased the risk of developing diabetes," Knip [one of the paper's author's] explains. <br /></p></blockquote><h2 style="text-align: left;">Combination of GABA and GAD Unsuccessful in Phase-II Trial</h2><p>I previously blogged on this study here: <a href="https://clinicaltrials.gov/ct2/show/NCT02002130">https://cureresearch4type1diabetes.blogspot.com/2018/08/gaba-starts-phase-ii-clinical-trial-in.html</a> <br /></p><p>Summary of results from the abstract:</p><p></p><blockquote>The primary outcome, preservation of fasting/meal-stimulated c-peptide, was not attained. Of the secondary outcomes, the combination GABA/GAD reduced fasting and meal-stimulated serum glucagon, while the safety/tolerability of GABA was confirmed. There were no clinically significant differences in glycemic control or diabetes antibody titers. ... although GABA alone or in combination with GAD-alum did nor preserve beta-cell function in this trial.</blockquote><p></p><p>The paper: <a href="https://www.nature.com/articles/s41467-022-35544-3">https://www.nature.com/articles/s41467-022-35544-3</a><br />The Trial Registration: <a href="https://clinicaltrials.gov/ct2/show/NCT02002130">https://clinicaltrials.gov/ct2/show/NCT02002130</a></p><p><b>Discussion</b></p><p>This is a classic example of "slow publishing means bad results". The study finished in 2019, but the results were not published until 2022.</p><p>Also, this is not good news for GAD, which Diamyd has been testing for many years. One group of this study got GABA and GAD, but did no better than the control group. If GAD were effective, you would expect to see some good effect in this group.</p><h2 style="text-align: left;">Abatacept Unsuccessful at Preventing the Onset of T1D</h2><p>I previously blogged on this study here: <a href="https://cureresearch4type1diabetes.blogspot.com/2020/04/possible-cures-for-type-1-in-news-april.html">https://cureresearch4type1diabetes.blogspot.com/2020/04/possible-cures-for-type-1-in-news-april.html</a> <br /></p><p>Summary of results:</p><p></p><blockquote>This trial of 1-year treatment with abatacept in participants with stage 1 type 1 diabetes did not show a statistically significant effect on progression to stage 2 or stage 3 type 1 diabetes.<br /></blockquote><p></p><p>This was a 200 person study (half got Abatacept, half got a placebo), for people at-risk of T1D (called "stage 1"). These are people with two or more autoantibodies, so the assumption is that they will move to abnormal blood glucose tests ("stage 2") and then diagnosis of T1D ("stage 3"), as the disease progresses. The goal was to delay this progression. <br /></p><p>News Article: <a href="https://www.hcplive.com/view/abatacept-misses-mark-for-preventing-type-1-diabetes-in-phase-2-trial">https://www.hcplive.com/view/abatacept-misses-mark-for-preventing-type-1-diabetes-in-phase-2-trial</a><br />Journal Article: <a href="https://diabetesjournals.org/care/article/doi/10.2337/dc22-2200/148547/Abatacept-for-Delay-of-Type-1-Diabetes-Progression">https://diabetesjournals.org/care/article/doi/10.2337/dc22-2200/148547/Abatacept-for-Delay-of-Type-1-Diabetes-Progression<br /></a>Note to the T1D Community: <a href="https://www.trialnet.org/our-research/completed-studies/abatacept">https://www.trialnet.org/our-research/completed-studies/abatacept<br /></a>Trial Registry: <a href="https://clinicaltrials.gov/ct2/show/NCT01773707">https://clinicaltrials.gov/ct2/show/NCT01773707</a></p><p><b>Discussion</b></p><p>Abatacept has been tested in several different clinical trials going back at least 15 years. In a case of unfortunate timing, researchers in Australia started a new Abatacept study about 3 weeks before the unsuccessful results of this study were announced:<br /><a href="https://www.clinicaltrials.gov/ct2/show/NCT05742243">https://www.clinicaltrials.gov/ct2/show/NCT05742243</a><br />The Australian study is enrolling people who have been diagnosed with T1D, while the earlier study was enrolling people who had 2 autoantibodies, but no abnormal blood sugar tests, and no other symptoms. So it is possible that one would be successful even though the other has failed, but I think it is a "long shot". <br /></p><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px; text-align: center;"><span style="font-size: x-large;"><span style="font-family: "Dancing Script";"><i>Joshua Levy</i></span></span></div><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px;"><div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: "courier new", courier, monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></div><div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: "courier new", courier, monospace;">publicjoshualevy at gmail dot com</span></span></div></div><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px; text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p></p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-17576781646473021142023-06-12T19:45:00.000-07:002023-06-12T19:45:07.426-07:00CELZ-201 Starts a Phase-I Trial (CREATE-1)<p>CELZ-201 is a stem cell product, where the cells are isolated from the umbilical cord, Wharton’s jelly, placenta, amniotic membrane, and/or amniotic fluid and then treated in a proprietary way. (I have not found any information on how the cells are treated.) These cells are used to create a cell line, which is then used to treat everyone who gets the therapy. This is not the kind of stem cell treatment where a person gets their own cells. The cells are injected into the dorsal artery of the pancreas. No immune suppression is required. <br /></p><h2 style="text-align: left;">The Study</h2><p>This is a pilot study / phase-I clinical trail, called CREATE-1, which will enroll 18 people within 6 months of diagnosis, who are between 18 and 35 years old. 2/3s will get the treatment and 1/3 will be a control group. This study is open label / not blinded.</p><p>The people enrolled will get one dose of the stem cell product infused into an artery. They will then be followed for two years. The primary end point is adverse effects after 6 months, and the most important end point (for me) is a C-peptide measure after one year, which they track as a secondary endpoint.</p>They started recruiting in April 2023, and are expecting to finish the trial in January 2026. The company involved is Creative Medical Technology Holdings Inc, specifically their AlloStem program. The study is being run by the Diabetes Research Institute (DRI).<br /><h2 style="text-align: left;">Recruiting</h2><p>Creative Medical Technology<span style="white-space: pre;"> </span>(480) 399-2822<br />clinicaltrials@creativemedicaltechnology.com<br />Diabetes Research Institute, University of Miami Miller School of Medicine<br />Miami, Florida, United States, 33136<br />Contact: Camillo Ricordi, MD 305-243-6913 </p><p>News of IND approval: <a href="https://creativemedicaltechnology.investorroom.com/2022-11-03-Creative-Medical-Technology-Holdings-Announces-FDA-Clearance-of-Investigational-New-Drug-IND-Application-for-AlloStem-TM-,-a-Novel-Cell-Therapy-for-the-Treatment-of-Type-1-Diabetes">https://creativemedicaltechnology.investorroom.com/2022-11-03-Creative-Medical-Technology-Holdings-Announces-FDA-Clearance-of-Investigational-New-Drug-IND-Application-for-AlloStem-TM-,-a-Novel-Cell-Therapy-for-the-Treatment-of-Type-1-Diabetes</a></p><p>Clinical Trial Record: <a href="https://www.clinicaltrials.gov/ct2/show/NCT05626712">https://www.clinicaltrials.gov/ct2/show/NCT05626712</a></p><h2 style="text-align: left;">Discussion</h2><p>This research fits into a long line of research trying to cure T1D in a similar way. It is a classic "stem cell" cure. For it to work, the stem cells that they are implanting will need to integrate into the pancreas (to absorb food and oxygen and shed waste products), produce insulin, not be attacked by the body's regular immune system, and avoid being targeted by the immune system (the same immune reaction which triggered T1D originally). <br /></p><p>Creative medical Technologies is a holding company that has several different technologies "in house". The CELZ-201 treatment comes from their AlloStem line. But another line of research they are working on is called ImmCelz, and they are currently testing two treatments from that line: CELZ-101 for brittle Type 1 Diabetes and CELZ-001 for Type 2 Diabetes. Both AlloStem and ImmCelz are cellular treatments (i.e. not chemical drugs, not specific proteins or peptides, but whole cells), and they both have CELZ numbers for identification. However, they come from different lines of research.</p><p>Their Type 2 Diabetes application (CELZ-001) recently had good results in a small trial: </p><p style="margin-left: 40px; text-align: left;">Researchers released early clinical trial results on an innovative cell treatment for people with type 2 diabetes. After one year, 93% of those who received the treatment safely reduced their insulin doses by at least 50%.</p><p>You can read more about it at DiaTribe: <a href="https://diatribe.org/positive-results-new-type-2-diabetes-cell-therapy-trial">https://diatribe.org/positive-results-new-type-2-diabetes-cell-therapy-trial</a><br /></p><p></p><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px; text-align: center;"><span style="font-size: x-large;"><span style="font-family: "Dancing Script";"><i>Joshua Levy</i></span></span></div><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px;"><div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: "courier new", courier, monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></div><div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: "courier new", courier, monospace;">publicjoshualevy at gmail dot com</span></span></div></div><div style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px; text-align: center;"><span style="font-size: x-small;">All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.</span></div>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-52959221569079470312023-05-09T20:17:00.000-07:002023-05-09T20:17:19.802-07:00Dompé Starts GLADIATOR, a Phase-III Clinical Trial of Ladarixin<p>Ladarixin is a drug being develop by Dompé (an Italian company). It inhibits activity on parts of the immune system called the IL-8 receptor (which has two subtypes: IL-8a and IL-8b). Dompé hopes that this will stop the progression of type-1 diabetes. </p><p>Before I discuss the phase-III study, I want to say something very important: A previous phase-II study, done by the same company (Dompé) of the same drug (Ladarixin) was successful when measured at 6 months, but unsuccessful when measured at 12 months (and 12 months was the primary end point). I discuss previous results below. However, the previous study gave people about 3 months of treatment, but the new study gives them about 12 months, a much longer treatment protocol.<br /></p><p><span style="font-size: large;"><b>The Phase-III Study</b></span></p><p>This is a big study. Phase-III studies for T1D are usually about 300 people, and this one is 327. Also, 2/3s of the people in the study will get the treatment; only 1/3 are controls who get the placebo. It started near the end of 2020, and they plan to finish in mid 2025.</p><p>This study will enroll honeymooners (within 180 days of diagnosis). About 200 will be children (aged between 14 and 17), and about 127 will be adults (between 18 and 45). <br /></p><p>Ladarixin is a pill which people will take twice a day for two weeks, and then not take for two more weeks, and then they will repeat this cycle for a year. They will then be followed for an additional year. The primary results are C-peptide and A1c measurements after the year of treatment, and secondary results include these same measures throughout the 2 year trial and several more interesting outcomes. These include time in range, low blood glucose episodes, and patients not requiring injected insulin (!).</p><p>An interesting design point of this study is that it is fully blinded for the first 18 months. This will cover the primary end point, and 6 months after that for all of the people enrolled, since it is measured from the last person enrolled, not the first. After that the blinding is lifted. I assume this will lead to faster publication (especially of the primary end points), since they will not need to wait the full 24 months to start the data analysis.<br /></p><p>First person given Ladarixin: <a href="https://www.dompe.com/en/media/press-releases/domp%C3%A9-announces-first-patient-enrolled-in-phase-3-trial-of-ladarixin-an-oral-investigational-cxcr1-2-inhibitor-in-new-onset-type-1-diabetes-t1d">https://www.dompe.com/en/media/press-releases/domp%C3%A9-announces-first-patient-enrolled-in-phase-3-trial-of-ladarixin-an-oral-investigational-cxcr1-2-inhibitor-in-new-onset-type-1-diabetes-t1d<br /></a>US Clinical Trial: <a href="https://www.clinicaltrials.gov/ct2/show/NCT04628481">https://www.clinicaltrials.gov/ct2/show/NCT04628481<br /></a>Europe Clinical Trial: <a href="https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001926-71/DE">https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001926-71/DE</a></p><p></p><p><b>Recruiting Locations </b><br /></p><p>This study is recruiting from 58 different locations, all over the world and the United States. It is a large endeavor. I can not list them all here, but they are listed on the clinical trial record: <a href="https://www.clinicaltrials.gov/ct2/show/NCT04628481">https://www.clinicaltrials.gov/ct2/show/NCT04628481</a><br /></p><p>If you are in Northern California, contact info is: Center of Excellence in Diabetes & Endocrinology (CEDE) , Sacramento, California, United States, 95821-2123, Contact: Gnanagurudasan Prakasam, MD prakasg@sutterhealth.org </p><p>United States locations include: Arizona, California, Colorado, Delaware, Florida, Georgia, Illinois, Indiana, Kansas, Kentucky, Massachusetts, New York, North Carolina, Pennsylvania, Texas, and Virginia.<br /></p><p>International locations include: Belgium, Georgia, Germany, Israel, Italy, Serbia, and Slovenia (many sites in most countries).<br /></p><p><span style="font-size: large;"><b>Results From A Phase-II Study</b></span></p><p>The results of this study were published as a paper, here:<br /><a href="https://pubmed.ncbi.nlm.nih.gov/35589610/">https://pubmed.ncbi.nlm.nih.gov/35589610/</a><br />and here are the key results:</p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhSmlPwJAd5akpPk2HSonYOnZhPMPnHEZaCddM21TBQ9ZcLjXq8l0uBtPzv3iTFzY5TBL5icIujVc4mWtBxnyBO5QU77csI49BOpc5tYj-lLLyf8Dwbo5a3c-SD8g-d1dgF3Dh4z4fwEN2X0YplLzk5JxIBY7YjykdsnMxS9DtHaqxzyONZl802Qga9/s615/DOM-24-1840-g004-cropped.jpg" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="256" data-original-width="615" height="266" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhSmlPwJAd5akpPk2HSonYOnZhPMPnHEZaCddM21TBQ9ZcLjXq8l0uBtPzv3iTFzY5TBL5icIujVc4mWtBxnyBO5QU77csI49BOpc5tYj-lLLyf8Dwbo5a3c-SD8g-d1dgF3Dh4z4fwEN2X0YplLzk5JxIBY7YjykdsnMxS9DtHaqxzyONZl802Qga9/w640-h266/DOM-24-1840-g004-cropped.jpg" width="640" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Copyright 2022.<br />Provided for educational purposes only.<br /></td></tr></tbody></table><p></p><p>You can see that the people who got the drug (blue line) did better than the people who did not (brown or orange line). However, the P value is too high to be statistically significant (.12 versus .05 or lower). But also notice that even for the treated group, the value was never higher than it started. To me, that suggests that this drug might have stopped beta cell destruction for a few months, but never led to beta cell regeneration. This result has been seen in the past for other drugs, but - so far - has not led to effective treatments. <br /></p><p>Press Release: <a href="https://www.biospace.com/article/releases/dompe-presents-phase-ii-clinical-trial-results-for-ladarixin-in-new-onset-type-1-diabetes-at-the-american-diabetes-association-s-scientific-sessions/">https://www.biospace.com/article/releases/dompe-presents-phase-ii-clinical-trial-results-for-ladarixin-in-new-onset-type-1-diabetes-at-the-american-diabetes-association-s-scientific-sessions/</a> <br /></p><p></p><p>Clinical Trial Registration: <a href="https://www.clinicaltrials.gov/ct2/show/NCT02814838">https://www.clinicaltrials.gov/ct2/show/NCT02814838</a></p><p></p><p>The results of this study were published as a poster in the ADA 2020 conference: <a href="https://diabetesjournals.org/diabetes/article/69/Supplement_1/249-OR/56830/249-OR-A-Randomized-Double-Blind-Phase-2-Trial-of">https://diabetesjournals.org/diabetes/article/69/Supplement_1/249-OR/56830/249-OR-A-Randomized-Double-Blind-Phase-2-Trial-of</a> <br /> <br /></p><p><span style="font-size: large;"><b>Discussion</b></span></p><p>The big discussion point here is: why is Dompé running a phase-III study when their previous phase-II study was unsuccessful at the primary end point? There are three answers to that question and they are all important in their own way:</p><p>First, although the results were unsuccessful at 12 months, the same measurements were successful at 6 months. An optimist would say that the treatment worked, just not in the time frame that had previously been selected as the primary outcome. By giving the treatment for a longer period of time (12 months instead of 3), the researchers hope to have a successful outcome. In real life, the important time frame is not 6 months or 12 months, but a lifetime, so quibbling over exactly when a treatment is measured may not be productive.<br /></p><p>Second, Dompé may know something that no one else knows, or they may be focusing on some specific results which they think is important to improving future results. Remember, they have been developing this drug for years. They also may have data from the earlier study which was not published, but which gives them hope not obvious to the rest of us. In fact, their ADA poster reporting on their previous results included this quote:</p><p></p><blockquote>Although primary endpoint was not met, secondary and subgroup analyses
suggest further investigation of LDX [Ladarixin] in new onset T1D may be warranted.</blockquote><p>This quote certainly covers the 6 month results (which were a secondary result), but could be referring to other results which give Dompé more hope of success in the future.<br /></p><p></p><p>Third, there is no requirement (legal, scientific, medical, or any other) that previous clinical trials must be successful in order to run more clinical trials on the same drug. As I'm fond of saying, in order to run the first clinical trial for a new drug, you need three things: a researcher who wants to run it, money to run it, and (in the US) a new drug approval from the FDA. However, the new drug approval only needs to show safety, not success of any kind. For a second clinical trial, you already have the new drug approval, so all you really need is a researcher and money.</p><p>In the past, this has lead to both good and bad results. In the case of Teplizumab, an early company chose bad end points, and had an unsuccessful clinical trial because of it. However, the researchers were able, years later, to get another company involved with different end points and have a successful trial. This led eventually to FDA approval. On the other hand, in the case of BCG, Faustman's lab ran unsuccessful trial after unsuccessful trial, using them as fundraising opportunities, but not (in my opinion) progress towards cure success.<span style="color: red;"><br /></span></p><p>My personal view is that Dompé's result is more like Teplizumab than like BCG. Also, giving the drug for longer seems like a direct way to convert the previous unsuccessful result to successful. So I'm optimistic about the overall chance of being successful in the primary outcome in the future. I'm much more curious as to the size of the result. It appeared that the untreated group's insulin production dropped (as expected during the honeymoon), but the treated group's insulin production stayed flat. Results similar to this have been seen before, but it remains a challenge to convert these types of results into a cure or a delay. Hopefully, this drug will do better.</p><p>Another interesting point about this study is that there is a secondary
end point, which is (to me) incredibly aggressive. If this end point
shows any response, it would be great news. It is "Percentage of
patients not requiring insulin therapy", which - in a certain sense - is
a measure of a practical cure. They are hoping that some people will not need
to inject insulin at all. <br /></p><p><span style="font-size: large;"><b>More To Read</b></span> <br /></p><p>Baylor participation: <a href="https://www.bcm.edu/healthcare/clinical-trials/h-49339">https://www.bcm.edu/healthcare/clinical-trials/h-49339</a></p><p>Phase-II Poster: <a href="https://diabetes.diabetesjournals.org/content/69/Supplement_1/249-OR">https://diabetes.diabetesjournals.org/content/69/Supplement_1/249-OR</a></p><p>Phase-II Press Release: <a href="https://www.prnewswire.com/news-releases/dompe-presents-phase-ii-clinical-trial-results-for-ladarixin-in-new-onset-type-1-diabetes-at-the-american-diabetes-associations-scientific-sessions-301076774.html">https://www.prnewswire.com/news-releases/dompe-presents-phase-ii-clinical-trial-results-for-ladarixin-in-new-onset-type-1-diabetes-at-the-american-diabetes-associations-scientific-sessions-301076774.html</a> <br /></p><p> </p><div style="text-align: left;"><div style="text-align: center;">
<span style="font-family: Dancing Script;"><span style="font-size: x-large;"><span><i>Joshua Levy</i></span></span></span></div>
<div style="text-align: center;">
<font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><font size="2">
</font><div style="text-align: center;">
<font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;">
<span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-74696565425813623272023-04-07T09:55:00.000-07:002023-04-07T09:55:25.061-07:00T1D Research News (Quick Bits from April)<p>This blog covers three pieces of news which do not apply directly to cure focused research, but which I found interesting anyway.</p><ul style="text-align: left;"><li>Tight Honeymoon Control Does Not Improve Long Term Insulin Production</li><li>Insulin Price Drops</li><li>Sanofi Buys Provention<br /></li></ul><h3 style="text-align: left;">Tight Honeymoon Control Does Not Improve Long Term Insulin Production <br /></h3><p>For many decades, there has been a theory that sugar itself was toxic to beta cells, and that tight blood glucose control during the honeymoon phase would result in longer beta cell survival, more natural insulin production, and therefore better long term results. I don't think this was ever the majority belief, but some people definitely did believe it, and they advocated for very tight controls in recently diagnosed people.</p><p>The study reported on below compared C-peptide production in people who used a hybrid closed loop at diagnosis to those who did not. Those with the hybrid closed loop were in range 14% more than those who did not, showing better control. However, this did not affect C-peptide production.<br /></p><p><a href="https://jamanetwork.com/journals/jama/fullarticle/2801975">https://jamanetwork.com/journals/jama/fullarticle/2801975</a></p><h3 style="text-align: left;">Insulin Price Drops</h3><p>The retail cost of insulin has been going up for decades, even as the manufacturing cost has been dropping (relative to inflation). However, that is ending as Sanofi, Eli Lilly, and Novo Nordisk have all announced huge price cuts in the United States. See <a href="https://www.cnn.com/2023/03/16/health/sanofi-insulin-price-reduction/index.html">https://www.cnn.com/2023/03/16/health/sanofi-insulin-price-reduction/index.html</a> (and many other news sites) for details. </p><p><b>Why Is This Happening?</b> </p><p>This is happening now because these companies are about to face a new competitor, who they have never faced before. In March 2022, JDRF announced that they would work with a non-profit, Civica to manufacture low cost insulin. In June, California announced that it would manufacture low cost insulin. Finally, in March 2023 California announced that they had signed a contract with Civica to manufacture insulin which would be distributed by CalRx for $30. During this same time, the US Senate passed a law capping insulin copays at $35/month for medicare patients, and several states also passed laws limiting insulin costs in various ways.</p><p>So the three commercial insulin manufacturers had little choice and dropped their prices by 90%. </p><p><b>Discussion</b><br /><br />A full discussion of this will take much more space than I have here. However, the very quick summary is that we have seen a huge "market distortion" for decades in the price of insulin. The insulins available have not changed in decades, their manufacturing has not changed, and yet their price (adjusted for inflation) has gone up very steeply and steadily. This is the exact opposite of what a market economy should do. If you look at the price changes (shown below) it is pretty clear that the companies involved have realized that they can make more money by raising prices when their "competition" does, rather than actually competing with them. <br /></p><p>But now we have a non-profit, with seed funding from the state of California, and the support of JDRF, competing with the three existing corporate insulin manufacturers. Just a few months after this competition was announced, all three of the corporate manufacturers have announced huge price cuts. My guess is that California (as a state) will end up cash positive before they even start distributing their insulin. The citizens of California will already have saved more money on insulin than California used to fund Civica. JDRF will be in even better shape, since their "cost" was only in publicity, lobbying, and coordinating, but (again) their membership will save real money every month.</p><p>For me, this is an interesting experiment. The last few decades have shown very clearly that the free market does not work for life-saving products when there are only a small number of manufacturers. Even economists understand that the free market does not work when there is a monopoly, but it is clear from the price of insulin, that it does not work for 3 companies, either. With 3 manufacturers, they learn that they can make a lot more money by not competing, than by competing. So that is what they do. As we move forward, we will see if 3 for-profit manufacturers and 1 non-profit/public-good manufacturer create a better market for society as a whole.</p><p>The big insulin manufacturers themselves claim that their profits motivate new breakthroughs and better products. This is obviously untrue for insulin. No actual improvements in insulin have been marketed in over a decade. Lantus was approved in 2000; Levemir in 2005, Humalog in 1996, and Novolog in 2000. <br /></p><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://i.insider.com/5919e239e559f1bc588b4dfe?width=800&format=jpeg&auto=webp" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="533" data-original-width="800" height="267" src="https://i.insider.com/5919e239e559f1bc588b4dfe?width=800&format=jpeg&auto=webp" width="400" /></a> <br /></div><p style="text-align: left;"><span style="font-weight: normal;"><br />From California: <br /><a href="https://www.healthcaredive.com/news/California-manufacture-insulin/626916/">https://www.healthcaredive.com/news/California-manufacture-insulin/626916/</a><br /> <a href="https://www.gov.ca.gov/2023/03/18/governor-newsom-announces-30-insulin-through-calrx/">https://www.gov.ca.gov/2023/03/18/governor-newsom-announces-30-insulin-through-calrx/</a><br />From JDRF: <br /><a href="https://www.jdrf.org/press-releases/jdrf-announces-support-of-civica-to-manufacture-and-distribute-low-cost-insulin/">https://www.jdrf.org/press-releases/jdrf-announces-support-of-civica-to-manufacture-and-distribute-low-cost-insulin/<br /></a></span></p><h3 style="text-align: left;">Sanofi Buys Provention (And Other Tzield News) <br /></h3><p>Provention is the company that just got FDA marketing approval for Teplizumab / Tzield for people at risk of T1D. The new news is that Sanofi is buying Provention. Obviously, Sanofi is a very large "big pharma" company, and Provention is a small "boutique" drug development company. I'll leave it to the business analysts to comment on this, but it is very common for big pharma companies to buy boutique drug developers when they have a successful product, so this should not surprise anyone. I would not expect anything to change for Teplizumab, but only time will tell with certainty. </p><p>In the long term I think this is good for T1D cure creation in general. Sanofi is paying good money for Provention, and that will motivate future investors and future executives to try to find disease modifying treatments for T1D. These guys made a huge pot of money doing exactly that. The stock price went up about 350%. That should motivate people!</p><p>One comment I've often heard in the years since I started the blog, is that companies that make a lot of money off of T1D are not going to invest in cures. This is not exactly that, but it is pretty close. Sanofi makes a lot of money off of insulin (see above), and Tzield should delay the start of that revenue stream in people who use it, and yet they still were willing to put a lot of money in Provention. And if they now kill it, that will be pretty obvious and very public. Sure they could do it, but not in secret.</p><p>Put another way, over the last 6 years, about 1/2 billion dollars have been invested in Provention, and it is now worth about 3 billion. That is great return on investment! Those investors will want to do that again, if they get the opportunity.<br /></p><p>News coverage: <a href="https://www.reuters.com/markets/deals/frances-sanofi-acquire-us-based-provention-bio-29-bln-2023-03-13/">https://www.reuters.com/markets/deals/frances-sanofi-acquire-us-based-provention-bio-29-bln-2023-03-13/</a></p><p><b>Other Provention/Tzield News</b></p><p>I've learned a few more things about Tzield:</p><ul style="text-align: left;"><li>A few people have gotten the Tzield in the Sacromento area, and a few people are about to get it in the San Francisco area. In all cases, the treatment was covered by their insurance.<br /></li><li>About half the people who get it get "flu like" symptoms, which last a few weeks.</li><li>Because it requires an infusion every day for 14 days, and these are done in clinics, you need to have access to a clinic which is open 7 days a week, and you need the time and transportation to get there. <br /></li></ul><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-83935681298713539112023-03-31T20:35:00.000-07:002023-03-31T20:35:51.228-07:00Results from a Phase-II Verapamil Study<p>Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems. It also lowers levels of a protein called TXNIP. Some researchers believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes. So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes. <span style="color: red;"> </span>In addition TXNIP is pro-inflammatory, so lowering it should lower inflammation, which could also have a good effect on type-1 diabetes. Verapamil has already undergone phase-II trials for T1D in the United States, which I discuss below. <br /></p><p>You can read my previous blogging on Verapamil here:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Verapamil">https://cureresearch4type1diabetes.blogspot.com/search/label/Verapamil</a></p><h3 style="text-align: left;">What Were The Results?</h3><p>The summary is that, after one year, people who got Verapamil generated 30% more insulin, than people who did not. However, it is important to remember, that one year after diagnoses, most people with T1D are generating almost no insulin at all. So 30% of almost nothing is a pretty small difference between the Verapamil and non-Verapamil groups.</p><p>Over the years that I have been following honeymoon clinical trials, there have been a couple of treatments which, when measured after a year, the treated people were generating twice as much insulin as the untreated people. So a bigger difference than seen here. However, twice a very small amount is still a very small amount, and none of these treatments have become successful from such a small starting point.<br /></p><p>JDRF's report: <a href="https://www.jdrf.ca/exciting-news-new-drug-in-clinical-trials-shows-slowed-type-1-diabetes-progression-in-newly-diagnosed-children-and-teens/?utm_source=ENTwitterVerapamil">https://www.jdrf.ca/exciting-news-new-drug-in-clinical-trials-shows-slowed-type-1-diabetes-progression-in-newly-diagnosed-children-and-teens/?utm_source=ENTwitterVerapamil</a></p><p>News Coverage: <br /><a href="https://www.medscape.com/viewarticle/988806?src=soc_tw_230228_mscpedt_news_endo_diabetes&faf=1">https://www.medscape.com/viewarticle/988806?src=soc_tw_230228_mscpedt_news_endo_diabetes&faf=1</a><br /><a href="https://jamanetwork.com/journals/jama/fullarticle/2801974">https://jamanetwork.com/journals/jama/fullarticle/2801974</a> <br /></p><p>This Study: <a href="https://www.clinicaltrials.gov/ct2/show/NCT04233034">https://www.clinicaltrials.gov/ct2/show/NCT04233034</a><br /><br /></p><h3 style="text-align: left;">Other Verapamil Studies <br /></h3><p>A previous, smaller study found that Verapamil treated people generated 40% more insulin after a year. So pretty similar to these findings.</p><p>Previous Verapamil Study: <a href="https://www.clinicaltrials.gov/ct2/show/results/NCT02372253">https://www.clinicaltrials.gov/ct2/show/results/NCT02372253</a></p><p>There is a third study underway, covering 138 people and expected to finish in February 2024. I blogged about that one last year: <br /><a href="https://cureresearch4type1diabetes.blogspot.com/2022/02/verapamil-sr-starts-phase-ii-trial-ver.html ">https://cureresearch4type1diabetes.blogspot.com/2022/02/verapamil-sr-starts-phase-ii-trial-ver.html </a></p><p>Another Verapamil Study: <a href="https://www.clinicaltrials.gov/ct2/show/study/NCT04545151">https://www.clinicaltrials.gov/ct2/show/study/NCT04545151</a> <br /></p><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p></p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-80528427820243229662023-03-20T13:48:00.003-07:002023-03-20T13:48:12.821-07:00Influenza Vaccination Starts a Phase-II? Clinical Trial<p>This is a straight forward clinical trial: people recently diagnosed with type 1 diabetes (in their honeymoon phase) will be given a standard flu vaccine to see if they will generate more of their own insulin as compared to people who don't get the vaccine. They are using a Sanofi Pasteur vaccine, VaxigripTetra™, which has been used for over 6 years in people 3 years and older. Previous versions of this vaccine have been in widespread use for decades.<br /></p><p>They are recruiting 100 children (between 7 and 17) who have been recently diagnosed with T1D. This study is a standard, high quality study: it is blinded, randomized, and has a placebo control group. The primary end point is a C-peptide measurement (showing how much insulin the person is naturally producing), and there are several secondary and tertiary end points covering both patient results and internal immunology results.<br /></p><p>They plan on gathering almost all of their data in the first year, but will monitor participants for safety issues for 5 years. This study started in Dec-2022 and they hope to finish in June-2026. <br /></p><p class="MsoNormal"><span lang="EN-US">They are recruiting at four hospitals in Denmark: </span><span lang="EN-US">Aarhus University Hospital, Aarhus, Aalborg University Hospital, Randers and Gødstrup regional hospitals.</span></p><p></p><p>Contact: Ole Frøbert, MD, PhD ole.fro@clin.au.dk<br />(There is additional contact information in the clinical trial registry.)</p><p>More Information</p><p>Clinical Trial Registration: <a href="https://www.clinicaltrials.gov/ct2/show/NCT05585983">https://www.clinicaltrials.gov/ct2/show/NCT05585983</a><br /><br /></p><h3 style="text-align: left;">Discussion</h3><p>For me, there are two interesting discussion points (and one uninteresting discussion point).</p><p>The obvious question is: why do the researchers think it will work? </p><p>The researcher, Ole Frøbert, recently published a study showing that flu vaccine administered shortly after a heart attack reduces the ongoing risk of death. Heart attacks come with high levels of inflammation and he believes that flu vaccination lowers this inflammation, causing the good outcome he saw. While flu vaccination raises immune response in general, it also lowers specific inflammation signalling. It is well known that in T1D inflammation is an important path for the destruction of beta cells, causing the start of the disease (or at least the start of the symptoms and the need to inject insulin). This researcher believes that flu vaccination lowers inflammatory signaling for the specific targets which are doing the damage in T1D. These targets are discussed in the following paper: <a href="https://pubmed.ncbi.nlm.nih.gov/34326232/">https://pubmed.ncbi.nlm.nih.gov/34326232/</a></p><p></p><p></p><p>I have not found any previous research testing if flu vaccines have any impact on existing T1D.</p><p>But there is good evidence that people with T1D get flu more than others, which is why people with T1D should get yearly flu vaccinations. A recent summary is here: <a href="https://www.frontiersin.org/articles/10.3389/fimmu.2021.667889/full">https://www.frontiersin.org/articles/10.3389/fimmu.2021.667889/full</a> and recommendations to do so from the CDC and the ADA are linked here: <a href="https://www.healthline.com/health/diabetes-and-flu-shot">https://www.healthline.com/health/diabetes-and-flu-shot</a>.<br /></p><p>There are also many studies showing that flu vaccines do not cause T1D and are safe for people with T1D. I have summarized these studies here:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2015/10/seasonal-flu-vaccine-and-type-1-diabetes.html">https://cureresearch4type1diabetes.blogspot.com/2015/10/seasonal-flu-vaccine-and-type-1-diabetes.html</a><br />and here is the statement from the US National Academies of Science, with many supporting links:<br /><a href="https://www.nationalacademies.org/based-on-science/is-it-possible-for-the-flu-shot-to-cause-type-1-diabetes">https://www.nationalacademies.org/based-on-science/is-it-possible-for-the-flu-shot-to-cause-type-1-diabetes</a><br /></p><p>The big issue for me, for this trial is: should I blog on it? Is this research aimed at a cure or are they just hoping for better control, maybe using less insulin? I blog on the first kind of research, but not the second. </p><p>When it is not clear if the researchers are aiming for a cure or a treatment, I look at what they are measuring as their primary result. C-peptides are a measure of insulin production, so if that goes up, it can (at least potentially) lead to a cure. On the other hand, blood glucose levels, A1c, and insulin usage are all treatment-oriented measures. For this study, the primary outcome measure is C-peptides, so I'm treating it as cure focused. They are also measuring blood glucose, A1c, and insulin levels, so if it turns out to have results that help treatment (but not cure), then I'll stop covering it.</p><p><span lang="EN-US">The investigators certainly do not expect that the <span class="il">influenza</span> <span class="il">vaccination</span>
will cure type 1 diabetes in this trial. However, even a modest improvement in insulin
generation would suggest a new research
direction into a possible, future, vaccine based, cure.</span> </p><p></p><p></p><p>The uninteresting discussion point is this: will it work? </p><p>The answer is simple: we don't know; that is the whole purpose of this trial. Since the trial is fully funded and underway, there is no reason to speculate as to whether or not it will work. All we need to do is wait and see. Guessing as to outcomes is a waste of time.<br /></p><p>Note: I classify this study as phase-II? because it is the size of a phase-II study, but the treatment has never been tested on people with T1D. Therefore, there is no T1D data available from a phase-I study, so I call it "phase-II?". Officially, it is phase-IV, because it is being done after the vaccine is on the market. <br /></p><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-29473698577671108902023-02-27T13:12:00.000-08:002023-02-27T13:12:06.729-08:00Ixekizumab (Taltz) Starts a Phase-II? Trial In Honeymooners<p>Ixekizumab, sold under the trade name Taltz, blocks a specific part of the immune system called Interleukin 17 (IL-17). It has been approved since 2016 in the US and the EU as a treatment for Plaque Psoriasis and Psoriatic Arthritis in people 6 years old or older. Over 120,000 people have used it.<br /></p><p>The researchers believe that Type 1 Diabetes and Psoriasis are similar diseases, and since Ixekizumab has been effective in treating Psoriasis, they hope it will be effective for T1D as well. This is a quote from their clinical trial registration: </p><p style="margin-left: 40px; text-align: left;">Psoriasis share several aspects with T1D, e.g. the patchy inflammatory
infiltrate consisting of tissue-resident memory (TRM) T cells, leaky
blood vessels that facilitate leukocyte migration and the increased risk
for systemic conditions. Moreover, interleukin (IL)-17 has shown to be
increased in both persons with psoriasis and T1D. Activation of
IL-17/IL-22 pathway is viewed to be both a hallmark of psoriasis and
human T1D. Ixekizumab, an anti-IL17 biological agent, has shown marked
therapeutic value in the treatment of subjects with psoriasis in several
randomized trials and is currently an approved clinical therapy. Due to
the many similarities in the current view of pathogenesis and
manifestation of T1D and psoriasis it is possible that Ixekizumab can
also influence the disease process of T1D. <br /></p><h2 style="text-align: left;">The Study</h2><p>This study is open to adults (18-35) who are in their honeymoon phase (within 100 days of diagnosis). They plan to enroll 127 people, and the study will follow them for a year to get primary data, but then continue to follow them for an additional 3 years for extended data.</p><p>Patients will get two injections (subcutaneous, much like insulin) the first week, and then one injection every other week for 12 weeks, and then monthly injections for the rest of the year.</p><p>The primary end point is C-peptide, which measures how much insulin a person is producing. Secondary end points include insulin dosage, A1c, time spent in range, and time spent low. There are 13 other end points being measured as well.<br /></p><p>They are recruiting in Sweden at 4 sites right now (Södra Älvsborg Hospital, Sahlgrenska University Hospital, NU-Hospital Group, and Uppsala Academic Hospital), but plan on expanding to 19. There are two contacts:<br /></p><ul style="text-align: left;"><li>Marcus Lind, MD, PhD +46(0)766-183142 marcus.lind@gu.se </li><li>Shilan Seyed Ahmadi, MD shilan.seyed.ahmadi@vgregion.se </li></ul><p>This study started in November 2022 and they hope to finish in 2027. <br /></p><p>Clinical trial registry: <a href="https://clinicaltrials.gov/ct2/show/NCT04589325">https://clinicaltrials.gov/ct2/show/NCT04589325</a></p><h2 style="text-align: left;">Discussion</h2><p>One question that comes up with research on commonly used drugs, like this one, is "T1D is relatively common, so if it helps, and it has been used on so many people, why hasn't anyone noticed?" There are two answers to this question: <br /></p><p>The first answer, at least in the United States, is that there is no central database of medical records, so there is no easy way to see if this is happening, and it is unlikely any doctor would notice in their own patients. For example, if 120,000 people have used this drug in the world, then maybe 40,000 of them are in the US. If about 1 in 400 people in the US have T1D, then this drug has been used on about 100 people with T1D. </p><p>For an individual doctor, they are unlikely to have more than 1 patient who has T1D and is taking this medicine, so unless the results are really extreme, the doctor will see it as just the natural variability of the disease. They are unlikely to see a pattern, because they are unlikely to have even 2 patients in the same situation. After all, there are only about 100 such patients in the whole of the US. <br /></p><p>However, there is no way to get get medical data on these 100 people, not even anonymously, and there is no way to even find out which 100 people it is. Some European countries do have these kinds of medical record databases, and they sometimes do publish this kind of research. However, their populations are much smaller, so the number of people reported on would be smaller as well. </p><p>In the last few years, we have moved, slowly, toward better medical record databases. For example, I have seen studies based on Kaiser's medical record database. Kaiser is unusual in that it is both an insurance company and a medical provider with its own hospitals, clinical, and staff. Therefore, it has the medical records, the motivation for improvement, the infrastructure, and the large scale, needed for this kind of record based research. </p><p>The second answer is that this is not likely to be a sudden cure at the standard dosage. Because that would, indeed, be too obvious. If people took the standard dose and were suddenly cured, even just once, some doctors would notice. However, it still may be true that this helps T1D, that it encourages insulin production, and can lead to a cure in a different dosage than currently given. <br /></p><p><br /></p><p></p><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-27428881708844716962023-02-09T18:18:00.000-08:002023-02-09T18:18:27.663-08:00OPT101 Starts A Phase-I Trial in Adults with Established T1D<p>OPT101 is a peptide derived from mouse CD154. What does that mean? A peptide is a small part of a protein. CD154 is a protein found on some immune cells in both mice and people. CD154 is also called CD40L, but must not be mixed up with CD40. CD154 and CD40 work together to regulate parts of the immune system.</p><p>You can think of the immune system as being a large collection of different cells, often with CD or IL names. These cells interact in various ways to attack (or ignore) certain cells. Many immune responses are controlled by a balance between two different types of cells. This is the relationship between CD154 cells and CD40 cells. They balance each other so the the immune system is aggressive enough to attack foreign cells, but not so aggressive as to attack the body's own cells. <br /></p><p>The researchers involved have been looking at the balance between CD154 and CD40 as part of the pathway to T1D for at least 20 years. There is a lot of research showing that CD154 (and the relationship between CD154 and CD40) is important to the path that leads to T1D. Therefore, it makes a lot of sense to test drugs that impact CD154.<br /></p><h3 style="text-align: left;">The Clinical Trial</h3><p>This is a Phase-I study of 18 people, but blinded, randomized, and placebo controlled study (so high quality). I think of it as the size of a Phase-I trial, but the design/quality of a phase-II trial. 2/3s of the people will get the OPT101 treatment, 1/3 a placebo. People in the study must be adults under 60 years old, who have had T1D for 20 years or less. This trial is for people with established T1D, not just honeymooners.</p><p>The study is divided into two groups, which differ by dosage. The second group will get about twice as much as the first group. Each group will have 6 people who get the treatment and 3 who get the placebo. </p><p>This study started in Sept-2022. The paperwork says they hope to finish by Oct-2022, but that is obviously a mistake. If they run both of their groups at the same time, they might be done by mid 2023, or by early 2024 if they run them one after the other.<br /></p><p>They are currently recruiting at two locations on the US West Coast: <br />Contact: Lisa Boswell, MS 303-503-9954 LB@op-t.com <br /><br />Diablo Clinical Research Center, Walnut Creek, California, United States, 94598<br />Contact: Meaghan Saint, PA-C, CDCES msaint@diablolclinical.com <br />Contact: Catherine Morimoto cmorimoto@diabloclinical.com <br /><br />Rainier Clinical Research Center, Renton, Washington, United States, 98057<br />Contact: Sarah Holtz 425-251-1720 ext 309 sholtz@rainier-research.com <br />Contact: Tina Mitchell, RN 425-251-1720 ext 313 tinam@rainier-research.com <br /></p><h3 style="text-align: left;">Discussion </h3><p>Two quick points:</p><p>The thing I like most about this trial is, because they are gathering data for only 3 months, we will have results quickly.</p><p></p><p>Another company, Eledon Pharmaceuticals, is also targeting CD154 (which they refer to as CD40L), and they registered two clinical trials for AT-1501. However they withdrew the registration before the studies started, and in any case, they were targeted at helping islet cell transplants and not directly curing T1D. <br /></p><h3 style="text-align: left;">More Information<br /></h3><p>Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT05428943<br />Company Web Site: http://op-t.com/<br />Background: https://www.frontiersin.org/articles/10.3389/fendo.2017.00208/full<br /><br /></p><p> </p><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-10610120929470309592022-12-26T15:43:00.002-08:002022-12-26T15:47:53.289-08:00Youtube Video Describing How JDRF Makes Funding Decisions<p>If you care about research aimed at curing type-1 diabetes, then you should care about JDRF's research funding. Year after year, they fund more than 2/3s of the research in clinical trials aimed at curing type-1 diabetes. (See my yearly "<a href="https://cureresearch4type1diabetes.blogspot.com/2022/10/jdrf-funding-for-cure-2022.html">JDRF Funding for a Cure</a>" blogs for details.)</p><p>This Youtube video:<br /><a href="https://www.youtube.com/watch?v=ARbbeAe8ky8">https://www.youtube.com/watch?v=ARbbeAe8ky8</a><br />is an official JDRF video describing (at a high level) how they make decisions about what research to fund. It is well worth 35 minutes of your time. Do not stop watching when the DEI section starts. That section is interesting in its own right, but also, after it is another section going into more details about JDRF decision making.<br /></p><p> </p><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-56583928443808017072022-12-15T22:14:00.001-08:002022-12-15T22:34:40.122-08:00ADSCC Starts Phase-I Clinical Trial of Extracorporeal Photopheresis (Opera)<p>This is a phase-I, 10 person trial which started in September 2022, and is expected to finish in January 2024. This trial is for adults (18-50 years old, within 3 years of diagnosis). Half the people will be treated with a standard level of Extracorporeal Photopheresis (ECP) and half will get a double dose. There is no placebo (untreated group). The trial is randomized but open label, meaning that each person will be randomly assigned to standard or double dose, but that everyone will know which group a person is in.</p><p>The standard dose is basically one treatment every two weeks for a six month period. The treatment takes about 3 hours and is done in a clinic. I discuss it in detail below, but it is basically: blood is removed, processed "off line" and then injected back into the person. The double dose is basically twice as often.</p><p>This trial has five primary end points. For me, the one that matters is C-peptide, but they are also measuring adverse effects, A1c, and insulin use, and the number of people who drop out of the trial. There are a bunch of secondary end points which measure changes in the immune system. Data will be collected for a year after treatment.<br /></p><p>Note that different sources have different information for this clinical trial. The US FDA clinical trial registry lists 10 people within 3 years of T1D diagnosis, but the literature at ASDCC says 40 people will be enrolled, and an earlier interview on Facebook says within 6 months of diagnosis. If you have any doubts about eligibility, the treatment, or the trial in general, I recommend you get in touch with ASDCC. This study is enrolling at one site:<br /></p><p>Abu Dhabi Stem Cells Center Abu Dhabi, United Arab Emirates, 4600<br />Contact: Yandy M Castillo-Aleman +971-26655155 ext 104 yandy.castillo@adscc.ae <br />Contact: Muhammad M Alam +971-26655155 ext 104 muhammad.alam@adscc.ae <br /></p><h2 style="text-align: left;">Previous Research</h2><p>There has been one clinical trial of ECP on people with T1D in the past, so it makes sense to look at those results.</p><p></p><p>In 2001 there was a 40 person study done on children (age 10 to 18) in their honeymoon phase. The indented text is paraphrased from the abstract:<br /><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1718876/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1718876/</a></p><p style="margin-left: 40px; text-align: left;">The actively treated children secreted significantly more C peptide in urine during follow up than control children. C peptide values in serum showed corresponding differences between the two groups. The insulin dose/kg body weight needed to achieve satisfactory HbA1c values was always lower in the photopheresis group; there was no difference between the groups regarding HbA1c values during follow up. <br /></p><p>The first thing to notice about this summery is that there are no specific numbers reported. That is usually a bad sign. I looked at the results in the paper, and my opinion is that there was no strong signal of success. The treated group did do a little bit better, so I would describe the results as hopeful, but not strong. The treated group did use less insulin, however. About 25% less, which is another interesting taste of hope.</p><p>In the next few years, this same group published a couple of papers looking at what changed in kids who got ECP vs. kids who did not. However, they used blood samples from the original group of kids, so there was no additional data on effectiveness.</p><h2 style="text-align: left;">More Discussion</h2><p><b>Differences from Previous Research</b></p><p>If previous research on ECP was not a strong success, and this research area has been dormant for about 20 years, it is reasonable to ask what is different about this clinical trial. Why do these researchers hope for better results? </p><p>The major difference I see is the number of treatments. The previous trial gave 5 treatments in 3 months. This trial is giving 7 treatments in 4 months to one group and about double that many to the other group. However, this treatment is more complex than just giving a drug, so it may be that there are other differences between the previous protocol and the current one.<br /></p><p><b>Why so many primary end points?</b></p><p>Clinical trials usually have 1 primary end point. I've seen 2 on occasion as well, but this is the first time I can remember 5 different primary end points. Why design a trial like that? The first question is, why do most clinical trials have a single primary end point? That is pretty straight forward: especially for phase-III studies, both the FDA and the company funding the work, need a clear success or failure decision. Of course they could analyze a bunch of results and synthesize a single success or failure out of a bunch of different primary outcomes, but no one wants to do that. Therefore, clinical trials are usually designed from the beginning to have one primary outcome, and that one outcome feeds the rest of the experimental design. </p><p>However, if the FDA will not be using the study to approve a drug, and a company will not be using the study to raise more money for drug development, then there is much less pressure to have just one primary end point. These researchers seem to have taken that idea farther than others, but there is no rule saying they cannot. <br /></p><p><b>Extracorporeal Photopheresis (ECP)</b></p><p>A person's blood is taken, white blood cells are separated out, and treated with a drug called 8-methoxypsoralen (8-MOP). The white blood cells are then injected back into the person. So this is a way of selectively treating just white blood cells and not any other part of the body. This treatment was FDA approved for one form of cancer in 1988, but is currently used for several other immune issues, especially graph vs. host disease and transplant rejections.</p><p></p>
<p>8-methoxypsoralen (8-MOP), also known as Methoxsalen, is an unusual drug in that it is activated by ultra violet light, as part of the treatment. This means that people getting this treatment must avoid sun light for 24 hours afterwards to avoid over-exposure. This link describes the treatment as used for transplantation issues by CHOP (great acronym for the Children's Hospital of Philadelphia):<br /><a href="https://www.chop.edu/services/extracorporeal-photopheresis-ecp">https://www.chop.edu/services/extracorporeal-photopheresis-ecp</a></p><p>There are also pills and creams, which have been available for decades. These forms are used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas. The skin is exposed to a very specific amount of ultraviolet (UVA) light from lamps or sunlight after taking the drug.<br />https://en.wikipedia.org/wiki/Methoxsalen</p>
<p><b>Abu Dhabi Stem Cells Center (ADSCC)</b></p><p>ADSCC is a private clinic in the Arab Emirates. It was founded in 2019, and is already involved in 5 clinical trials: 2 are completed, 2 are in progress, and 1 is waiting to start. Several of these involve applying ECP to different diseases or in combination with other treatments.<br /></p><p>Note that although ADSCC has "stem cells" in its name, the Opera trial discussed here (and ECP in general) is not a stem cell treatment. I would describe it as a "cellular therapy".</p><p>Sources:</p><p>New Article: <a href="https://www.arnnewscentre.ae/news/uae/uae-explores-new-treatment-options-for-diabetes-multiple-sclerosis/">https://www.arnnewscentre.ae/news/uae/uae-explores-new-treatment-options-for-diabetes-multiple-sclerosis/</a><br />New Article: <a href="https://www.weqaya.ae/en/posts/adscc-conducts-clinical-trials-for-diabetes-ms-treatment">https://www.weqaya.ae/en/posts/adscc-conducts-clinical-trials-for-diabetes-ms-treatment</a><br />Video: <a href="https://www.facebook.com/watch/?v=1907192579465520">https://www.facebook.com/watch/?v=1907192579465520<br /></a>Clinic Web Site: <a href="https://www.adscc.ae/">https://www.adscc.ae/</a> (takes a long time to load)<br />Clinical Trial Registry: <a href="https://clinicaltrials.gov/ct2/show/NCT05413005"> https://clinicaltrials.gov/ct2/show/NCT05413005</a> <br /></p><p> </p><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-79525950449676178902022-12-03T11:11:00.002-08:002022-12-03T11:11:34.510-08:00The FDA Approves Teplizumab Under The Name TZIELD™ (teplizumab-mzwv)<p>On 17-Nov-2022, The USA FDA approved Teplizumab. This is the first drug ever approved in the United States which changes the course of Type-1 Diabetes. This is a long blog which will discuss the approval from several different points of view.</p><p>As you read this blog remember that it is the first blog I've ever written on a treatment that has been approved for use in the US. I'm in new territory here; we all are. If you want an excellent (and shorter) overview of Teplizumab, I recommend this diaTribe article:<br /><a href="https://diatribe.org/fda-approves-tzield-teplizumab-delay-type-1-diabetes">https://diatribe.org/fda-approves-tzield-teplizumab-delay-type-1-diabetes</a></p><p>Here is the official FDA announcement:<br /><a href="https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes">https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes</a> <br /></p><h2 style="text-align: left;">What Was Approved? What Will It Do? <br /></h2><p>First: This is not a cure for type 1 diabetes.<br />It was approved because it delayed the onset of T1D for an average of 2 years. Continued testing suggests the actual delay might be 3 years or even longer. However, the current information is that this drug delays the onset of T1D. It is not being approved to prevent or to cure T1D.</p><p>This drug was approved only for people who are 8 years old or older and have stage 2 of type 1 diabetes. Other uses are "off label" which I'll discuss below. What does "stage 2" mean? Type 1 diabetes moves through three stages. Stage 1 is when someone has two or more autoantibodies associated with T1D. Stage 2 is when they also have abnormally high blood glucose levels after meals. People in stage 2 don't have obvious symptoms, and so will not know their blood glucose levels are high unless they test. Stage 3 is when people start to have obvious symptoms of T1D. This is when T1D is usually diagnosed. TZIELD™/Teplizumab is not approved for people who have already been diagnosed with T1D or are in their honeymoon phase. </p><p>The treatment is a 14 day series of infusions. One infusion per day, and each one takes 30-60 minutes at a clinic. This is not an under the skin injection, nor can it be given by a random person at home, like insulin. Infusions require a trained professional working in a clinic.<br /></p><p>In terms of "what will it do?" The official answer is, it will delay the onset of T1D symptoms (and therefore the need to inject insulin) for two years on average. However, the average delay may be longer than that. If you follow patients for 3 years, the longest delay you can measure is three years, but as you follow them longer, you might see a longer delay. The 2 year figure came from the original study (which followed people between 2 and 7 years (average of 4 1/4). Follow on data suggested that the the delay might be 3 years, based on following people longer. Therefore, as time moves forward and we continue to follow treated people, we might find that the average delay is even longer than the 3 years from the current data.</p><p>Teplizumab does have side effects. To quote the FDA: "The most common side effects of TZIELD include decreased levels of certain white blood cells, rash and headache." All of these resolved themselves soon after the infusions. Temporary Epstein–Barr virus reactivation was seen in one patient and has been seen occasionally in people who got other anti-CD3s treatments as part of organ transplantation. Obviously, anything that changes the immune system could have a long term side effect, but these have not been seen in people treated with Teplizumab.<br /></p><p>Provention Bio (the makers of Teplizumab) has priced TZIELD at $193,000 (wholesale) to treat one person. That is not a typo. One hundred, ninety three thousand dollars US. Of course, that is the public price and it is not clear what insurance companies will really pay, or what the out of pocket will be for individuals. </p><p></p><p>This is from the company's press release:</p><p style="margin-left: 40px; text-align: left;">Provention Bio has launched COMPASS, a patient support program with a
staff of dedicated personnel available to answer questions and help
navigate coverage, reimbursement and access for patients that are
prescribed TZIELD. Provention Bio offers financial assistance options
(e.g. copay assistance) to eligible patients for out-of-pocket costs.
Patients are encouraged to speak to their healthcare providers to find
out whether TZIELD is appropriate for them, and patients who have been
prescribed TZIELD and their healthcare providers can call
1-844-778-2246, Monday through Friday from <span class="xn-chron">8AM-8PM EST</span> or email a COMPASS Navigator at <a href="mailto:COMPASS@proventionbio.com" rel="nofollow" target="_blank">COMPASS@proventionbio.com</a>.</p><p>Note: although this text makes it sound like only prescribed patients can use this facility, on their conference call, it was very clear that this phone number and email can be used by anyone who are interested in the treatment, even if they are not yet prescribed users. You can listen to Provention Bio's conference call here: <a href="https://app.webinar.net/nDvPqlJY9o8/on-demand">https://app.webinar.net/nDvPqlJY9o8/on-demand</a><br /></p><h2 style="text-align: left;">Should I Use It? Should My Child Use It?</h2><p>You need to work with your medical team to answer this question. </p><p>This treatment is not targeted at people who have already been diagnosed with diabetes. Rather, it is focused on their siblings (and other first degree relatives). TZIELD is approved for people who test positive for two or more autoantibodies, and who have abnormal blood glucose levels after a meal, but are not yet seeing the symptoms of T1D (like thirst, excessive urination, weight loss, flu like symptoms, etc.) From a practical point of view, this makes siblings (and other first degree relatives) the first target of this treatment.<br /></p><p>So the first thing to do, if you have not already done it, is to test siblings and other first degree relatives for autoantibodies, and then for dysglycemia. </p><p>JDRF's T1Detect program lists several ways to get tested for autoantibodies:<br /><a href="https://www.jdrf.org/t1d-resources/t1detect/">https://www.jdrf.org/t1d-resources/t1detect/</a><br />If a relative has T1D, then TrialNet will usually do it for free. Anyone can also order tests through their doctor, and there are free programs for some people in Colorado, South Dakota, and Washington state. In the past, I know a lot of people did not want to join TrialNet, because they thought "even if my child tests positive for autoantibodies, there is nothing I can do, so I would rather not know". Well, now there is something you can do. You can treat with TZIELD and delay the onset.<br /></p><p>The next thing is to talk to your medical team about testing for dysglycemia, which is abnormally high blood glucose levels after a meal. <br /></p><p>If you have two or more autoantibodies and dysglycemia, then you can talk to your medical team. This is a prescription drug, and only someone on the team can prescribe it, plus you need a clinic to actually administer it.</p><h2 style="text-align: left;">What Happens Next?</h2><p>Provention believes that they will have supply to distribute by "the end of the year", which I interpret to be the end of 2022. They further believe that insurance will approve coverage for this drug in the next 6 or 9 months. <br /></p><p>I have three thoughts on what is going to happen:</p><p>First, people are slowly going to start using TZIELD, which means that we are going to start learning what happens in actual use. There are two things to remember. The first is that drug approval is not like opening a faucet. It is not that thousands of people are going to suddenly start using the drug the day after it is approved (or even the first day it is available on the market). There is a long, slow time where patients and doctors become comfortable using the drug and recommending its use. The first question, which will take months or even years to answer is: will doctors recommend this and will people use it? Insurance coverage and real cost to people will matter as well. Once that is answered, we will move on to the second question, which is: are the benefits and risks the same as what was seen in the clinical testing? Just because a drug delayed the onset of T1D symptoms for 3 years in testing, does not mean it will do the same in real usage. Some drugs do better, some worse, and some the same. The same is true with side effects. They can be better or worse or the same as in testing.</p><p>Second, Provention Bio (the makers of Teplizumab) are going to try to get it approved for people in the honeymoon phase of T1D. That is, people in stage 3 of type 1 diabetes. Their PROTECT study is scheduled to finish in May 2023. If it does, and if it is successful, then use of Teplizumab use could expand after that. The PROTECT study is enrolling people in their honeymoon phase (within 6 weeks of diagnosis), who get two courses of therapy (so two different 14 infusion series, six months apart). </p><p>Provention Bio is also interested in getting TZIELD approved for people under 8 years old, and then later combining TZIELD with other treatments for a stronger response.<br /></p><p>Third is off label use. In America, when a drug is approved, it is approved for a specific indication. An indication is a collection of symptoms that a patient has; both the patient and the symptoms are part of an indication. For example, TZIELD has been approved for people in stage 2 of type 1 diabetes (symptoms) who are 8 years old or older (patient). However, a doctor can prescribe any approved drug for any indication, not just what it was approved for. If they prescribe it for any other situation, that is called "off label use". This is not a legal grey area (although it sounds like one). It is perfectly legal. </p><p>There are some practical limitations to off label use. Insurance often will not pay for it, doctors are often reluctant to prescribe it, and the company can not talk about it at all. But the bottom line is that once TZIELD is available, a doctor could choose to prescribe it to someone who was in their honeymoon, had established T1D, or was younger than 8 years old. If this does happen, however, we might not hear about it. In general, the FDA forbids companies to mention any off label uses of their drugs<span style="color: red;"></span>. So even if one doctor notices that a particular off label use is successful, it is traditionally hard to communicate that to others. Although I suspect with modern social media, it is a lot easier than it used to be.<br /></p><h2 style="text-align: left;">How Long Did It Take?</h2><p>One of the key questions people ask me is, how long does it take the FDA to approve a cure for T1D? Up until now, the true answer to that question has been, since it has never happened, we don't know. In theory, it should take a drug about 15 years to work though the process of three phases of clinical trials and marketing approval as required by the FDA. But since it has never happened, no one knows for sure. That is all still true, of course, because Teplizumab is not a cure. But it is the closest we've gotten, so asking how long did it take is a reasonable question.</p><p></p><p>Teplizumab took a "wrong turn" on the way to approval, going through these four development phases: <br /></p><ol style="text-align: left;"><li>It took about 10 years to move into clinical trials. From the late 1980s to the late 1990s. </li><li>It took at least 7 years to move from NOD mouse success to human trials (1992 to 1999) <br /></li><li>It then took about 11 years, from 1999 to 2010, to get from start of phase-I trials to the end of phase-III clinical trials. However, these trials were ultimately unsuccessful, and the company doing development dropped it.<br /></li><li>Clinical trials by TrialNet continued and the drug was picked up by another company. This second round of development took about 12 years from the previous failures though additional clinical trials and the marketing approval process, from 2010 to 2022.</li></ol><p>In a broad sense, this supports my previous estimate that a drug can go from start of phase-I trials to market approval in about 15 years, if it is successful the first time. But the total research time for this treatment, from start of research (about 1986) to FDA approval (2022) was 36 years.</p><p>On a personal note, they started researching this about 15 years before my daughter was born and yet it is ready too late to help her, since she is now over 18 years into her established T1D.<br /></p>Note: a longer, more detailed timeline is here:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2019/09/teplizumab-phase-ii-results-for.html">https://cureresearch4type1diabetes.blogspot.com/2019/09/teplizumab-phase-ii-results-for.html</a><br />and there are more timeline dates in this article:<br /><a href="https://www.jdrf.org/blog/2022/11/17/fda-approves-tzield-teplizumab-watershed-moment-t1d-community/">https://www.jdrf.org/blog/2022/11/17/fda-approves-tzield-teplizumab-watershed-moment-t1d-community/</a><h2 style="text-align: left;">Why Did The First Round of Phase-III Clinical Trials Fail?</h2><p>This is an important question. If the first round of clinical trials had been successful, then it is very reasonable to assume Teplizumab would have been approved 8 or even 10 years ago. A lot of people could have used it in that time period, so the question has real impact.</p><p>There are (at least) two answers to this question.</p><p>The first batch of research, which occurred between about 1999 and 2012 was trying to cure people who were in their honeymoon (stage 3) phase of T1D. It was the phase-III trial from this line of research that was unsuccessful.</p><p>However, there was a second batch of research, which was really just one clinical trial from 2010 to 2018, which was focused on delaying the onset of T1D during the "at risk" (stage 2) phase, and that was the research which ended up getting approved.</p><p>So two answers to the "why failed" question, are that the research that was unsuccessful was aiming "too high" at curing T1D, and the successful research was aimed lower, at delaying the onset of T1D. Also that the unsuccessful research was during the later stage 3 phase of T1D, but the successful research was during the earlier stage 2. But taken together, those two issues are not the whole story, because the phase-III study which was unsuccessful also used an unfortunate primary end point. This choice of end point might have led to the clinical trial being unsuccessful, even if the treatment later turns out to be successful. That brings up a discussion of end points and why they matter.<br /></p><p>An end point is an official measure of success in a clinical trial. Clinical trials usually have one primary end point, a few secondary end points, and sometimes some tertiary end points. The primary end point determines success. It is what everyone looks at. For a phase-III clinical trial, it needs to measure the overall success of the treatment. It also has to be practical to measure, and meaningful to patients and doctors alike. </p><p>For the last 20 years, the primary end point for clinical trials aimed at curing type-1 diabetes has been C-peptide levels. C-peptide has many advantages as an end point: it is easy and reliable to measure, and it accurately reflects how much insulin a person's body is generating, separate from how much they are injecting. Even if the person is not completely cured, C-peptides measure progress towards the cure. It is a good primary outcome. But this was not always known. Consensus that measuring C-peptides was the best primary outcome occurred in the 2001-2004 time frame.</p><p>The big phase-III trial (which ended up failing) used a combination of insulin use and A1c (not C-peptides) as a primary end point. In retrospect, that might have been a mistake. Provention Bio is currently running a phase-III trial testing Teplizumab's ability to help people in the honeymoon phase, and they are using C-peptide as the primary end point. If this newer trial is successful, it will be clear that choice of end points had a big impact.</p><p>A related question is why didn't the earlier researchers focus more on delaying T1D and less on curing it, so they could have been successful earlier? That is easy to answer: it was not possible to research treatments which might delay the onset of T1D, until TrialNet's landmark Pathway to Prevention research. That started in 2004 and took several years to gather enough data so that it was understood what normal progression of T1D was, or how to measure it. Prior to that, there was simply no way to even evaluate a treatment which might delay onset.<br /></p><h2 style="text-align: left;">Who Should We Thank?</h2><p>Mythology requires heroes, so everyone wants to point at one person (or maybe two) and say they are the heroes. They did it. But real science rarely works that way. There are always a lot of different people bringing a lot of different skills to the party.</p><p>If you want to go the mythical hero route, then I suggest Jeffery A Bluestone and Kevan C Herold, as your heroes. They collaborated in the development of Teplizumab from the very earliest research to the most recent clinical trials and corporate sponsorship. Also, they pursued this research even in the face of setbacks, and ended up overcoming all the issues.<br /></p><p>On the other hand, if you want a more realistic group, reflecting the large number of people required to develop an immunological treatment, the long history of this treatment, and the many factors that came together to lead to its success, then add:<br /></p><ul style="text-align: left;"><li>All the researchers who worked on anti-CD3 based treatments for T1D in both animals and people. Collectively, they authored dozens of papers which led to the treatment we have today. It would be an interesting project to get every name on every paper. My guess is that there would be over 100 researchers in the list, and that doesn't cover the people who contributed in ways that did not end up as paper authors. As part of this blog, I tried to find out who was the lead author of the first paper that showed an anti-CD3 worked against T1D in animals. My two leading contenders are Anthony R. Hayward and Lucienne Chatenoud, but there may be even earlier examples.</li><li>All the patients who participated in the 14 clinical studies on Teplizumab, and all the researchers who ran them. FDA approval is based on data, and these studies created the data.</li><li>The JDRF, for several contributions. First, is the money. They funded Teplizumab throughout its development (roughly 35 years), from the earliest pre-clinical research, through the clinical trials, and right up to providing venture capital style funding to Provention Bio through their T1D Fund. Money matters. Second, JDRF was part of the T1D community which pushed the use of C-peptides as the best primary end point, and also the "stages" view of the natural history of T1D. Both of these scientific policies were critical to the eventual success of Teplizumab.<br /></li><li>TrialNet for two different reasons. First, their "Pathway to Prevention" trial completely changed how we thought about the onset of T1D, leading to the "stages" model. TrialNet gave us the data foundational to the very idea of delaying the onset. Second, they sponsored the one clinical trial (called TN-10) which succeeded, and they did it after commercially sponsored trials ended unsuccessfully. This shows some "guts".<span style="color: red;"><br /></span></li><li>Provantage Bio, which invested money in a drug that had already failed
previous phase-III clinical trials. They had the foresight to try
again, and were successful. This is something that rarely happens in
the world of pharmaceuticals. </li></ul><h2 style="text-align: left;">More About Teplizumab / TZIELD</h2><p>Teplizumab is a humanized monoclonal antibody which targets CD3 cells in the immune system in order to lower (or stop) the body's autoimmune response. This treatment tries to prevent type-1, or lessen it's severity, by "turning down" the immune system's attack on the body's own pancreas cells. This basic approach has resulted in treatments (but not cures) for other autoimmune diseases. This is a highly targeted approach; it is not lowering the whole immune system, but rather a specific part involved in T1D.<br /></p><p>Monoclonal antibodies are therapies created by cloning a single cell that attacks the kind of cell you don't want. You end up with a vast number of identical cells, all of which attack the kind of cell you don't want. By carefully choosing the starting cell, you can "target" the monoclonal antibody to attack a very specific type of immune cell. Because of how they are produced, early monoclonal antibodies were targeted at mouse cells, rather than human cells, and this sometimes caused problems. Later techniques were developed to make the cells more human like, but still not completely human. These were called "humanized" or "chimeric" monoclonal antibodies. Finally, techniques were developed to create fully human monoclonal antibodies, and these are called "human" or "fully humanized". Teplizumab is a fully humanized monoclonal antibody.<br /><br />There are scores of monoclonal antibodies (of all three types) approved for use in the United States, for a wide variety of illnesses. Different monoclonal antibodies have different safety profiles. Most have names ending in "mab".<br /></p><h2 style="text-align: left;">More Reading</h2><p>Pricing information comes from these articles:<br /><a href="https://endpts.com/provention-gets-fda-nod-on-drug-to-delay-type-i-diabetes-kicking-off-us-launch-with-sanofi/">https://endpts.com/provention-gets-fda-nod-on-drug-to-delay-type-i-diabetes-kicking-off-us-launch-with-sanofi/</a></p><p>C-peptide as the best primary end point:<br /><a href="https://pubmed.ncbi.nlm.nih.gov/14693724/">https://pubmed.ncbi.nlm.nih.gov/14693724/</a></p><p>Presentation on why Teplizumab works:<br /><a href="https://www.easd.org/media-centre/home.html#!resources/studies-of-the-mechanism-of-teplizumab">https://www.easd.org/media-centre/home.html#!resources/studies-of-the-mechanism-of-teplizumab</a></p><p>Official press release:<br /><a href="https://investors.proventionbio.com/2022-11-17-TZIELD-TM-teplizumab-mzwv-approved-by-FDA-as-the-first-and-only-treatment-indicated-to-delay-the-onset-of-Stage-3-type-1-diabetes-T1D-in-adult-and-pediatric-patients-aged-8-years-and-older-with-Stage-2-T1D">https://investors.proventionbio.com/2022-11-17-TZIELD-TM-teplizumab-mzwv-approved-by-FDA-as-the-first-and-only-treatment-indicated-to-delay-the-onset-of-Stage-3-type-1-diabetes-T1D-in-adult-and-pediatric-patients-aged-8-years-and-older-with-Stage-2-T1D</a><br /><a href="https://medicine.yale.edu/news-article/fda-approves-first-drug-that-delays-onset-of-type-1-diabetes/">https://medicine.yale.edu/news-article/fda-approves-first-drug-that-delays-onset-of-type-1-diabetes/</a> <br /></p><p>These are the earliest successful anti-CD3 in NOD mouse studies I could find:<br /><a href="https://pubmed.ncbi.nlm.nih.gov/1532716/">https://pubmed.ncbi.nlm.nih.gov/1532716/</a><br /><a href="https://pubmed.ncbi.nlm.nih.gov/8278351/">https://pubmed.ncbi.nlm.nih.gov/8278351/</a></p><p>Historical read:<br /><a href="https://endpts.com/we-kept-at-it-jeffrey-bluestone-plots-late-stage-comeback-after-teplizumab-shown-to-delay-type-1-diabetes/">https://endpts.com/we-kept-at-it-jeffrey-bluestone-plots-late-stage-comeback-after-teplizumab-shown-to-delay-type-1-diabetes/</a><br /></p><h2 style="text-align: left;">End Notes</h2><p>I refer to Teplizumab as a drug throughout this posting. Teplizumab is actually a biologic. Drugs are chemicals, while biologics are biological material. Teplizumab is a very specific type of cell. The FDA has separate sets of regulations for drugs vs. biologics. However, I feel using the word "drug" makes the blog more understandable to more people.</p><p>The product's name is TZIELD™ in Provention Bio's marketing literature. At least what I saw. However, it is Tzield™ on the bottle. I don't know which is correct, so I'm using all caps.<br /></p><p>TZIELD is pronouced "TEE-zield" the second part is like "shield" but with a z sound. The International Phonetic Alphabet form is /tizil̩d/ or /tiziəld/.</p><p>Provention Bio is a publicly traded company, meaning you can buy and sell stock right now. Therefore, there are a bunch of financial websites and stock news service articles on the company as an investment opportunity. (I don't have an opinion on that.) However, reading these articles does give a completely different view of the company and product. We care about: does it work? They care about: how profitable will it be? <br /></p><p> </p><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-50486214349803837842022-11-16T19:35:00.000-08:002022-11-16T19:35:24.296-08:00Results from MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London<p>This is the most recent result from a long line of research led by <span _ngcontent-kxb-c153=""><span _ngcontent-kxb-c153=""><span _ngcontent-kxb-c153=""><span _ngcontent-kxb-c153="" class="contact-funding-item-text-hspacing"></span></span><span _ngcontent-kxb-c153=""><span _ngcontent-kxb-c153="">Colin Dayan and Mark Peakman, at Cardiff University and </span></span></span></span><span _ngcontent-kxb-c153=""><span _ngcontent-kxb-c153=""><span _ngcontent-kxb-c153=""><span _ngcontent-kxb-c153="">King's College London.</span></span></span></span> The goal here is to train the body's immune system not to attack itself, by using either one peptide (in the first trial) or several peptides (in the more recent trial). A peptide is a small part of a protein, and these peptides are part of the insulin molecule. The idea is vaguely similar to
giving people tiny amounts of peanut protein to desensitize them
from peanut allergies. However, it is important to remember that type-1 diabetes
is NOT a classic allergy; the analogy is not perfect, but gives the
general idea. <br /></p><p>You can read my summary of the results of the first clinical trial, using one peptide, here:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2017/11/results-from-phase-i-clinical-trial-of.html">https://cureresearch4type1diabetes.blogspot.com/2017/11/results-from-phase-i-clinical-trial-of.html</a></p><p>This study was done on adults, within 4 years of diagnosis. This is a little unusual, as most studies either pull from "honeymooners" (within 1 year of diagnosis) or "established" (longer than that). The average time after diagnosis for everyone in this study was about 20 months. So while this study does contain a mix of honeymooners and established T1Ds, there are more people with established T1D. <br /></p><p>Here is an image overview of the results. The line with the square is insulin production in the group that got the placebo, while the triangle covers everyone who got the treatment (in three different doses). My summary is two fold: (1) the treated group did better than the untreated group (2) neither group actually got better, it is just that the treated group dropped less than the untreated group. <br /></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqwGPHRsdcnOcMLgm9sCtoAecFVy4Z_Evy-JTWvG9TennQSVuZYzB2DhfuNxt7CfwRsXv5wTDpXYOzTsRwKosEUqaxbSIYKAY5q3impoWRmekNR_2eTvwVBsq1XxnyNzf2C5gurw4a2ff3OhZ3TxUAYnNSbf9r90wPGtCl8iD_uwH839msW-ILk7rx/s1216/poly2.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="898" data-original-width="1216" height="296" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqwGPHRsdcnOcMLgm9sCtoAecFVy4Z_Evy-JTWvG9TennQSVuZYzB2DhfuNxt7CfwRsXv5wTDpXYOzTsRwKosEUqaxbSIYKAY5q3impoWRmekNR_2eTvwVBsq1XxnyNzf2C5gurw4a2ff3OhZ3TxUAYnNSbf9r90wPGtCl8iD_uwH839msW-ILk7rx/w400-h296/poly2.jpg" width="400" /></a></div><p>Another way to view the results is this graph:</p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj1O4dN2ARtKGl4VWg7XvAFZJDXgbwb8y5IbTox0qXlxmTeP8evcQNEpE9bbP585n_6bg7yR1nQgVGlPXeshbycwvEI3cdgaY8tZ-hEVdEw9RxfXhn7hGkMHmuzIOmktmiN-RhoYePmGFX-EYQpSTiOA0tLJAk7ynxzda7j1eVCUJBD8EROx1zGOfDW/s1581/poly1.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1002" data-original-width="1581" height="254" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj1O4dN2ARtKGl4VWg7XvAFZJDXgbwb8y5IbTox0qXlxmTeP8evcQNEpE9bbP585n_6bg7yR1nQgVGlPXeshbycwvEI3cdgaY8tZ-hEVdEw9RxfXhn7hGkMHmuzIOmktmiN-RhoYePmGFX-EYQpSTiOA0tLJAk7ynxzda7j1eVCUJBD8EROx1zGOfDW/w400-h254/poly1.jpg" width="400" /></a></div><p></p><p>And notice that in the placebo group, everyone gradually lost C-peptide production during the 6 months of the study. That is what we expect, since people gradually loose insulin production throughout their honeymoon. However, the people who got the smallest dose, two of them actually went up. They were generating more C-peptide after 6 months. The official summery is "Taken together, these findings provide some encouragement for the evaluation of efficacy signals in future, well-powered studies."<br /></p><h2 style="text-align: left;">Discussion</h2><p style="text-align: left;">For myself, I consider C-peptide results to be successful when they go up, and unsuccessful when they go down. Here, the C-peptide results for the treated people went down, so that is disappointing. It is important to see that the study was successful because the treated group generated more C-peptide than the untreated group, and this difference was big enough to be statistically significant. However, both groups (treated and untreated) actually went down in C-peptide production. It is just that the treated group dropped less than the untreated group. So even though this study was scientifically successful, I don't think of the results as successful.</p><p style="text-align: left;">But there is another issue here, which the researchers touched on: "responder vs. non-responder". The overall results in the first chart, the average of everyone who got the treatment and compare this to the average of everyone who did not, and those were the disappointing results. However, the second chart shows all people individually. Certain people got noticeably better, while others did not, or even went down. If you happen to be one of the people who's C-peptide numbers went up, you would be very happy with the results. </p><p style="text-align: left;">So, when evaluating these results should we look at an average of everyone, or focus on specific responders?</p><p style="text-align: left;">It's a complex discussion, too complex to go into here. However, one of the key questions is, do you know ahead of time who will be a responder? Do they share some characteristic or test result, so you know they will be a responder? If so, you can give the treatment only to the responders, and see some big results. If that is the case, the responder result is the important one, and focusing on it is a reasonable thing to do.<br /></p><p style="text-align: left;">However, if you do not know who will respond, or why they respond, then hyping the responder success is just an excuse to exclude data that makes your treatment look bad. In this research, there is no indication of why some people respond and some don't, but the research is still in its early stages. If they do discover why some people respond, while others do not, then suddenly this research could become very valuable to people who are "responders".<br /></p><p>Abstract: <a href="https://pubmed.ncbi.nlm.nih.gov/35073398/">https://pubmed.ncbi.nlm.nih.gov/35073398/</a><br />Full Paper: <a href="https://diabetesjournals.org/diabetes/article/71/4/722/140961/Immune-and-Metabolic-Effects-of-Antigen-Specific">https://diabetesjournals.org/diabetes/article/71/4/722/140961/Immune-and-Metabolic-Effects-of-Antigen-Specific</a><br />Clinical Trial Record: <a href="https://beta.clinicaltrials.gov/study/NCT02620332">https://beta.clinicaltrials.gov/study/NCT02620332</a><br /></p><p>Thanks to ADA's "Diabetes" journal for making this article free, and thanks to all the people who pressured (and continue to pressure) all scientific journals to make these results freely available. <br /></p><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-30948932439313152022-10-16T18:20:00.005-07:002022-10-16T18:20:55.783-07:00JDRF Funding for a Cure 2022<p>In the US, we are in the "Walking Season" when JDRF (Juvenile Diabetes Research Foundation) asks us to walk
to raise money for a cure for type-1 diabetes. So I'd like to do my part, by reminding you
all of how important JDRF is to the human trials of potential cures for T1D, which I track.<br />
</p>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">Let
me give you the punch line up front: 65% of the treatments currently in
human trials have been funded by JDRF. (And the number is 78% for the
later phase trials!) This is a strong impact; one that any non-profit
should be proud of. Below is a list of all the treatments, grouped by
phase, and separated into trials that JDRF has funded, and those JDRF
has never funded. </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">I've made two big changes to how I track treatments this year. </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><ul style="text-align: left;"><li>In the past, I counted each combination of treatments separately. For example, Diamyd, Etanercep, and Vitamin D was considered one possible cure and Diamyd alone was a separate possible cure, and Diamyd and Vitamin D was a third. This year, I'm changing my methodology to group all of these possible cures together as one, since they are all really based on Diamyd.</li><li>In the past, I counted a possible cure separately if it was tested in different phases of type-1 diabetes. For example, TOL-3021 was being tested on honeymooners, but also in people with established T1D, so it got counted twice. This year, I'm no longer doing that. Another example is Teplizumab. It is in the approval process for at-risk people, but in phase-III trials for honeymooners, so it is listed in both phases but only counted once.<br /></li></ul><p><b>The List, Divided by Phases<br /></b>Below is the list of all treatments, divided into five phases: In Process (of FDA Approval), Phase-III, Phase-II, Phase-II?, and Phase-I. Phase-II
trials are "classic" phase-II trials, which are done after a Phase-I trial. What I call Phase-II? trials are done
on treatments which never went through phase-I trials on people with T1D. They've been shown safe in other diseases, so have skipped phase-I trials on people with T1D. These Phase-II? trials
might be Phase-II from the point of view of size and safety, but they
are Phase-I in terms of effectiveness, so I'm putting them in their own
category. <br /></p></div><b>In Process of FDA Approval</b><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">Summary: currently
there is 1 drug which has been submitted to the US FDA for approval
for sale, and it was funded by JDRF.
<ul><li>Teplizumab by Provention Bio (At Risk)</li></ul>In the forth
quarter of 2020, Provention Bio submitted Teplizumab for FDA
approval. Unfortunately, there have been some delays, but there is hope of an FDA decision in November 2022. This application will cover people who are "At Risk" (as
described below) for T1D, and the aim will be to delay the onset of T1D
by 2-3 years. <br /></div>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<b><br /></b><b>Phase-III Human Trials</b><br />
<div>
Summary:
currently there are 2 treatments in a phase-III clinical trial. Both are funded by JDRF:<br />
<ul><li>Oral Insulin (Preventative)</li><li>Teplizumab by Provention Bio </li></ul>
<b>Phase-II Human Trials <br /></b></div>
Summary: there
are 16 trials in phase-II, and 12 of them have been funded by JDRF,
while 4 have not. Here are the treatments that have been funded by JDRF:<br /><ul style="margin: 0.5em 0px; padding: 0px 2.5em;"><li>ATG and GCSF by Haller at University of Florida (Established) </li><li>Abatacept in honeymooners and as a prevention by Orban at Joslin Diabetes Center and Skyler at University of Miami (Prevention) </li><li>Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK </li><li>Diamyd in several combinations by Ludvigsson at Linköping University and Larsson at Lund University (Honeymoon and Prevention) <br /></li><li>Gleevec by Gitelman at UCSF </li><li>Gluten Free Diet: Three Studies (Preventative)</li><li>Stem Cell Educator by Zhao (Established) </li><li>Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute </li><li>TOL-3021 by Bayhill Therapeutics (Honeymoon and Established) </li><li>Umbilical Cord Blood Infusion by Haller at University of Florida </li><li>Ustekinumab by University of British Columbia</li><li>Verapamil by Shalev/Ovalle at University of Alabama at Birmingham</li></ul>
Not funded by JDRF:<br />
<ul><li>ATG and autotransplant by several research groups: Burt, Snarski, and Li </li><li>Dual Stem Cell by Tan at Fuzhou General Hospital </li><li>Stem Cells of Arabia (Established)</li><li>Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)</li></ul>
<b>Phase-II? Human Trials</b><br />
Summary: there are 13 trials in phase-II?, and 7 of them have been funded
by JDRF, while 6 have not. Here are the treatments that have been funded
by JDRF:<br />
<ul><li>Alpha Difluoromethylornithine (DFMO) by DiMeglio</li><li>GABA by Diamyd</li><li>Golimumab by Janssen (Honeymoon and Established)</li><li>Hydroxychloroquine by Greenbaum (At Risk) </li><li>Intranasal Insulin by Harrison at Melbourne Health (Prevention)</li><li>Iscalimab (CFZ533) by Novartis <br /></li><li>Rituximab by Pescovitz at Indiana University</li></ul>
Not funded by JDRF:<br />
<ul><li>Azithromycin by Forsander </li><li>Ladarixin by Emanuele Bosi of Dompé Farmaceutici</li><li>Liraglutid (At Risk)</li><li>NNC0114-0006 and Liraglutide by Novo-Norsk (Established)<br /></li><li>Rapamycin Vildagliptin Combo by IRCCS (Established)</li><li>Visbiome by Medical College of Wisconsin </li></ul>
<b>Phase-I Human Trials</b><br />
Summary: there are 22 trials in phase-I, and 15 of them are funded by JDRF, while 7 are not. Here is the list funded by JDRF:<br />
<ul><li>AG019 and Teplizumab by ActoGeniX</li><li>DIMID1 (Faecal Microbiota Transplantation) at AMC Hospital <br /></li><li>CGSF by Haller at University of Florida </li><li>Golimumab (At Risk)</li><li>MER3101 by Mercia (previously IBC-VS01 by Orban) </li><li>MonoPepT1De by Cardiff University</li><li>Mozobil by University of Alberta (Established)</li><li>MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London</li><li>Nasal insulin by Harrison at Melbourne Health (Prevention)</li><li>PRV-101 (Coxsackie B Vaccine) by Provention Bio (Prevention)<br /></li><li>Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University</li><li>TOPPLE T1D by Novo Nordisk (Established) <br /></li><li>Pro insulin peptide by Dayan at Cardiff University </li><li>VC-01 by Viacyte (Established)</li><li>VCTX210A by Viacyte/CRISPR (Established) <br /></li></ul>
Not funded by JDRF:<br />
<ul><li>AVT001 by Avotres<br /></li><li>Baby Teeth Stem Cells by CAR-T Biotechnology </li><li>Gluten Free Diet by Carlsson at Lund University</li><li>Mesenchymal Stromal Cell by Carlsson at Uppsala University</li><li>NN1845 (Glucose Sensitive Insulin) by Novo Nordisk</li><li>PIpepTolDC at City of Hope Medical Center</li><li>ProTrans by NextCell (Established)</li></ul>
<b>Summary of all Trials</b><br />
52 in total<br />
34 funded by JDRF<br />
So 65% of the human trials currently underway are funded (either directly
or indirectly) by JDRF. Everyone who donates to JDRF should be proud of
this huge impact; and everyone who works for JDRF or volunteers for it,
should be doubly proud.<br />
<div style="background-color: white; color: #666666; font-family: "trebuchet ms", trebuchet, verdana, sans-serif; font-size: 13.2px; line-height: 1.4;">
<br /></div>
<b>Just Looking at Trials on Established Type-1 Diabetics</b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b> </b><br />
12 of these treatments (23%) are being tested on people with established T1D.<br />
Of these, 8 are funded by JDRF.<br />
So 66% of the trials recruiting people with established T1D are funded by JDRF.<br />
<br />
I'm not comparing these numbers to the 2020 numbers because I've changed the way I count potential cures, so the numbers are not equivalent. However, I did do a quick comparison applying the older methodology to this year's data, and there was little change: 4 more phase-I trials, and 1 less phase-II trial. <b><br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<br />
<b>A Little Discussion</b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> <br />The money that we donate does many things:</div><ol style="text-align: left;"><li>It finances more clinical trials (especially early clinical trials).</li><li>It finances making clinical trials (especially early clinical trials) larger and better designed. <br /></li><li>It helps push possible cures to the next level of trial. It finances moving phase-I trials to phase-II, and phase-II to phase III.</li></ol><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">I like to say that there are two reasons for donating money for research into T1D. People who like the research being done should donate money to move it forward, faster. People who don't like the research being done should donate money to start up different research which (presumably) they will like more. So no matter which group you are in, you should donate. 😀 <br /></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> <b> </b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>Trial Populations<br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">The
list above uses the following marks to show the nature of the
treatments, and if one treatment is being tested in different
populations, then it will be listed more than once. <br />
<b>Honeymoon:</b> Most trials are done on people within the first year
of diagnosis. All the studies listed above which are not Established,
At Risk, or Prevention are in this Honeymoon category. <b><br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>Established:</b> One or more trials are open to people who have had type-1 diabetes for over a year. <br />
<b>At Risk:</b> One
or more trials are open to people who have 2 or more autoantibodies,
but have not yet started showing symptoms of type-1 diabetes.<br />
<b>Prevention:</b> This treatment is aimed at preventing type-1 diabetes, not curing it.<br />
If a trial is not marked, then it is for people in the honeymoon (first year) of T1D. <br />
<div style="background-color: white; color: #666666; font-family: "trebuchet ms", trebuchet, verdana, sans-serif; font-size: 13.2px; line-height: 1.4;">
<br /></div>
I
give an organization credit for funding a treatment if they funded it
at any point in development; I don't limit it to the current trial. </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> </div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">I also give credit if
JDRF funds research indirectly, through another organization. For example, JDRF
funds both nPOD and Immune Tolerance Network and so I give JDRF credit
for clinical trials based on their work.<br /></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"> <b><br /></b></div><div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;"><b>How I Count Trials for This Comparison</b></div>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<ul><li>I mark the start of a research trial when the researchers start
recruiting patients (and if there is any uncertainty, when the first
patient is dosed). Some researchers talk about starting a trial when
they submit the paper work, which is usually months earlier. </li><li>For trials which use combinations of two or more different
treatments, I give funding credit, if the organization in the past
funded any component of a combination treatment, or if they are funding
the current combined treatment. </li><li>I have made no attempt to find out how much funding different
organizations gave to different research. This would be next to
impossible for long research programs, anyway. </li><li>Funding of research is not my primary interest, so I don't spend a
lot of time tracking down details in this area. I might be wrong on
details. </li></ul>
Some Specific Notes:<br />
<ul><li>I only include intervention studies here, because those are the only
type of study that the FDA will accept for the eventual approval of a
new treatment. </li><ul><li>The PreventT1D study (Vitamin D and Omega-3s) is a "field study" so not included. </li><li>A Rotavirus Vaccine study which was published a few years ago was a population based study, so also not included.</li></ul><li>Oral Insulin: This trial was a phase-III trial, meaning that it was
large and designed to provide enough information so that, if
successful, the treatment could be widely used. However, as it turned
out, only part was successful, and that part was phase-II sized, so I
don't think we will see widespread use based on this trial alone. You
can think of this as a phase-III trial with phase-II results.</li></ul>
This is an update and extension to blog postings that I've made for the previous twelve years:<br />
<ul><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2020/10/jdrf-funding-for-cure-2020.html">https://cureresearch4type1diabetes.blogspot.com/2020/10/jdrf-funding-for-cure-2020.html </a><br /></span></li><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2019/10/jdrf-funding-for-cure-2019.html">https://cureresearch4type1diabetes.blogspot.com/2019/10/jdrf-funding-for-cure-2019.html</a> <br /></span></li><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2018/10/jdrf-funding-for-cure-2018.html">https://cureresearch4type1diabetes.blogspot.com/2018/10/jdrf-funding-for-cure-2018.html</a> </span></li><li><span style="font-family: "times" , "times new roman" , serif;"><a href="https://cureresearch4type1diabetes.blogspot.com/2017/10/jdrf-funding-for-cure-2017.html">https://cureresearch4type1diabetes.blogspot.com/2017/10/jdrf-funding-for-cure-2017.html</a></span></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2016/10/jdrf-funding-for-cure-2016.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2016/10/jdrf-funding-for-cure-2016.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2015/10/jdrf-funding-for-cure-2015.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2015/10/jdrf-funding-for-cure-2015.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html%20"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html</span></a></li><li><a href="https://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html"><span style="font-family: "times" , "times new roman" , serif;">https://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html</span></a></li></ul>
</div>
<div class="post-body entry-content" id="post-body-7084183799663881625" itemprop="description articleBody" style="position: relative; width: 616px;">
<div style="background-color: white;">
<span style="background-color: transparent;">Please
remember that my blog (and therefore this posting) covers research
aimed at curing or preventing type-1 diabetes that is currently being
tested in humans. There is a lot more research going on than is counted
here.</span><br />
<span style="background-color: transparent;"><br /></span></div>
Please
think of this posting as being my personal "thank you" note to all the
JDRF staff, volunteers, and everyone who donates money to research a
cure for type-1 diabetes:<br />
<div style="background-color: white; color: #666666; font-family: "trebuchet ms", trebuchet, verdana, sans-serif; font-size: 13.2px; line-height: 1.4; text-align: right;">
<span style="font-size: large;"><i><span style="font-family: "times" , "times new roman" , serif;">Thank You!</span></i></span></div>
<br />Finally,
if you see any mistakes or oversights in this posting, please tell me!
There is a lot of information packed into this small posting, and I've
made mistakes in the past.
<div style="background-color: white;">
<br /></div>
</div><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-75296293171266295632022-09-16T19:42:00.000-07:002022-09-16T19:42:23.916-07:00Research Dropped As A Practical Cure <p>Every year I have the sad job of removing some projects from my list of active research aimed at curing T1D. In the perfect world, I would remove research when it was unsuccessful: when clinical trials testing it failed or the researchers working on it stopped. However, in the real world, I often don't know that a clinical trial was unsuccessful because those results are not published. Researchers sometimes continue working on a project long after it is clear that it has failed, or simply move on to something else without anyone noticing that their previous research has been dropped.<br /></p><p>My policy is to stop following research 2 years after the end of the last active clinical trial aimed at curing T1D, even if there is no specific publication of failure. </p><p>These are the research projects which I have stopped covering recently:<br /></p><p><b>AAT (Alpha-1 Antitrypsin) by Kamada </b></p><p>AAT is an anti-inflammatory/immunomodulatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that one of AAT's effects (lowering inflammation, immune modulation, or wound healing) can cure/prevent/treat the disease. </p><p>The last results from an AAT study were two unsuccessful results published in 2018, and there are no ongoing studies now. During the 2010s, there were a total of 7 studies done on AAT, and not one of them was a success.</p><p>The company producing the drug (Kamada) no longer even lists T1D as a "Therapeutic Focus Area" nor is it listed in their research pipeline.</p><p><b>Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital</b></p><p>The idea behind this research is that umbilical cord-blood derived stem cells microvesicles may reduce inflammation and hence improve natural insulin production (more β-cell mass) in people with T1D. <br /></p><p>This referred to a Phase-I clinical trial started in 2014, which was expected to finish later in 2014. As of 2020 a summary article reported no results had been published. I also did a literature search and was not able to find any suggestion that results had been published, or that follow on research had been started. <br /></p><p>References:<br /><a href="https://www.clinicaltrials.gov/ct2/show/NCT02138331">https://www.clinicaltrials.gov/ct2/show/NCT02138331</a><br /><a href="https://doi.org/10.3389/fcell.2020.00149">https://doi.org/10.3389/fcell.2020.00149</a></p><p> <b>Alefacept / Amevive® by TrialNet</b><mark class="hl-synonym" title="alefacept → Amevive"></mark></p><p>Alefacept is a drug that has been used to treat the skin condition,
psoriasis. Psoriasis is generally considered to be an autoimmune
disease, similar to type-1 diabetes, but with the body attacking its
own skin cells, rather than its own beta cells. So trying a drug
already approved for Psoriasis on type-1 diabetes seemed like a
reasonable thing to do, and these researchers did it. Back in 2016 I reported on the results of the phase-2 trials, which were OK, but not great:<br /><a href="https://cureresearch4type1diabetes.blogspot.com/2016/02/alefacept-reports-on-phase-ii-results.html">https://cureresearch4type1diabetes.blogspot.com/2016/02/alefacept-reports-on-phase-ii-results.html</a> <br /></p><p>Unfortunately, in a certain sense, none of this matters. The company
that made Alefacept stopped production in 2011, so it has not been
available for years. I don't know of any planned clinical trials with
Alefacept, nor any similar fusion proteins. <br /></p><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></font></div><div style="text-align: center;"><font size="2"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></font></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0tag:blogger.com,1999:blog-5472921328078253036.post-56722213061432530472022-07-11T10:37:00.000-07:002022-07-11T10:37:16.541-07:00Provention Bio Update<p>Provention Bio is a small biotech company targeting several autoimmune diseases. It has two drug candidates which target T1D: teplizumab (PRV-031) and a coxsackievirus B vaccine (PRV-101). This blog is a quick update on both of them.</p><p><b>Teplizumab (PRV-031)</b></p><p>I've blogged many time before and you can read them here (which includes more details than are included in this blog posting):<br /><a href="https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab">https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab</a></p><p>Clinical trials done to date suggest that Teplizumab will delay the onset of T1D (the first symptoms) by about 3 years. For example, if someone has 3 autoantibodies, they have a 35% chance of having symptoms of T1D within 5 years. However, treatment with Teplizumab will change their chances to 35% but only after 8 years.<br /></p><p>Provention has submitted this drug for FDA approval to delay the onset of T1D when used after 2 autoantibodies have been detected, but before symptoms of T1D are detected. This is the first drug to be considered for marketing approval which would change the course of T1D (insulin treats the symptoms but it does not change the underlying disease).</p><p>The approval paperwork was submitted in Nov 2020. In April 2021, the FDA identified a serious issue involving manufacturing changes impacting drug testing. After much discussion between Provention Bio and the FDA, Provention submitted more data in Feb 2022 to address this issue. The hope was that the FDA would approve it by Aug 2022. However, in June 2022 the FDA announced that the decision would be made on 17 Nov 2022. This was strictly a delay by the FDA; no additional data needs to be submitted. In Oct 2022 there would be an announcement about required labeling and post-marketing studies (if required).</p><p>So the recent change is that we will now hear the decision on approval in Nov 2022 (with a strong hint in Oct 2022) instead of in Aug 2022 as we had previously hoped. From my point of view, this is a pretty small change. There is no point in guessing if the FDA will approve it or not; in just 4 months we will know for sure. <br /></p><p><b>Coxsackievirus B Vaccine Candidate (PRV-101)</b></p><p></p><p>Background: There is a theory that part of the trigger which causes the onset of T1D is infection by a virus. Over the years, several common viruses have been investigated as possible triggers. I've previously blogged on Polio family viruses and Rotaviruses as possible triggers for T1D. Coxsackie B viruses are another family of viruses which might be a trigger. If Coxsackie B viruses trigger T1D, then preventing infection might prevent (or delay) T1D, and we know that vaccines prevent infection. So if this theory is correct, then a Coxsackie B vaccine could prevent or delay T1D.</p><p>Wikipedia: <a href="https://en.wikipedia.org/wiki/Coxsackie_B_virus">https://en.wikipedia.org/wiki/Coxsackie_B_virus</a> <br /></p><p>Provention Bio is testing a Coxsackie B vaccine in the hopes that it will prevent or delay T1D, and in March 2022 they announced the results of their phase-I study. The two key findings were:</p><ol style="text-align: left;"><li>There were no major adverse effects (ie. no bad side effects).</li><li>Six months after treatment, between 90% and 100% of the people who received a high dose of vaccine had strong immunity to Coxsackie B viruses.</li></ol><p>This is the official word on the future of this research: "The Company is currently exploring partnership opportunities to further the clinical development of PRV-101." My translation of this sentence is (very roughly) "The results were good, but we don't have enough money to run a phase-II trial for a vaccine, so we need to partner with someone who does." <br /></p><p> </p><div><div style="text-align: center;"><span style="font-size: x-large;"><span style="font-family: Dancing Script;"><i>Joshua Levy</i></span></span></div><div style="text-align: center;"><span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">http://cureresearch4type1diabetes.blogspot.com</span></span></span></div><div style="text-align: center;"><span style="font-size: x-small;"><span><span style="font-family: "courier new", "courier", monospace;">publicjoshualevy at gmail dot com</span></span></span></div></div><div style="text-align: center;"><span style="font-size: x-small;">All
the views expressed here are those of Joshua Levy, and nothing here is
official JDRF or JDCA news, views, policies or opinions. My daughter has
type-1 diabetes and participates in clinical trials, which might be
discussed here. My blog contains a more complete non-conflict of
interest statement. Thanks to everyone who helps with the blog.</span></div><p> </p>Joshua Levyhttp://www.blogger.com/profile/05300553471793001620noreply@blogger.com0