Combo of Rituximab and Abatacept Starts a Phase-II In Honeymooners (T1D RELAY)

Rituximab is FDA-approved to treat several autoimmune diseases, including Rheumatoid Arthritis (RA).  About 10 years ago there were a couple of clinical trials testing it for T1D, and the results were medium-good. I blogged on those: https://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab

Abatacept is FDA-approved to treat adult Rheumatoid Arthritis, as well as Juvenile Idiopathic Arthritis (JIA) in children as young as six.  I blogged on those: https://cureresearch4type1diabetes.blogspot.com/search/label/Abatacept but not on the most recent results, which are here: https://diabetesjournals.org/care/article/46/5/1005/148547/Abatacept-for-Delay-of-Type-1-Diabetes-Progression and were unsuccessful on the primary end point, but some interesting data on the lessor end points.

Rituximab suppresses CD20 cells, which are a subset of the immune system's B cells (different from the pancreas's beta cells).  Hopefully this will block the autoimmune attack. B cells communicate with the T cells, which actually attack the body's beta cells in the pancreas. By targeting the B cells, it is hoped this treatment will stop or lower the attack of the T cells.

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.  

So you can see how these two drugs can work together to have a stronger effect than either alone.

The Study

This study will enroll 76 honeymooners (within 100 days of diagnosis), between 8 and 45 years old.  Everyone will be treated with Rituximab once a week for 4 weeks.  This is an IV infusion which will take 3-8 hours. There is then a 3 month period without treatment, and then 2/3s of the people will get Abatacept.  That is a weekly injection (much like injecting insulin) which will go for 20 months.  1/3rd of the people will get a placebo and be the control group.  (So everyone gets Rituximab, but not everyone gets Abatacept.)

Everyone will then be followed for a total of 4 years, so 2 years after the last treatment.  The primary end point is C-peptides and secondary endpoints include immune measurements to see how the treatment effects people.

The study started in Oct-2023 and is expected to end between Oct-2027 and Oct-2029.  However, since they are still recruiting, and the study follows people for 4 years, I don't see how it can finish before mid-2028.

They are recruiting in 13 locations in the United States plus Melbourne, Australia.  The full list is in the clinical trial link below or you can get in touch with the study contacts:
Ariana Rojas  +1-813-974-682    ariana.rojas@epi.usf.edu
Melissa Parker  +1-813-396-9378   melissa.parker@epi.usf.edu 

Web Site: https://www.trialnet.org/our-research/newly-diagnosed-t1d/t1d-relay
Clinical Trial Registration: https://www.clinicaltrials.gov/study/NCT03929601

Discussion

This study tries to combine two treatments with lackluster results into something better.  Of course, I have no idea if it will work, but if it does, that is good news in two different ways.  First, as a promising honeymoon treatment to delay or even prevent T1D, that is the direct goal of this trial.  But second, many researchers believe that two different immune drugs (with two different mechanisms) might be a lot better than one immune drug alone.  They may interact synergistically.  A success here would show that two drugs together could be much more than either one alone, and that could open the flood doors of combination drug trials.

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 kid has type-1 diabetes and has participated 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!

 

Possible Cures for Type-1 in the News (mid January)

Data from 2 Year Follow up of Rituximab (anti-CD20)

Rituximab works by suppressing a specific cell in the immune system, which is involved in communicating and organizing the body's autoimmune attack.  (Specifically: it suppresses B-cells with the CD20 marker, which is why it is refered to as an "anti-CD20".  Immune B-cells have nothing to do with pancreatic beta cells, except a similar name.)

My previous blogging on this trial is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab

Here are the most important parts of their results, from my point of view:

The rate of decline of C-peptide was parallel between groups [treated and untreated], but shifted by 8.2 months in Rituximab treated subjects.

In recent-onset T1DM, Rituximab delays the fall in C-peptide, but does not appear to fundamentally alter the underlying pathophysiology of the disease.

Discussion

From a cure point of view, this is not a great result, and is similar to several other immune drugs, which tend to delay/extend the honeymoon period.  Years ago, I was hopeful that by combining these drugs or maybe by tweaking doses, that we could turn results like these into a cure. However, I'm less optimistic about this now.  Mostly because I have not seen any research into combinations, or any clinical trials that are trying larger, more frequent doses, or anything else that might squeeze better results out of the drugs that are giving these small results.

Abstract: http://care.diabetesjournals.org/content/early/2013/09/05/dc13-0626.abstract.html?papetoc

Vitamin-D Not Associated with Type-1 Diagnosis

Previous studies done on Vitamin-D being associated with type-1 diabetes has been mixed. Some studies show a correlation between low Vitamin-D and type-1, while other studies do not. This study comes down on the side of "no association".

Here is the title of the paper, which makes a good summary, as well:

No Difference in Vitamin D Levels Between Children Newly Diagnosed With Type 1 Diabetes and Their Healthy Siblings: A 13-Year Nationwide Danish Study

Abstract: http://care.diabetesjournals.org/content/36/9/e157.extract.html?etoc
Full text: http://care.diabetesjournals.org/content/36/9/e157.full

Previous blogging on Vitamin-D is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Vitamin%20D


Teplizumab Commentary

I have previously blogged on Teplizumab, and the following link goes to some commentary on the results that I blogged about in September: http://diabetes.diabetesjournals.org/content/62/11/3656.full

Here is some more commentary on Teplizumab, including some interesting notes on type-1 diabetes in India.  As you read, remember that the author is assoicated with the company that produces Diamyd, which is a direct competitor to Teplizumab:
http://diabetes.diabetesjournals.org/content/62/11/3669.full

Factoid: In One Study 1/3 of Type-1s Had Some Retinopathy After 20 Years

In the study below, the researchers were trying to predict which people with type-1 diabetes would have retinopathy (eye-damage) and which would not.  But to me, the more important information was the overall number.  One third of the people who were followed for 20 years, had some level of retinopathy.  For me, that was a surprisingly high number.  But maybe I just wasn't paying attention.  I actually think that the real number might be much higher, because this study required that the patients go to the same doctor for all 20 years, and that they have A1C numbers from that entire time, so that is a very stable group of people.  It may well be that people who visit multiple doctors over the course of 20 years (which is to say, most people) have a higher level of retinopathy.

Abstract: http://care.diabetesjournals.org/content/36/11/3812.abstract?etoc.

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, JDCA, or Tidepool 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.

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

I feel like I'm about two month behind, but this will get me closer to current news.

Kamada Reports Early Results from A Phase-I Trial

News: http://www.globes.co.il/serveen/globes/docview.asp?did=1000799026&fid=1725
Press Release: http://www.kamada.com/press_item.php?ID=29
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01304537

I struggled quite a while with their press release, but in the end, this is my summary:

Kamada releases results from their phase-I trial, which they describe as "positive". However the data in the press release is too vague for me to come to any conclusion about weather their drug worked. I'm looking forward to a complete, peer reviewed paper.

Kamada manufactures Alpha-1 Antitrypsin (AAT).   You can read more about it here:

http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html

and my previous blogging here:

http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

AAT is an anti-inflammatory chemical which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person doesn't make enough of it on their own.

These are the first results from the first phase-I clinical trial completed.  Unfortunately, there was no control group for this trial, so there is no way to compare people who got AAT with people who did not. The company's press release said that "almost all patients reached glycemic control below 7.5%" and that "the majority of the patients maintained levels of C peptide higher than ... 0.2 pmol/mL".

None of that is bad news, but this trial was for honeymooners (within 6 months of diagnosis).  So none of those results sound particularly stellar to me.  This is where a control group would be particularly helpful, because we could have seen a difference between the two groups, if there was one.  Because people with type-1 diabetes naturally vary a lot during their honeymoon, it is at this time that control groups are most important.  

I've asked the company when the full results will be published, and those might be much more interesting.  At the very least we should be able to see how the C-peptide numbers change over the  study.  That can be compared to the "normal" drop during the honeymoon phase.  My general feeling is that if this data is all the data they publish, then the trial was a failure.  They need to publish more data, especially C-peptide changes to show success.

Discussion

This study is important for a couple of reasons.  First, because of the number of AAT clinical trials. I know of a five AAT clinical trials aimed at type-1 diabetes going on now.  That's a lot; more than any other single drug.  So having mediocre results from the first study completed is not welcome news for any of the others.  Second, because of it's impact on the inflammation theory of type-1 diabetes.  This theory holds that inflammation destroys the beta cells in the pancreas.  The autoimmune reaction triggers inflammation, but does not directly destroy the beta cells.  This theory has never been the majority viewpoint (most researchers think that inflammation is a side effect of the destruction of beta cells, rather than a cause) but it is an active minority opinion.  Since AAT is an anti-inflammation drug, it is one of the first drugs to test this theory.  Since AAT does not appear to have a strong effect, that suggests that the whole inflammation theory might be wrong as well.  That would be unfortunate, since stopping inflammation is a lot easier than stopping the auto-immune attack!  Because there are lots of anti-inflammatories out there, there would have been lots of potential drugs to prevent type-1, if this theory panned out.

It is interesting to me, that even though this study did not have a placebo group (an untreated group), they did have three different levels of treatment.  Some people got 40mg of AAT, some people 60mg, and some people 80mg.  The press release did not include any difference in results between these groups.  That's a little ominous for me.  For a drug that is effective, I would expect one dose to be the most effective; others less so.  On the other hand, if the drug has no effect, then all the groups would be the same, and in this case, no differences were reported.

LCT Updates

Background: LCT is developing an encapsulated pig beta cell cure for type-1 diabetes.
The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunsuppression drugs (as you would for a normal beta cell transplantation).

When last we left LCT, they were finishing a small phase-II trial in New Zealand, and starting a small phase-II trial in Argentina.  Links to press releases for the results and the follow on trial are below:
http://www.lctglobal.com/html/blob.php/121122%20LCT%20-%20Strong%20interim%20results%20in%20Argentinian%20%20DIABECELL%20trial.pdf?attach=0&documentCode=4774&elementId=20084
http://www.lctglobal.com/html/blob.php/121122%20LCT%20starts%20DIABECELL%20Phase%20IIb%20trial%20in%20Argentina.pdf?attach=0&documentCode=4775&elementId=20084

The Argentinian Trial

All the patients got two rounds of implanted islet cells, 12 weeks apart.  Half the patients got a base level, and the other half got twice this level.  The patients who got more islets had better results, which were:

• average insulin dose reduced by 20%
• a reduction of HbA1c from a pre-transplant average of 8.6% to an average of 6.7% at 12 weeks following the second implant
• up to 70% reduction in unaware hypoglycaemic events.

Obviously, this isn't a cure in it's current form (but see below for follow on products).  This study involved a total of 8 people, and so an obvious thing to do is to expand it, and the expansion was also announced.  LCT will implant an additional 20 people, all at the higher dose level.  For me the most interesting information in their press release is this:

“We are using an ‘adaptive trial design’ for our pivotal studies and so the data generated in this 20 patient trial will likely form the foundation data for our registration package,” said Dr Andrea Grant, Chief Executive, LCT. “We remain on track to meet our goal of completing clinical trials of DIABECELL by 2015 and having a product commercially available by 2016.”

I'm not an expert in this area, but I would be surprised if they could register a new medical implant for use in the US based on data from one study of 20 people (and their previous studies which contain about 24 people all together).  Especially with no clinical trials actually done in the US.  I assume that commercial availability will be in one or more of the countries where they have done research: New Zealand, Argentina, etc.

If you want even more information, you can read their CEO presentation, also done in November 2012, here:
http://www.lctglobal.com/html/blob.php/LCT%20AGM%20CEO%20Presentation%20Nov%202012.pdf?attach=0&documentCode=4762&elementId=20084

Which includes a slide "DIABECELL -- The path to patients" which lists four studies:
      A New Zealand phase II study [8 people]
      An Argentinian phase-II study [8 people]
      An Argentinian phase-II/III study [20 people, discussed above]
      A New Zealand and/or German Phase-III study [unknown size, not discussed above]
That forth study would make more sense to me, although I'm still not sure that this would get them approved in the US.  For comparison, the recent anti-CD3 drug approval attempts used two 300 person studies, one of which was done in the US.  And the pivotal DiaPep277 studies on-going right now are the same: two studies of 300 people each.  Maybe implants require less, but that much less?

No News from Russia

I'm also a little mystified because LCT had previously announced that their product had already been approved for sale in Russia:
http://cureresearch4type1diabetes.blogspot.com/2010/12/lct-gets-commercial-approval-in-russia.html
However, since then I can not find any reference to anyone selling it in Russia, or LCT getting any revenues from such sales. (But I don't speak Russian so can't search effectively in that language. If there are any Russian speakers out there, who would like to do some searches, please look for "LCT Biomedical Limited" (the company name) and/or "Natalia Dolgova" (the first company director) and tell me if they are selling anything in Russia.  If you find the web pages, I can Google Translate them.  But so far, I haven't even found them.)

LCT General Update

It is very rare for any executive at a medical company to make predictions about the future.  There are all kinds of rules about what they can and can not say.  So I was quite surprised (and happy!) to see these public posts from "elliott" in a posting on www.islet.org.  Dr. Bob Elliott is a founder of LCT.

Multi-centre Phase 3 studies will comemnce Q1 2013 and be completes by Q1 2015.
Registration based on a successful outcome will take anything up to a year, so we anticipate the LCT product will be marketed by Q1 2016 ie three years from now.
It will not cure diabetes, but is likely to be a valuable way of treating unstable diabetes.
'Fast follower' products will start to be tested clinically in 2014.

'Fast Follower' refers to the next generation of products. We are always seeking ways to improve the product but each improvement as seen in preclinicla studies in animals has to be tested in humans.   I have not give up on the idea of complete insulin independence, and we are making steady progress.

'Unstable' diabetes is the indication we are working on in the trials. But of course all Type 1 diabetics have unstable blood glucose control to a greater or lesser degree, so it really becomes a matter of how bad things are. 

He also said that they have improved the product since the peer-reviewed results were published in 2007, with the implication that they expect better results in the future then they reported in 2007.

Note that his statement that "Registration ... will take anything up to a year" might be true in some countries, but my belief is that in the US, marketing approval (our version of commercial registration) takes 1 to 2 years, especially if measured from the end of a phase-III trial.  I would not be surprised if other countries where LCT operates have faster registration processes.

Finally, I want to say that although LCT describes this 20 person Argentinian trial as "Pivotal" and "Phase-III", I will continue to refer to it as phase-II because of it's size. To be honest, I've seen phase-I trials with more than 20 people enrolled, so I think calling it a phase-II is proper.  Now if LCT gets approval in the US based on a 20 person trial, then I might change my standards. :-)

LCT's web page is http://www.lctglobal.com

Rituxan Safety in Rheumatoid Arthritis

Rituxan (also known as Rituximab or MabThera) is a monoclonal antibody which is being tested as a possible cure, or part of a cure, for type-1 diabetes.  My previous blogging is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab
Monoclonal antibodies are a relatively new technology for developing drugs (only about 20 years old), but already about half of new drug approvals are monoclonal antibodies.  However, some people have expressed worries that, as a class, monoclonal antibodies are unsafe, or their safety profile is unknown or suspect.

This study is a big step towards putting those fears to rest. Since Rituximab is already approved for rheumatoid arthritis, these researchers followed people who used it for that purpose for many years.  The basic result was that people on the drug had a lower disease rate than similar people not on the drug:

The rate of serious infectious events for the 1,145 patients on Rituximab for more than 5 years was 2.76 per 100-person-years, and the rate for the 818 placebo patients in the studies was 3.6 per 100-patient years, they said.

"No new safety signals were observed with increasing duration of exposure including in patients with more than 5 years of follow-up."

"the rates of myocardial infarction [type of heart attack] (0.40 per 100 patient-years) and malignancies were consistent with those observed in epidemiological data from other RA cohorts (0.48 to 0.59 per 100-patient years for MI)."

News: http://www.medpagetoday.com/MeetingCoverage/ACR/35895

Note that many monoclonal antibodies have names that end in mab.  So if you see a drug named Joshuamab or Curecommoncoldmab or anything ending with mab, it is likely to be a monoclonal antibody.

Rituxan as an Injectable Drug

Currently, Rituxan must be given intravenously, rather than being injected under the skin, like insulin.  The difference is important, because intravenous administration usually requires a "medical setting" (like a hospital or clinic, or at least trained medical staff).  While we all know that under skin injections are commonly done everywhere and by anyone, with a little training.

Recently Roche announced publication of two studies showing that they had a formulation of Rituxan which could be injected and was "not inferior" to the intravenous formulation already approved.  Since "not inferior" is the FDA's requirement for approval in situations like this, that's good news.  Even better news is that the basic technology that they used to convert a previously intravenous formulation into an injectable formulation can be applied to other drugs as well.  So with luck, they will be able to make lots of drugs easier to administer.

Press release: http://www.roche.com/med-cor-2012-12-08b.htm

Update from Scott King on Islet Sheet Project

An Islet Sheet is a specific beta cell encapsulation technique, similar to what LCT is trying to do.  Because Islet Sheets have not yet started human trials, I don't follow this research very closely.  However, I know others are very interested in it, and Scott King posted an update on his blog, which you can read here:
http://www.hanumanmedicalfoundation.org/blog/2012/11/26/signal-breakthrough-islet-sheets-thrive-in-pig/

They are hoping for more animal trials in 2013.  King is a very insightful guy and previous blog postings are interesting as well.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

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

More News on Rituximab

Background on the drug: Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's beta cells in the pancreas. By targeting the B cells, it is hoped this treatment will stop or lower the attack of the T cells. Rituximab showed some effectiveness in preserving the beta cell function of honeymoon type-1 diabetes in a phase-II trial, and there is a second trial underway. Rituximab is a monoclonal antibody, a product of Genetech (now a division of Roche), and already approved by the US FDA for rheumatoid arthritis and several cancers (and used off label for several other diseases).

Background on antibodies: Type-1 diabetes is triggered when the body's own immune system attacks it's own beta cells in the pancreas, which create insulin. Autoantibodies are part of the process of this self-attack. In type-1 diabetes four different types of autoantibodies have been measured: GAD, Insulin, IA2, and ZnT8. There might be a few more autoantibodies that we don't yet know about. People with type-1 diabetes usually have one or more autoantibodies in their system, and this starts before they are diagnosed. I think that GAD is the most common, and IAA is second, but I'm not up on the details.

For this study, 49 patients where given four doses of Rituximab, while 29 got the placebo.  For all patients, measurements were made for each different type of autoantibody.  What they found was that  Rituximab was very good at lowering IAA autoantibodies, but much less effective on the other three known types of autoantibodies.  This was the biggest finding:

A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients.

So that means that Rituximab was highly selective as to what antibodies it shut down. This is a very interesting finding, at least for me.  In terms of impact on patients, we need to see the C-peptide numbers, which were not in the abstract.

Next Steps?

In light of these results, one obvious clinical trial to run would be to treat honeymoon type-1 diabetics, who only have autoantibodies to IAA, with Rituximab, and see what happens.  The results above imply that over a third of these patients would end up having no autoantibodies remaining, and it would be very interesting to see what happens to these patients.  What effect will it have on their insulin production?  Will they still have type-1 diabetes?  Will their pancreases regrow?  If so, how quickly?  These are critical questions.

Another interesting clinical trial to run would involve patients that did not have type-1 diabetes, but were being tracked by TrialNet's Natural History Study, and are known to only have IAA autoantibodies.  Basically, does treating these specific people with Rituximab delay or reduce the onset of type-1 diabetes?

And finally, there is a potential study for established type-1 diabetics who only have IAA antibodies.  Would giving them this drug have good effects?

I have no idea if any studies like these are feasible, or are being planned, but I hope so!

Abstract: http://diabetes.diabetesjournals.org/content/early/2011/08/05/db11-0674.abstract
News article: http://www.doctorslounge.com/index.php/news/pb/22439
Wikipedia: http://en.wikipedia.org/wiki/Rituximab
More on Autoantibodies: http://www.msdlatinamerica.com/diabetes/sid683880.html


News about News on DiaPep277

DiaPep277 is the longest running phase-III study aimed at curing type-1 diabetes.  It is a honeymoon only treatment. Results from the phase-II study were (in my opinion) "mixed".  (I know that doesn't sound very definitive and I really should go back and review their phase-II results in more depth, but I haven't had time.)  My most detailed discussion of their phase-II results is here, but it's not much:
http://cureresearch4type1diabetes.blogspot.com/2009/11/possible-cures-for-type-1-in-news-nov.html
and all of my blogging on DiaPep277 (hsp60) is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/DiaPep%20277

The following quote is from a news article on them, and is the most recent news I have heard about when they might have some phase-III results.  The key news is that the study should be done late this year, which is not very far away.  With a little luck, we'll see results in 2012.

In the first Phase III studies being conducted at 40 medical centers in Europe, South Africa and Israel, diabetes patients aged 16 to 45 have been receiving DiaPep277 injections once every three months. The study began in 2005 and is ending late this year.

They have a second phase-III study already underway, and expected to finish in 2014.  (Remember, you need two in order to get FDA or EU approval.)

News coverage: http://www.shalomlife.com/health/15810/promising-treatment-for-diabetes/

Rilonacept is Recruiting for a Phase-I Trial

I know there is a lot of frustration about  studies that are targeted at "honeymoon" diabetics.  And it is certainly true that most current trials are aimed at honeymooners.  However, "most" does not mean "all".  Dr. White is running a study on Rilonacept that is open to people within 5 years of diagnosis.  Also, this study has no placebo group, so if you are in the study, you know you are getting the treatment.

I have previously blogged on this clinical trial, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Rilonacept

This drug is already approved in the US under the trade name "Arcalyst", but not for type-1 diabetes.  In addition to this approval, it is currently being used in about 12 other clinical trials for a variety of inflammation related diseases.  Dr. White has told me (via email) that there have been "no untoward effects thus far".  The trial is being run in Dallas, Texas.  Contact information is in my previous blogging (link above).

Trial web site: http://www.childrens.com/specialties/endocrinology/rilonacept-study/
Clinical Trial Site: http://www.clinicaltrials.gov/ct2/show/NCT00962026

Some Background Reading

Below is a link to a short interview with Dr. Arthur Caplan, a bioethicist at University of Pennsylvania, which makes for some interesting reading.  It is about the ethics of overseas medical research.  Something that we are seeing a lot of in type-1 diabetes research.  Dr. Caplan is an interesting guy and a good speaker.  UPenn is my alma mater:
http://www.pbs.org/newshour/rundown/2011/08/sending-us-drug-research-overseas.html

The following Wikipedia article covers accuracy of home glucose monitors.  Many people are shocked to learn that they are only accurate to within 20%.  So you might get 310, 340, or even 360 at the same time: http://en.wikipedia.org/wiki/Clarke_Error_Grid
Thanks to swellman at CWD for pointing this out to me and many others.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

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

Exsulin's Phase-II Trial is Data Complete 

The exact update I got on the Exsulin phase-II trial is this: "We have finished recruitment for this trial. We are still in the process of finalizing the results".  I interpret this to mean, not only have the finished recruting all their patients, but they have all their data, and are now working on the data analysis / paper writing part of the research.  This is great news, because I'm hopeful that we will hear the results in a few months.

Rituximab Starts another Phase-II Trial

Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's beta cells in the pancreas. By targeting the B cells, it is hoped this treatment will stop or lower the attack of the T cells.

Comment: Most treatments aimed at stopping the autoimmune attack are very focused on stopping the "bad" T cells which directly attack the beta cells in the pancreas. This treatment (if successful) opens up a whole 'nother way to stop the attack: by targeting the immune systems communication and support system, the B cells.

The current research (which I consider phase-II, although the researchers list it as phase-IV) is very similar to the a previous trial which I blogged on before (link below).  The current trial has already started enrolling 50 people at First Affiliated Hospital, Nanjing Medical University (Nanjing, Jiangsu, China). If you are interested in enrolling, contact Tao Yang, PhD at phone 86-25-83718836 ext 6466 or email yangt@njmu.edu.cn.  There is no placebo group in this trial: everyone is treated.  They started in July 2010, and hope to complete it by December 2013.  This is for people with type-1 diabetes for less than one year.

clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01280682

A Sad Note to the Previous CD20 Research
The previous Rituximab research was led by Dr. Mark Pescovitz who died in a car crash at the end of last year.  That work was published by the prestigious New England Journal of Medicine, and was just one part of a distinguished research career.
http://www.boingboing.net/2010/12/13/mark-pescovitz-1955-.html
http://www.jdrf.org/index.cfm?page_id=114825

My previous blogging on Rituximab is here: http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab

Sitagliptin Completes Enrollment on a Phase-II Trail (as a Treatment)

This is a large (140 person) trial which started in late 2010 and is the follow on to a trial which I've blogged about before.  The goal of this is to lower A1Cs for type-1 diabetics by about 0.3, by lowering BG levels more quickly after a mean than is done now.  The 0.3 number is pretty close to what they did in an earlier, smaller trial. Sitagliptin is already approved for type-2 diabetes.  It's trade name is Januvia.

They completed enrollment in February 2011, I think.  The record is not 100% clear, and it might have been earlier.  If they did complete enrollment in February, then they will finish collecting data about June.  The clinical record says the trial will complete in July 2011, so I think it is reasonable to see results by the end of this year for this research.  This same group published their previous results very quickly after the study was done.

Clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01227460
Previous trial: http://www.clinicaltrials.gov/ct2/show/NCT00978796
Results from related trial: http://cureresearch4type1diabetes.blogspot.com/2011/02/possible-cures-for-type-1-in-news-late.html (but this was combining this drug with another)

Extra Reading

Dr. Skyler has written a wonderful summary of some of the more interesting clinical trials in type-1 diabetes done between June 2009 and July 2010:
http://onlinelibrary.wiley.com/doi/10.1111/j.1742-1241.2010.02580.x/full
One of the things I particularly liked about this paper, is that for each clinical trial, there is a summary of the abstract and then Dr. Skyler's comments.  These comments often put the research into context, discuss next steps, or give his opinions on it.  That perspective is missing from the raw scientific papers.  (Although he wrote this before the two anti-CD3 treatments had failed in phase-III trials, so those are discussed here, although they are already dead as cures.)

Here is part of his summary of the whole year:

That negative studies continue to dominate the field, and that the positive ones still show decline in β-cell function over time, has led to more calls for combination approaches. When I [Dr. Skyler] have advanced such prospects at meetings of paediatric diabetologists, I hear groans. Yet when I have advanced these prospects at meetings of immunologists and transplant surgeons, I hear cheers.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

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

Canakinumab Completes Enrollment
Canakinumab is a monoclonal antibody, which is designed to lower inflammation.  It targets IL-1β (interleukin-1 beta) which causes inflammation.  The drug was approved in 2009 (both US FDA and EU EMEA) for a collection of rare autoimmune based inflammatory diseases.  (And type-1 is an autoimmune disease which causes inflammation, but it is not clear how important the inflammation is to the symptoms of the disease.)  Good results have been seen in people with type-2 diabetes, and it has been used in children as young as 3.

They have completed enrollment of their phase-II clinical trial (66 people) as of March 2011. Because this drug is already FDA approved, there was not a phase-I trial in people with type-1 diabetes.  So the results from this trial will be the first type-1 results that we see.

Why is completing enrollment important? For two reasons.  First, because it is now possible to predict when they will finish collecting data.  This study runs for 2-4 years, so they should have data collected by March 2015 at the absolute latest, and might have some early data by March 2013.  Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants.  It is often unclear how hard it will be to recruit people, and long it will take.   But that this point, all that uncertainty is behind the researchers.  From now on, it is just gather data, then analyze data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT00947427
Wikipedia entry: http://en.wikipedia.org/wiki/Canakinumab

Xoma 052 Fails (Mostly) in Phase-II for Type-2

Xoma 052 is a monoclonal antibody which is a broad anti-inflammatory, and works by blocking the IL-1 inflammation pathway.  The news is that Xoma announced that their Xoma 52 phase-II trial for type-2 diabetes had missed it's primary end point (which was better BG control).  They are still hopeful that it will lower bad cholesterol and be marketable for that purpose.  But that's a big come-down: they were hoping to lower BGs which is a big, sweeping treatment for type-2, but now they are hoping to help one particular symptom.  Plus, there are already other drugs that lower bad cholesterol.

Why is this important? Xoma is also testing this drug on type-1 diabetics.  That trial is ongoing and results are not expected until around October 2011.  But obviously, this is not good news.  However, since the mechanisms behind type-1 and type-2 are very different, we really need to wait and see what happens in their type-1 clinical trial.

Reminder About The Blog
This blog generally only covers research results.   Occasionally related topics are discussed.   However, I generally don't discuss funding issues, stock issues, new hires (such as presidents, new board of director members, etc.)  patient issues, mergers and acquisitions ("M&A"), director or C-level resignations, etc.  These are all news worthy, but they are not the kind of news that I cover here.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Possible Cures for Type-1 in the News (late Nov)

Here are various news items on possible cures for type-1 diabetes which are in human trials, and related items:

Diamyd Completes Enrollment of their Second Phase-III Trial

Since this study follows people for about 15 months, it is very reasonable to expect that it will complete in mid 2012.  Since this is the second phase-III trial, if successful, market approval might come in 2013 or 2014.  Diamyd is a vaccine like treatment designed to teach the body's own immune system to stop attacking it's own beta cells.  The company's description is this: "Diamyd® is thought to induce tolerance to GAD, thereby intervening in the autoimmune attack and preserving the capacity to produce insulin in patients with autoimmune diabetes".  Remember, the phase-III trials are only in honeymoon diabetics.

Press release: http://www.marketwatch.com/story/diamyd-medical-diamyd-completes-screening-for-us-phase-iii-study-2010-11-10?reflink=MW_news_stmp

Leptin Starts a Phase-I Clinical Trial, but as Treatment, not Cure

I have blogged in the past about Leptin:
http://cureresearch4type1diabetes.blogspot.com/2010/04/possible-cures-for-type-1-in-news-april.html
http://cureresearch4type1diabetes.blogspot.com/2008/09/discussion-of-recent-press-reports-of.html

And here is the press release for the new news:
http://www.prnewswire.com/news-releases/juvenile-diabetes-research-foundation-and-amylin-pharmaceuticals-partner-to-investigate-metreleptin-as-potential-therapy-to-improve-blood-glucose-control-in-type-1-diabetes-108399354.html

Back in 2008 Leptin was presented (in the news, at least) as a possible cure, but by April 2010 it was presented as a possible new treatment.  This most recent news makes it clear that it is a possible treatment for type-1 diabetes, not a cure.  I don't expect to cover this research moving forward.  Remember that even as a treatment, it takes 10 years to move through the regulatory process and get approved.

Single case of Putting Type-1 into Remission for One Year
This is a single patient report (not a research study).  The patient had two diseases: ITS and type-1 diabetes.  To treat ITS, she was given Rituximab about 15 months after being diagnosed with type-1.  The result was that her type-1 diabetes went into remission for 11 months.  (No need for external insulin during that time).   This is reported here:  http://care.diabetesjournals.org/content/33/9/e122.full

Obviously, this is interesting.  Especially since there has already completed a phase-II study on type-1 diabetics, and got good results there, too.  (Although I'm embarrassed to say that I've not blogged on the specific results of that study.)

Rituximab targets the CD20 part of the immune system's B cells (different from the pancreas's beta cells) to try to prevent the autoimmune attack. B cells are part of the body's immune system and communicate with the T cells, which actually attack the body's  beta cells in the pancreas.  By targeting the B cells, it is hoped this treatment will stop or lower the attack of the "bad" T cells.

Comment: Most treatments aimed at stopping the autoimmune attack are very focused on stopping the "bad" T cells which directly attack the beta cells in the pancreas.  This treatment (if successful) opens up a whole 'nother way to stop the attack: by targeting the immune systems communication and support system, the B cells.

I have previously blogged on Rituximab here:
http://cureresearch4type1diabetes.blogspot.com/2009/07/update-on-pescovitzs-rituximab-phase-ii.html
And reported status here:
http://joshualevy.pbworks.com/w/page/13864073/DiabetesCureReadyForHumanTrials#RituximabbyPescovitzatIndiana

Cautionary Note: Possibly Faked Phased Clinical Trial Data
This news article made me very nervous; the impact could be to many other clinical trials. 
Here is the article:  http://www.russia-ic.com/education_science/science/science_overview/1202/

The basic summary is this:  MannKind is developing an inhaled insulin doing several clinical trials in foreign countries, using contract clinical trial companies.  (These are companies that specialize in just doing clinical trials for other companies.  They don't develop drugs.  They do testing of other company's new drugs.)  A MannKind employee claims that some of the data reported by the contract clinical trial company in Russia is obviously false.  All patients had the exact same blood pressure.   Since FDA relies on these studies to do approvals, this is a big deal.  This one case impacts MannKind, but the general problem could effect others treatments as well.  Did that contract clinical trial company do other trials for other drugs?  Is the problem limited to one company, or does Russia have systematic problems that put all Russian clinical trials at risk?  You get the picture: it's bad.

Omission from Previous Blog Entry
In my last blog (comparing Burt's treatment with LCT's) I did not include the fact that LCT's clinical trials were all people with established type-1 diabetes, while Burt's were all honeymooners (people with recent onset type-1 diabetes).  This is a serious omission.  Working on established type-1 diabetes is a huge advantage over honeymoon type-1 diabetics, and that is a strong point in LCT's favor that was not included in the comparison.  I'm sorry for this omission.
 

General Background Information

All "Animal Models" are not Equal
This is an interesting blog entry about "animal models" used to test type-1 cures:
http://www.solvingdiabetes.org/2010/10/24/animal-models-of-autoimmune-diabetes/

General Background for Understanding Type-1 Research
This article describes the immune system in general, what is meant by "honeymoon" and other useful words and ideas, but the Teplizumab clinical trial it talks about has since been stopped.  Also the phase-I/phase-II/phase-III description is for new drugs or treatment.  Already approved drugs or treatments can follow a slightly different path.
http://www.jdrftalk.org/2010/09/28/diabetes-and-autoimmunity/

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Update on Pescovitz's Rituximab Phase-II trial

Pescovitz (and team from TrialNet) have finished a phase-II human trial of Rituximab, and the results have been accepted for publication at a big-name scientific journal. Unfortunately, that journal has embargoed the result data until publication, so I don't actually know the details of how well it worked. The good news, is that the study's authors did an oral presentation at ADA 2009, and (I'm told) that the results were good, but not as good as with the anti-CD3 monoclonal antibody drugs from Macrogenics or ToleRx. Those drugs preserved beta cell functionality for at least a year after treatment. Basically, untreated people lost half their ability to produce insulin in the year after onset of type-1 diabetes, but treated people retained about 95% of their ability. Rituximab was not as successful as that, but did preserve some insulin production.

Rituximab is a monoclonal antibody, a product of Genetech (now a division of Roche), and already approved by the US FDA for rheumatoid arthritis and several cancers. You can read more about it here:
http://en.wikipedia.org/wiki/Rituximab

It works by attacking B cells that have the CD20 marker. These B cells are part of the immune system and completely different that the beta cells (sometimes called B cells) in the pancreas. The immune system has many different types of both B cells and T cells. Most drugs currently being tested to cure type-1 diabetes target T cells. (For example: MacroGenics, ToleRx, Diamyd, Faustman, ATG, Abatacept, etc.) Rituximab is targeting a completely different type of cell (B rather than T). It is thought to work because B cells may interact with T cells influencing their targeting to attack beta cells. So this study is interesting, both because the results are good, but also because it potentially opens up a whole new area to understand as part of the cause of type-1 diabetes, and that means a whole new area where a cure or treatment might be found.

A follow on trial of Rituximab is currently being designed. It will probably involve repeated dosing of the drug. Obviously, I'll post when that clinical trial starts.

Discussion (Why many different treatments might be more effective.)

Right now, we have at least 5 drugs in phase-II or III human trials that, when given during the honeymoon phase, result in the patient loosing only half as much insulin production capacity, as if they were not given the drug. These include Rituximab, Diamyd's GAD65, several different anti-CD3s, and (maybe) Alpha Interferon. There are three ways of looking at these results:

The pessimist: "I don't want five half-way cures. I want one actual cure. Come back when you have something that works."

The engineer: "If it works half way now, then maybe we can improve it a little so it is three quarters working in a year or two, and 90% working a year or two after that and...."

The optimist: "Maybe we don't need a single cure. Maybe the proper combination of the many half cures we have will work right now, or will work for some people."

So if you're an optimist, then having several different treatments for type-1 diabetes which each target a different part of the autoimmune attack, is a good thing. We're used to thinking of a cure as being one pill or one operation or one something. In fact, for many of the more complex diseases (such as cancers, etc.), it is a cocktail of drugs which work together to have the best effect. And type-1 diabetes is surely a complex disease!

Of course "drug cocktails" are harder to test and harder to get approval for, and generally slower to market. In the past there has been discussion of pairing something that stops the autoimmune attack with something that regrows beta cells. That is one type of "drug cocktail", but it also may be that the thing that stops the autoimmune attack with the fewest side effects is itself a mixture of several drugs which target different parts of the autoimmune response.

Thanks to Dr. Gitelman for insightful discussions of this research. All mistakes here are my own.

Clinical Trial Record for the Rituximab trial is here:
http://www.clinicaltrials.gov/ct2/show/NCT00279305

Joshua Levy