Saturday, August 15, 2020

Update On Teplizumab

Here are three recent updates on Teplizumab.  You can read my previous summary of this drug here:https://cureresearch4type1diabetes.blogspot.com/2019/09/teplizumab-phase-ii-results-for.htmland all my Teplizumab postings here:https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab

Updates from ADA 2020

The Teplizumab update from ADA 2020 contained several important pieces:

The average delay in onset of T1D rose from about 2 years in the previous reports, to 3 years.  This is based on following the same group of people but for a longer period of time.  My interpretation of this is that some people are simply not helped by this treatment, and they are later diagnosed with T1D.  However, for the people the treatment does help, it prevents T1D for a relatively long time, and as we follow these people for longer, that time gets longer too.  This is a good thing.

People treated with Teplizumab generated more C-peptide, in response to food, in the six months after treatment, then they had before.  This is important because usually, during this phase of the disease, C-peptide generation is slowly decreasing.  (And that was seen in the untreated group.)  C-peptide is generated by beta cells as part of their generation of insulin.  So generating more C-peptide means the beta cells are recovering or regenerating in some way.  Previous studies (in Teplizumab and other drugs) have sometimes shown preservation of insulin production by beta cells.  They stop decreasing.  But to the best of my knowledge, this is one of the few times a drug has shown increases in insulin production by beta cells in a human trial.

People in this study seemed to go through three phases: during the 6 months after treatment, their C-peptide numbers increased.  Then those numbered stayed mostly stable for months or years.  Some people continued to stay stable and were not diagnosed with T1D, while others started dropping and about 6 months after their C-peptide levels started dropping they were diagnosed with T1D.

Obviously, there are a couple of key questions that we don't know the answers to:
  1. Will repeated dosing of Teplizumab continue to delay the onset of T1D?
  2. Will dosing of Teplizumab in people with established T1D lead to increased insulin production, and therefore make their T1D easier to treat?  This study shows that increase for people who are at-risk of T1D, but we don't know about people who already have T1D.
  3. Is there are some way to know ahead of time what sort of at-risk people will be helped by this treatment, and which will not?
Great write up from JDRF / Beyond Type-1: https://beyondtype1.org/teplizumab-updates-ada-2020/
Abstracts of the two ADA 2020 presentations:

Starting A Phase-II Trial In Honeymooners

The same group that ran the successful study to see if Teplizumab could delay the onset of T1D are now running a follow-up trial.  People previously treated with Teplizumab, but who later came down with T1D, are treated again with Teplizumab to see if it has any effect on the course of their T1D.   Remember, the previous effect was to delay the onset of T1D, so now we will learn if doses after diagnosis make for a slower onset or preserve some beta cells.
This is a 30 person study.  Everyone will get the treatment and will be followed for 18 months.  No control group.  The study's primary end points are safety related, but the secondary end points include C-peptide production (showing if the body is generating its own insulin) and several other measurements.  They started in March 2020 and hope to finish in August 2024.
This study is only open to people who took part in the earlier Teplizumab study titled Teplizumab for Prevention of Type 1 Diabetes In Relatives "At-Risk"  which is TrialNet study TN-10. The contact information for this study is Provention Bio Chief Medical Officer, 908-356-0514, eramos@proventionbio.com

Ongoing PREVENT Trial

There is also the ongoing PREVENT trial of Teplizumab.  This is a phase-III study being done on honeymooners.  Due to COVID-19, they have paused recruiting new patients into this study, but when the emergency is over, they will restart recruiting.  This study needs 300 people.  You can read the study's web page here: 
and the trial registry here:


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
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.

Monday, August 3, 2020

Two New Clinical Trials (HCQ and Baby Teeth Stem Cells)

Hydroxychloroquine to Prevent Type 1 Diabetes

Hydroxychloroquine (HCQ) has been in the news recently because of claims that it may treat/cure COVID-19.  However, for this blog, I thought I'd update people on the clinical trials that are testing Hydroxychloroquine as a prevention of T1D.  (Note that HCQ has some T2D applications, which I'm not discussing here.)

Hydroxychloroquine is approved in the US for treatment and prevention of Malaria and some autoimmune diseases, such as Lupus and Rheumatoid Arthritis.  There are two reasons to think it might help with type-1 diabetes.  First, it helps with other autoimmune diseases.  Second, it is an anti-inflammatory and inflammation is seen in the pancreas of people with type-1 diabetes.

A large HCQ  trial started in Aug-2018 and is expected to run until Aug-2024.  The goal is to enroll 201 people who have tested positive for two autoimmune antibodies, but have not shown any symptoms of T1D.  During the study, people will take a pill, either HCQ or a placebo.  They will be followed for years to see how many are diagnosed with type-1 diabetes.  It is being run by the Type 1 Diabetes TrialNet, led by Carla Greenbaum, and JDRF is helping to fund it.

The study is double blinded, so publishing any information prior to completion in 2024 would be very difficult, and (to the best of my knowledge) no interim results have been published.

The study is recruiting people at 40 different sites all over the US.  You can read more about the study here:
the list of recruiting locations is in the Clinical Trial Registry:
to see the limitations due to COVID-19 read this:

Personal note: I know there is a lot of interest in HCQ as a COVID-19 treatment.  I have not been systematically tracking every study done in that area.  However, I can boil down what I have seen into six bullet items:
  1. In order to get a drug approved for use in the US, in normal times, there must be three high quality studies done which show safety and effectiveness (one phase-II study and two phase-III studies).
  2. Right now, there are zero high quality studies showing HCQ's impact on COVID-19.  Zero.  And that covers trials which were successful and trials which were unsuccessful.  Every trial I've seen reported, in both the scientific literature and the popular press, has been low quality.  By low quality I mean either no control group, no randomization, or it is not an intervention study at all:  very basic stuff.  I'm not quibbling about size, protocol, or even publication.
  3. There have been several low quality studies done on HCQ and COVID-19.  These studies show approximately a 1 to 2 to 1 ratio of good to bad to neutral outcomes.  So for each 4 low quality studies done, 1 has shown success (improved outcomes), 2 have shown failure (meaning higher death rates or other bad effects), and 1 has shown no difference.
  4. Because high quality research is slower and more expensive than low quality research, under normal circumstances I would never expect anyone to fund a high quality clinical trial based on the terrible results of the low quality studies done so far.  However, these are not normal circumstances, so there might be a high quality study done.  If one is done, those results will carry more weight than the stuff published so far. 
  5. Because of how clinical trials work, low quality research is far more likely to be positive than high quality research.  If you are getting unsuccessful results 3 out of 4 times with low quality results, you're not going to get successful results in higher quality studies.  That's just not the way it works.
  6. The last gasp of the true believers in a situation like this is to point at the large number of unsuccessful results, and say that they are all low quality results.  (The same is true of the small number of successful results as well, but they will not dwell on that.)  Therefore the idea is not disproven, because a high quality result would carry the day, if it were done.  Notice the switch where they are requiring mainstream science to prove their idea wrong, rather than the scientific method where new ideas must be proven correct by the proponents.  However, in real life, no one will ever do the high quality study, because the low quality studies are failing.  The true believers will blame a conspiracy, and the matter will die. 

Stem Cells From Baby Teeth Starts A Phase-I Study

This study is of personal interest to me.  My daughter was diagnosed when she was 18 months old.  When she started loosing her baby teeth it was known that each one contained a tiny amount of adult stem cells and there were companies that could freeze the teeth for later use.  At the time, little was known about how to get adult stem cells or what they could do.  But since our daughter already had T1D it seemed like something worth doing.  So we had some of her teeth preserved.   However, a few years later, there were many more known sources of adult stem cells, and the uses of adult stem cells were better known and T1D had not shown any successes with these kinds of adult stem cells.  So we stopped paying our storage fees.

Now, many years later, this is the first clinical trial I have seen that attempts to use the adult stem cells in baby teeth.

This study started in January 2019 and is expected to finish in December 2020.  It enrolled 24 people who had either T1D or T2D.  There is no control group.  Each person will get three injections of stem cells from baby teeth and then be followed for a year.  Primary outcomes are insulin usage and C-peptides (which measures how much insulin the person is creating naturally).  Secondary outcomes include A1c, blood sugar numbers, and proinsulin generation (another measure of how much insulin the person is creating naturally).


The clinical trial record contains this note, and I've never seen anything like it before: "Note: at 1 month follow-up (V5) after the last transplantation of several cells, the subjects were still unable to discontinue insulin, and then began the second course of stem cell therapy. After the second course of treatment, the follow-up plan was resumed."

My interpretation of this is that the study is fully enrolled, and that (so far) no one has been cured.  This comment seems to imply that the researchers thought they might see some outright cures in the study, and these seems very optimistic to me.


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
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.

Friday, July 3, 2020

News from ADA 2020

June 12th to 16th was ADA 2020, the scientific sessions of the American Diabetes Association, which is the largest diabetes focused medical conference in the world.  This year, the scientific sessions were all on line.   As in previous years, I did not attend, but I did read publicly available information and watched the tweets and Facebook posts which discussed the talks.  Finally, I exchanged information with the JDCA as they covered the sessions as well.

There are scores of talks and 100s of posters; far too much for me to cover all of it.  Also, about 90% of the content was focused on type-2 diabetes.  After all, about 90% of the people who have diabetes, have T2D.  So what I've done is included a paragraph describing some of the bigger, more interesting news ideas, and after each paragraph some links which can tell you more about it.

I've divided the blog up into these sections:
  1. Summaries
  2. Cure Focused Research
  3. Better Devices
  4. Treatment News
  5. Diversity and Diabetes Research

Summaries

Overall, I think that BeyondType1 has great summaries of the news from ADA 2020:

The JDRF did a video summary of each day:
ADA
diaTribe's Sunday summary: https://bit.ly/2YJh8yB

Cure Focused Research

I hope to write blog postings on each of these results in the future.

Teplizumab Gets Better
Teplizumab already had some of the strongest results seen in terms of being able to delay the onset of type-1 diabetes, and there was an update this year which showed longer, stronger results.  My previous blogging is here: https://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab
Anti-IL-21 and Liraglutide
Combining Treg and anti-CD20
These two treatments have both been tried before, but this is the first time they have been tried together.
Ladarixin

Better Devices

There was a lot of news about new and improved devices.  Here are three summaries:
Medtronic
The big news was results of pivotal trials of the 780G (also called "AHCL") which just got approved in Europe and should be approved in the US soon.
Insulet
Tandem
There was some belief that the next generation of Artificial Pancreas / Automated Insulin Delivery devices might be so good that the main barrier to use would be the sets, rather than them pumps:
DIY ("We are not waiting.")
There was a lot of buzz about various "do-it-yourself" devices.  I'm sorry I only saved this one reference, because there was a lot more going on:

Treatment and General News

T2 Movie On PBS
There was a lot of excitement about this movie, although it focuses on T2 rather than T1:
New, Faster Insulin
Patients like faster insulins because they lower BGs; companies like newer insulins because they are covered by patents for longer.  This Insulin is faster and newer.
Weekly Insulin
There were phase-II results from a clinical trial on a weekly insulin.  This is a basal insulin (like Lantus) except that it only needs to be injected once a week, not once a day.  It was compared to Lantus and was just as effective.

TIR vs. A1c
Another debate which I expect to remain "hot" for the next few years is the Time In Range (TIR) vs. A1C debate.  Which is better for measuring the success of a new drug or device, and therefore which is better for patients?  Because better measurements in research lead to better treatments and hopefully cures in the future.
I have two opinions on this debate:  First, I don't see how it is that important.  I have never seen a study where TIR led to a different conclusion than A1c.  Quite the opposite, in studies that measure both, if the TIR data shows one device is better than another, then the A1c data will show the same thing.  So arguing about which is "better" is pointless splitting of hairs.  Second, there are clear differences in how easy they are to use, and that is likely more important than one being "better" (ie. more predictive) than the other.  For example, TIRs can be measured at home, by the person with T1D.  But A1c is a single number with no ambiguity so easier to use in data analysis.   (A1c of 5.5 is better than 5.6, but if someone has BG way too high for 1 hour is that better or worse than being a little too high for 2 hours?)  But, it is a lively debate, and I don't think it will end soon.

TP-399 (treatment, not cure)
This drug is being tested as therapy that you take for T1D in addition to insulin.  The study found that it could lower A1c by .32 or raise your time in range by 2 hours.
One Hormone vs. Two
I suspect that the next big debate in devices will be between Artificial Pancreas devices which use insulin vs. those that use insulin and Glucagon.  The current trade off seems to be an average of 10 points lower BG numbers vs. the added hassle of two drugs as opposed to one. 

Microbiome based prevention:
The idea that bacteria in the gut might cause T1D or impact it's severity is comes up most years at ADA.  This is a summary of some JDRF funded research looking into it:

TEDDY

Two T1Ds or One?
This is another topic which might turn into a larger debate.  It is generally understood that people who get T1D when they are younger have faster onsets (shorter honeymoon phases) and generally stronger disease symptoms.  But is this because younger people are struck by a different (and stronger) form of the disease, or does everyone get the same form of the disease, it is just that people diagnosed younger have the disease for longer?  Are there two forms of type-1 diabetes (younger onset and older onset), or just one form (which varies in strength from person to person)?

Hiding Cells from the Immune System
Something about beta cells is targeted by the immune system.  This research is attempting to change beta cells, so that the immune system can not target them:

Diversity In Diabetes Research

This ADA conference was held against the backdrop of Black Lives Matter.  I've included some of the more eye-opening research on race and diabetes below.  (Personal note: I tried to write a short introduction to racism and diabetes research for this section.  However, the subject is too complex and too impactful to be summarized so briefly, at least with my writing skills.  I hope to blog on it in the future, giving it the space it deserves.)

Black vs. White Gestational Diabetes


AP with Different Starting Points
When companies test new devices they often end up testing them on "good diabetics" by which I mean people who already have good management, already see their doctors regularly, and have the money to buy good medicine in the US.  So the tests end up showing that someone who is already in good shape will be even better with the new device.  But that excludes people who are not doing well to start (who arguably need new devices more), and does not give a realistic whole-population view of the new device.


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
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.

Saturday, June 13, 2020

Possible Cures for Type-1 in the News (June)

This blog posting is a summary of four small updates.  Unfortunately, they include research delay, two unsuccessful trials, and one trial unreported for so long that I'm now assuming that it failed.

Tianhe Delays Phase-II Trial of Stem Cell Educator

You can read my previous blogs on Tianhe's Stem Cell Educator here:
The quick summary is that the stem cell educator is a machine which takes the immune cells from a person's blood, exposes them to various organic molecules which change their behavior so they learn not to attack beta cells. The cells are then returned to the body.

Unfortunately, the new news is that clinical trials for the Stem Cell Educator have been delayed by three months because of the COVID-19 pandemic.  You can read the announcement here: https://www.facebook.com/tianhecell/posts/1149765802041857

I suspect that some other clinical trials are getting delayed as well, but since there is no central clearing house for these kinds of announcements, it is hard to know for sure.

Also new (to me) is that Dr. Zhao has a fund raising page through the hospital where he does his research.  So if you want to fund his research directly, you can do it here:
https://secure2.convio.net/humc/site/Donation2;jsessionid=00000000.app20058a?4622.donation=form1&DONATION_LEVEL_ID_SELECTED=1&NONCE_TOKEN=F031AB361B3FAE40A58FDBF166E9EE74&df_id=4622&idb=0&mfc_pref=T&fbclid=IwAR0fYn6E7Y--EzfHeoR5rcNLKdQK-3WWUrgywEZH6zPZEVx2EI8N87tg6Xo

Unsuccessful Phase-II? Study of Albiglutide

Albiglutide (tradenames Eperzan and Tanzeum) is a GLP-1 inhibitor, similar to Byetta, Victoza and other drugs commonly used by people with type-2 diabetes.  GlaxoSmithKline tested it in people with type-1 diabetes, to see if it had the potential to delay T1D or cure them.

Unfortunately, it was not successful.  Their conclusion was:
In newly diagnosed patients with type 1 diabetes, Albiglutide 30 to 50 mg weekly for 1 year had no appreciable effect on preserving residual β-cell function versus placebo.
I previously blogged about this research here:

Unsuccessful Phase-II for Low-dose IL-2

Interleukin 2 (IL-2) is a protein that the body's immune system uses for communications.  It is part of the system that helps the immune system identify the body's own cells from foreign cells.  Since the root cause of type-1 diabetes is a failure in this process, IL-2 is a possible cure.

This study enrolled 24 children in their honeymoon phase into 4 different groups: one placebo group and three different treatment groups.  The primary outcome was higher levels of a specific immune cell called a Treg cell.  Higher levels of Tregs are thought to help prevent T1D.  Secondary outcomes included direct measures of T1D: how much insulin the person produced naturally (as measured by C-peptides) and A1c numbers.

The study showed that treated honeymooners did generate more Tregs. This result was statistically significant and was higher in the higher dose treatments.  However, the secondary outcomes (which measured effect on T1D symptoms) were not statistically significant.

In 2016, I published a blog which was a summery of the 6 clinical trials using IL-2 at that time:
You can read all my blogging on IL-2 here:

My informal summary of all this research is that IL-2 causes more Tregs to be generated, but does not cause more insulin to be made, or impact A1c.  The key measure of progress to a cure is how much insulin a person is naturally creating and (so far) IL-2 is not increasing that.

Unsuccessful Phase-I Study of Ustekinumab and INGAP: No Results After Three Years

My policy is that any study which has not published within two years of completion is unsuccessful.  My experience has always been that studies that are successful are published quickly: within one year.  So when a study goes three years, as this one has, without publishing its results, I'm very comfortable assuming that it was unsuccessful.

I have tried, more than once, to contact the researchers involved to get an update, but never got a reply.

Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2016/01/exsulin-ustekinumab-combo-starts-phase.html


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
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.

Tuesday, June 2, 2020

Strong Results from a Single Case use of Fenofibrate and Start Of A Clinical Trial

This blog is different from most of my blogs because I'm reporting on a case study rather than a clinical trial.  A case study is the experience of one person who got a treatment, as reported in a medical journal.  Even the smallest (phase-I) trials usually have 10 or more people enrolled.  But this journal article reports on a single person's experiences with a new treatment.

I'll discuss exactly what happened in more detail below, but the summary is that a 19 year-old woman was diagnosed with type-1 diabetes.  She quickly started taking Fenofibrate, which is an FDA approved drug usually used to reduce cholesterol and triglycerides (fatty acids) in the blood.  The results were shocking: her need for external insulin quickly dropped to zero.  After approximately 14 months she stopped testing her blood glucose daily.  She did not need to inject or inhale insulin for 21 months, at which time she still was not using external insulin. (!)

Results

The table below shows two separate data points on each day after treatment started.  The blue line is injected insulin levels per day, and use the blue numbers on the left.  The red line is blood glucose numbers, and use the red numbers on the right.  For blood glucose, they use European units, but the 5 is about 90 in American units, 10 is 180, and 15 is 270.

Image is from the journal article and is presented for educational purposes only.

Starting on day 19, she stopped taking any insulin at all, with one exception: while backpacking in Sri Lanka she was admitted to a hospital with a high fever.  The doctors told her to take insulin as a precaution, and she took 2 units.  You can see that on the 133rd day. 

Prior to treatment, her blood glucose numbers were high, as would be expected of someone newly diagnosed.  Her A1c was 13.5 at diagnosis.  However, her blood glucose numbers rapidly normalized.  After she stopped taking insulin, her blood glucose averaged about 90, with A1c around 5.7%.

As you look at this data, which is amazing, it is important to remember that it is from just one person.

Background on Fenofibrate

Fenofibrate is commonly prescribed for high cholesterol and high triglycerides. In 2017, it was the 70th most commonly prescribed medication in the United States with more than eleven million prescriptions.  However, it is not approved for use in children under 18. It is also sometimes prescribed for diabetic retinopathy (eye damage from long term diabetes), and (off label) for gout.

With a 45+ year history of use in Europe and 25+ years in the US, my assumption is that Fenofibrate is a safe and well understood drug.  As with all drugs, it has side effects, some serious.  However, this drug has been in use for a long time, by a lot of people, who typically use it for a long period of time, so it starts out with as good a reputation as you could hope for.  It has no black box warnings, which are the most serious FDA warnings.  To the best of my knowledge, it has no safety controversies (no class action law suits, no exposés on 60 minute, etc). 

The Clinical Trial

Obviously, the women described in this case study has had the onset of her type-1 diabetes delayed for 21 months (and counting), or possibly it has been entirely prevented, as long as she keeps taking Fenofibrate.  So the key question is: how common is this result?  Is this one person a fluke, or is this the result we should expect from treatment with this drug soon after T1D diagnoses?  The only way to answer that question is through a clinical trial.

A phase-I clinical trial has already (as of 16-April-2020) been started.  It is being run by Dr.     Flemming Pociot at the Steno Diabetes Center in Copenhagen, Denmark.  This trial will enroll people between 16 and 46 years old who are within 6 weeks of their first injection of insulin (ie. just diagnosed).  The primary end point is how much natural insulin the person is creating, as measured by C-peptides.  Secondary end points include A1c numbers and insulin use.  Patients will be followed for 2 years.  There are expected to be 10 children and 48 adults in this study.

Discussion

This follow up clinical trial is exactly what I would expect.  It has more than enough people and they will be followed long enough to get a good feel for the treatment.  It's a randomized, controlled, double blind trial, so the highest quality.  This trial is a safe and conservative way to be sure, in three years, if this treatment is worth an even larger study or not. 

Normally, I would be all in favor of a rigorous study like this.  And I am in favor of doing this study, but I also think it is time to be more aggressive.  The results from this single case study are so strong and so unexpected, that I think we should also start a quicker, smaller  trial, so we can get some data in 6 months rather than 3 years.

The bottom line, is that (because of the 3 year duration and the double blinding), we will not know if this works for 3 years.  However, in the case study, the patient stopped using insulin after only 19 days, and that is a huge, good effect that would benefit honeymooners immediately, and would be obvious if it happened even in a smaller trial.

So I hope that another research team does a second study, starting right now, and running at the same time as the slow, careful, high quality study described above.  This second study would be about 20 people, run maybe 3-6 months, and be open label / no control group.  The advantage of this study is speed.  If this study (which I'll call a "pilot study") is as successful as the case study, then it will be plenty big enough and long enough to show an effect.  In this case study, the patient's insulin use stopped at 19 days, so even a 90 day trial (which is short) would have more than enough time to see that effect.

It is important to remember that some people naturally go through a period during their honeymoon where they don't have to inject insulin (called "spontaneous remission"), or who need to inject very little insulin ("spontaneous partial remission").   I have not been able to find a paper that has a specific number of how often it happens, but it is described in the literature.  This period lasts for a few weeks or a few months, so is much shorter than the 19 months seen in this case study.  However, since it is seen, it is important that the pilot study be large enough to make sure we are seeing a result of the treatment, and not this "spontaneous remission".

Furthermore, the drug is inexpensive and safe.  Even if the drug has no effect at all, the danger of taking a common drug for a few months is tiny.  On the other hand, if the drug has a good effect, it is already approved for use, and could start having that good effect for people with honeymoon T1D years before the slower study would complete.

This is a sort of "fail fast" plan which is common in Silicon Valley web startups.  I'm usually not in favor of "fail fast" for medical research because of the impact on safety.  However, in this case, the drug is well known, and the advantage of a quicker result is large (for honeymooners).  Indeed, I would argue that the fast plan is safer, because if it doesn't work, the people will have gotten the drug for a shorter period of time, and if it does work, they can continue with an "off label" prescription knowing that it does work.

And I want to emphasize, that this plan is not extreme.  With the publication of a (very) successful case study, the next obvious step is a pilot or phase-I study.  For T1D, such studies are commonly about 20 people, commonly 3-6 months, and often don't have control groups.  So they are exactly what I am proposing.  The difference here is that the original researchers are running a larger, longer, more complex study: something closer to a phase-II study.

Questions and Answers About The Case Study

Are we sure she had type-1 diabetes?

It is a good question.  Since all our data comes from one person, if her diagnosis is a mistake, then we have nothing.  When she was diagnosed, her A1c was 13.5% and her max blood glucose level was around 540.  When a 19 year old shows up with those numbers, I don't think anyone would fail to diagnose type-1 diabetes.  In addition she had "minor diabetic ketoacidosis", "polydipsia" (drinking a lot) and "polyuria" (peeing a lot), all of which are classic T1D symptoms.  She tested positive for two T1D autoantibodies.  Although none of her 1st or 2nd degree relatives had type-1 diabetes, her mother had a different autoimmune condition.

Are we sure she did not have MODY diabetes?

MODY, also called monogenic diabetes is a group of rare diabetes which are caused by specific genetic defects.  It is not one disease (like "type-1" or "type-2") but a class of related diabetes.  By some estimates, 1% of the people who think they have type-1 diabetes, actually have a form of MODY diabetes.  These people sometimes need insulin to treat their diabetes, but sometimes oral drugs can be used instead, and sometimes no drugs are needed, except in times of stress (such as pregnancy or flu).  The journal article did not discuss any genetic testing for MODY diabetes.

Has this happened before?

There have been a few cases over the years where someone diagnosed with type-1 diabetes went into remission for a long period of time.  None of them involved Fenofibrate.  You can read three examples below:
For me, these show why a clinical trial is needed.  There is always the chance that this remission was just a random happening, and had nothing to do with the Fenofibrate she was taking.

Might This Cure People with Established Type-1 Diabetes?

I think it is premature to discuss this at all.  The case study was someone who starting taking Fenofibrate within days of diagnosis, so was very much a honeymooner.  But in terms of guessing about the future, there is both positive and negative information.  On the positive side, when it was tested on NOD mice, it cured about half of the mice who already had T1D, and that is a hopeful sign.  On the negative side, because this is a widely used drug, I'm sure it's been used by people with long established T1D, and I would think that someone would have noticed if it cured them.  Similarly, it is surely used on many people who have type-2 diabetes (who often have  high cholesterol or high triglycerides), and it's not known to help their blood glucose levels.

Even more on point: there is a long running clinical trial where people with established type-1 diabetes are given Fenofibrate to stop the progression of retinopathy (eye problems).  This study started in 2016, and is expected to run until 2025.  Blood glucose, A1c, and amount of injected insulin are not end points for this study, however, I would expect that if many patients started using much less insulin (and especially stopped taking insulin at all) someone would have noticed.

But, as with honeymooners, the only way to know if Fenofibrate will work on established T1Ds is to test it in a clinical trial specifically designed to look at this result as a primary end point.  Right now, no such clinical trial has been registered.

Why did this person start taking Fenofibrate right after being diagnosed?

Basically, the woman's father saw a paper which showed that Fenofibrate had good results when used on NOD mice in their honeymoon phase, and so she started taking it.  After 19 days she had this wonderful result, and never stopped taking it.  My understanding is that this was done under the Danish version of "off label use".  The family contacted the researchers who had done the NOD mice study and they wrote up this case study.

Can I take Fenofibrate if I have been recently diagnosed with Type-1 Diabetes?

No.  And yes.  (And this is not medical advice!)  Fenofibrate is a prescription medicine, so you cannot just go out and buy it.  However, it is approved for use in the US since 1993 (and longer in Europe), so your doctor can prescribe it for any purpose.  In the US, this is called "off label use".  I am in no way suggesting that anyone should take Fenofibrate.  That is a question that only your medical team can answer.

Is this for real?

I don't usually discuss researchers when I discuss clinical trials.  My opinion has always been that it is the results of the research that matters and not the previous achievements of the researchers.

However, when I report on especially good results from early research, I am often asked "are these guys for real?"  Of course, "for real" means different things for different people.  However, the three authors of this case study are all at the Copenhagen University Hospital in Denmark.  The have published 200+ 25+, and 10+ papers respectively.  One is a full professor, another the chief of endocrinology.  The person running the clinical trial (who is not one of the authors of the case study), has published over 190 papers, and is at the Steno Diabetes Center, which is world famous. 

In short, these researchers are very much "for real" by my standards.  But the real question is, and always will be, will they be successful?  Will the results from this single person case study be replicated in clinical trials?

More Reading

Australian Clinical Trial (for retinopathy): https://clinicaltrials.gov/ct2/show/NCT01320345
Background Material:

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
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.

Monday, May 11, 2020

Possible Cures for Type-1 in the News (May)

Some smaller news items from May.

A Phase-I Trial of DFMO is Fully Enrolled 

Alpha Difluoromethylornithine (DFMO) is approved for two quite different issues.  The first is to remove/prevent facial hair in women, while the second is to treat sleeping sickness.  Neither of these are related to type-1 diabetes.   However, this drug was effective in preventing diabetes in NOD mice (which are predisposed to an autoimmune diabetes, similar to human type-1 diabetes), when given to these mice before they developed T1D.  That is what motivated this trial.

This trial finished enrolling new patients in Oct-2019.  Once a trial is fully enrolled, everyone knows when it will end, or at least when they will finish gathering the required data. So in a very real sense, we can see the end of the tunnel now. This trial will collect data for 6 months, so the data should be collected by April-2020, and (hopefully) will be published soon.  However, with COVID-19, nothing is certain.  My policy is to wait two years for a publication.  In fact, my experience is that successful studies are usually published in less than a year.  So from a practical point of view: if it is not out in a year, it is not likely to be successful.

Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2018/06/alpha-difluoromethylornithine-dfmo.html
Clinical Registration: https://clinicaltrials.gov/ct2/show/NCT02384889


Unsuccessful Results for a Phase-II? Trial of GNbAC1

While this trial was underway, the treatment got a new and improved name.  It is now called Temelimab.  Do not mix this drug up with Teplizumab or Tocilizumab.  All three of these drugs are different.

GNbAC1 is a monoclonal antibody which was developed by GeNeuro SA and has completed phase-II testing for treating Multiple Sclerosis, which (like type-1) is an autoimmune disease. This phase-II? trial finished in May-2019, but unfortunately was not successful.  The key sentence in the results section was this:
Concerning exploratory endpoints, there was no difference in the levels of C‐peptide, insulin use or HbA1c between treatment groups ...
Results: https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.14010
Previous Blogging: https://cureresearch4type1diabetes.blogspot.com/2018/06/gnbac1-starts-phase-ii-trial.html
Clinical Registration: https://clinicaltrials.gov/ct2/show/NCT03179423

Notes on Understanding Research Conclusions

Here is the entire Conclusions section for the results of the GNbAC1 study together with how I interpret them:
Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti‐insulin antibodies) under temelimab were observed. Markers of β‐cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.
Although if read quickly this sounds positive, it is (in fact) reporting on a failure.  So let me break it down into what each sentence actually means:
Temelimab appeared safe in patients with T1D.
Paradoxically, this is bad news when it is the first sentence in the conclusions.  Almost all T1D studies get information on both effectiveness and safety.  Because effectiveness is the more important information, if they lead with safety results, then that means the effectiveness results were not good.  For a successful study, one that gets us closer to a cure, a sentence about safety will be farther back in the conclusion section.
Pharmacodynamics signals (hypoglycaemia and anti‐insulin antibodies) under temelimab were observed. 
These results are not critical for curing T1D, especially when you remember the key result (no difference in C‐peptide, insulin use or HbA1c).  This is just reporting on what tiny crumbs of good news they could find at the bottom of their research data.   "Signals" usually means small (ie. not statistically significant) changes.  It sounds like the patients had slightly fewer low BG episodes and slightly fewer anti-insulin antibodies.
Markers of β‐cell functions were not modified by treatment. 
This is the most important result, because beta cell function means insulin production, but this did not change.  This is what matters in terms of a future cure.
These results need to be further explored in younger patients with T1D with earlier disease onset.
Normally, calls for more research should be ignored, because any research can be followed up with more research.  It is meaningless for a researcher to call for more research, because they always do this.  However, this sentence is more negative than most, because it says that the research should be done on different people than this study, which implies that more studies on these people would not be useful.  And, to make things worse, none of the conclusions suggest that this other group of people would have better results.


Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
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.

Saturday, April 4, 2020

Possible Cures for Type-1 in the News (April)

This posting contains some bits and pieces of interesting news.

A Phase-II Abatacept Trial to Prevent T1D in At-Risk People Finishes Recruiting 

You can read my previous postings on Abatacept here:
https://cureresearch4type1diabetes.blogspot.com/search?q=Abatacept
Abatacept is a treatment that prevents T-cells from becoming activated.  Presumably, for type-1 diabetes, it works by blocking the "bad" killer T-cells from activating.  This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia.

This is a large (212 person) trial started in 2013, and recruited it's final person in February 2020.  Since they plan to collect data from each person for at least a year, this trial is likely to finish in February 2021.  The goal of this trial is to see if Abatacept can be given to people before they are diagnosed with T1D, and prevent or delay the onset of the disease.  The people enrolled in this study have tested positive for two or more autoantibodies, so they are almost certain to be diagnosed with type-1 diabetes sometime in the next 10 years.

History and Discussion

Abatacept has already been tested on people with T1D in their honeymoon period, and the results were that people treated with Abatacept continued to generate about 50% more of their own insulin, than those not treated.   The amount of insulin generated years after diagnosis is pretty small, so the actual difference is half of a tiny number.  One way to view these results was that Abatacept delayed the "end of honeymoon" by 9.5 months.  Someone who got the drug generated the same amount of insulin 36 months after diagnosis as someone who did not get the drug generated 27 months after diagnosis.

So this result is similar to the recently published Teplizumab results, although the Teplizumab results were a little stronger.

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT01773707

Phase-I Clinical Trial of Substance P Is Over Two Years Overdue

Substance P is a peptide (a part of a protein) which is used by several different organs and for several different purposes.   Research done in the early 2000s found that a specific type of neuron (called "TRPV1(+) pancreatic sensory neurons") control islet inflammation and insulin resistance. Removing these neurons from NOD mice prevented diabetes from developing.  Injecting NOD mice with Substance P, which affects these neurons, has increased beta cells in mice, and also lowered inflammation.   This clinical trial tested this same treatment in people, rather than mice.

The trial started in 2016 and was expected to finish in 2017.  The clinical trial record has not been updated since 2016, and I cannot find any published data from this study or the company that sponsored it (Vanilloid Genetics Inc).  Twice I've sent email to the researchers running this study, and I have gotten an "on vacation" email back from one of them, so I know they are still at the University where this research was done, but I have not gotten any other reply.  I have not found any corporate email info for Vanilloid Genetics. 

So therefore, I'm going to remove this study from my list of active studies.  If I ever see positive results, then I'll put it back on.

Clinical Trial Registry:  https://www.clinicaltrials.gov/ct2/show/NCT02820558

PROCHYMAL® (Adult Stem Cells) for the Treatment of Recently Diagnosed T1D

Way back in 2012, I reported on an unsuccessful Phase-II- study of PROCHYMAL (adult stem cells) by a company called Osiris.  However, in March 2020, the clinical trial record for that trial (now completed for 8 years) was updated.  The changes made were all small, and I would describe them as "cosmetic".  I don't know what this means.  If it means anything at all.  But it is unusual for the clinical trial record for a trial completed so long ago to be changed.

Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT00690066


Changing Terminology: At-Risk Instead of Presymptomatic

In the past, I have used the term "presymptomatic" to describe people who have two autoantibodies, but none of the classic signs of type-1 diabetes.  TrialNet has published data over the last few years that shows that just about all of these people will have symptoms of T1D within 10 years.  Therefore many researchers consider that people with two autoantibodies, but no other symptoms, really do have T1D, it is just that they don't have symptoms, yet.  So I used the term presymptomatic to describe the studies being done on these people.

But "presymptomatic" is a mouth full, and it is not a natural sounding word.  Also, people who don't inject insulin and don't count carbs don't think of themselves as having T1D at all.  So therefore, I'm going to start using the term "at-risk" to refer to these people, and the clinical trials that enroll them.  I think it is a more natural English phrase to describe people who are not showing symptoms yet.  


Joshua Levy 

http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com

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.