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 (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.

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

DiaVacs Starts a Phase-II Trial of Dendritic Cells (DV-0100)

DiaVacs is a newly created company with a goal of further developing the Dendritic Cell research done in Dr. Trucco's lab.  You can read my previous blog posting on this research here:
http://cureresearch4type1diabetes.blogspot.com/2011/11/results-from-truccos-phase-i-dendritic.html

The idea behind this research is to remove dendritic cells from a person, grow them out, and then put them back in.  The hope is that they will then regulate the immune system and cut down on the autoimmune attack.  Dendritic cells are part of the immune system which find foreign cells and "present" them to T-cells (another part of the immune system) so that they know what to attack.  You can read more about them here: http://en.wikipedia.org/wiki/Dendritic_cells  The goal of this therapy is to interrupt the immune system's internal communications so as to stop the immune attack on beta cells, without stopping immune attack on foreign cells.

The goal is to enroll 90 people, eventually.  The first 10 will need to be adults, and then the hope is that the safety record from those first patients will be used to get the FDA to approve children.  Since this is a honeymoon trial (within 6 months of diagnosis), limiting recruiting to adults will slow everything down, but the FDA will not approve a trial on children without some safety data from adults, if they can possibly avoid it.

Treatment is expected to last 3 months, and then patients will be followed for another year. Primary goal is safety, secondary goal is C-peptide production (as a stand-in for insulin production) 12 months after treatment.  C-peptides are measured because they are created naturally when insulin is generated by the body.  So they are a measure of natural insulin production.  Insulin measurements can't be used, because there is no way to tell if the insulin was injected or created naturally.  So all modern research measures C-peptide to determine insulin production.

A Little Discussion

When I heard this group was doing a phase-II trial, I was a little surprised.  If you look at my summary of their phase-I trial, I did not see a clear success in their Phase-I results.  There were some results that the researchers viewed positively, but there was no improvement to insulin generation (for example).  However, that first study was done on established type-1 diabetics.  My understanding is that they expect this treatment to stop the immune attack, but not automatically regrow beta cells, so it should be much more effective in the honeymoon phase, because there are still some beta cells at that time.

Put another way, the researchers did not expect this treatment -- by itself -- to cure established type-1 diabetes.  They did expect it to have some impact on the immune system, and think that it did, and think that the impact of these changes will be seen when used on honeymooners.

In some ways, this treatment is similar to the "Polyclonal Tregs" treatment, which is in phase-I trials for honeymooners.  One difference is that different immunology cells are being amplified  (a specific type of T-reg cell vs. a dendric cell).

News: http://www.news-medical.net/news/20140106/FDA-grants-orphan-drug-designation-for-DiaVacs-type-1-diabetes-mellitus-therapy.aspx
http://www.post-gazette.com/news/health/2014/02/10/Type-1-Diabetes-A-treatment-s-in-sight-but-where-s-the-funding
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01947569
Corporate Site: http://www.diavacs.com/
Facebook: https://www.facebook.com/DiavacsTheCureForJuvenileDiabetes

DiaPep277 Starts an Extension to Their Phase-III DIA-AID2 Study

In the past I have thought that DiaPep277 might result in a cure, but I no longer think that is likely, but it still maybe be used as a treatment or a honeymoon extender.  In case people are still interested, you can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/DiaPep%20277

The recent news, is that they have started treating their first patient in an extension to their phase-III clinical trial.  That means the main part of the phase-III study is done, and this is the second such trial.  So they have the option of starting the process of getting marketing approval (so they could actually sell it, and we could buy it).  I don't think any truly new treatment for type-1 diabetes has ever entered the FDA's marketing approval phase before.  (Not counting different versions of insulin.)

Opinion

It will be interesting to see if these guys try to get it approved, and if so, will the FDA approve it, and will insurers pay for it?  My take is that the impact of the treatment is pretty small.  The safety profile is good, however, so the FDA could approve it as a small impact, small risk treatment.  But they could decide the impact is so small that it should not be approved.   Even if the FDA approves it, some insurance companies might not pay for it, arguing that it does not give a large enough benefit, or does not give a cost effective benefit.

Here are some recent news stories:
http://online.wsj.com/article/PR-CO-20140112-900596.html
http://www.pharmabiz.com/NewsDetails.aspx?aid=79410&sid=2

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. ("Bad" killer T-cells are those which target the body's own beta cells rather than the foriegn invaders they are supposed to target).  This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia. It regulates (or modulates) T-cells, rather than depleting them, so the hope is that it will have fewer side effects than other immunosuppressives.

This was a honeymoon study. It was a placebo controlled, double blind trial with 112 patients. About 2/3s (77 people) got the treatment and 1/3 (35 people) did not. The treatment consists of three infusions the first month, and one a month thereafter for two years. C-peptide production in response to a meal was measured after two years.  Those results were discussed in a previous blog:
http://cureresearch4type1diabetes.blogspot.com/2011/09/results-from-phase-ii-trial-of.html

Now, the researchers have published a follow-on paper, which contains data for a C-peptide production a year later.  So this is one year after the last dose of Abatacept, and three years after diagnosis (approximately).

Results

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 insulin generation" 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.

Discussion

My view of this drug is very similar to my view of Rituximab in a blog posting last month. (Which makes sense, since the results were similar.)  By itself, it's not a big step towards a cure.  I used to hope that by combining drugs or changing doses, researchers would take so-so results like these, and create a cure or a preventative.  However, I have yet to see many clinical trials where these sorts of drugs are combined, or doses changed significantly, or any other way of improving on these results.  And these results, as reported here, are not going to lead to a cure.

Abstract: http://care.diabetesjournals.org/content/early/2013/11/22/dc13-0604.abstract?papetoc

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.

Results from a Phase-II Trial of Abatacept (Orencia)

Results from a Phase-II Trial of Abatacept (Orencia)

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.  It was just recently approved for home use via under skin injections (similar to insulin).  Previously it required an infusion, and this study used the infused form.  It regulates (or modulates) T-cells, rather than depleting them, so the hope is that it will have less side effects than other immunosuppressives.

This study attempts to preserve beta cells during the honeymoon phase by giving newly diagnosed patients Abatacept.  This was a placebo controlled, double blind trial with 112 patients. About 2/3s (77 people) got the treatment and 1/3 (35 people) did not.  Three infusions the first month, and monthly thereafter for two years.  C-peptide production in response to a meal was the measured after two years.  The results where clearly better in the treated group.  Basically they produced 60% more of their own insulin at each point in the trial.  (Remember: C-peptide is a marker for insulin production.)  Also, the treated group had better A1c numbers.  The researchers estimate that this is similar to a 6-9 month delay in beta cell loss of type-1 diabetics at diagnosis.

Since Abatacept blocks some T-cell activation, infection was a worry, but the infection rates were the same in treated and placebo groups, as were injection site issues.  There were more mild side effects (things like headaches and nausea) in the treated group.

The researchers are going to continue to follow the patients to see what happens in the months after they stop getting regular doses of the drug.  They will see if the dosed patients stay ahead of the placebo group or not.

Next Steps

I'm not exactly sure what the next steps are in this line of research.  Are these results "good enough" so that you'd just move the same dosing into phase-III trials and then into the market?   Would you change the dose to try to get a better result?  (It looks like the researchers used the standard rheumatoid arthritis dosing for the trial.)  Would collecting data for a longer period of time, help planning the next move?  Belatacept is a follow on drug to Abatacept which was just approved in June 2011 (but not for type-1 diabetes), so would you move forward with Abatacept,  Belatacept, or both?

Another whole set of options involves combining Abatacept with another treatment.  The study chair for this trial is Dr. Tihamer Orban, who is also working on a B-chain insulin treatment (which already completed a phase-I trial, and which I've blogged on in the past), and he is interested in combining these two approaches. 

Abstract: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60886-6/abstract
News: http://www.medpagetoday.com/MeetingCoverage/ADA/27312
Previous blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Abatacept
Clinical trial record: http://clinicaltrials.gov/ct2/show/NCT00505375 
More News: http://www.marketwire.com/press-release/new-hope-immune-therapy-children-young-adults-with-type-1-diabetes-founder-orban-biotechs-1546447.htm
Related news: http://www.medicalnewstoday.com/articles/232194.php
Wikipedia: http://en.wikipedia.org/wiki/Abatacept

This study was run by TrialNet.  Thanks to Dr. Tihamer Orban for providing me we a pre-print of the Lancet article.  And thanks to everyone who provided help and information for this posting.

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

New Phase-II clinical trial: Abatacept

I'm in the process of adding a new human trial to my list of clinical trials aimed at curing type-1 diabetes. This is a phase-II trial of Abatacept, a drug already approved for rheumatoid arthritis. It is a honeymoon treatment. The hope is by giving this drug early in the process, some insulin production can be preserved, or (if that fails) the honeymoon phase can be extended.

This drug is already approved for use on rheumatoid arthritis (in certain situations), and is currently part of many human trials for several different "self immunity" based diseases such as Psoriasis Vulgaris, Asthma, Scleroderma, Ulcerative Colitis, Lupus, Multiple Sclerosism and Graft or Organ Rejection.

Unfortunately, there was no phase-I trial targeting type-1 diabetes for this drug, so there is no data on it's effectiveness against type-1 diabetes. Since it was already approved for use in people, they could skip the phase-I trial because the drug's safety was already known. It did prevent diabetes from developing in NOD mice.

Estimated Enrollment:	108
Study Start Date:	February 2008
Estimated Study Completion Date:	June 2013
Estimated Primary Completion Date:	February 2012 (Final data collection date for primary outcome measure)

Sponsors include several US government agencies (NIDDK, NIAID, and NICHD) , JDRF and ADA.

The ClinicalTrial record for this study is: http://www.clinicaltrials.gov/ct2/show/NCT00505375
Wikipedia has general article on Abatacept: http://en.wikipedia.org/wiki/Abatacept
TrialNet's record for this trial is here: http://www.diabetestrialnet.org/patientinfo/studies/CTLA.htm

This study is recruiting people right now. The first requirement is that you be within 100 days of diagnosis. You can get more information from TrialNet (link above) or by calling 800-HALT-DM1 (1-800-425-8361). It is being run out of 15 different US sites, and a couple of sites in other countries. For the locals: both UCSF and Stanford are trial sites.

The primary investigator is Orban, out of the Joslin center. The same guy who took Faustman's research in a different direction. I think he has the distinction of being the only guy with two different human trials to try to cure type-1 diabetes active at the same time, or almost the same time. He must be one busy dude.

Joshua