Wednesday, May 4, 2022

NN1845 (a glucose sensitive insulin) Starts A Second Phase-1 Clinical Trail

One approach to creating a "practical cure" for T1D is sometimes called "smart insulin", "glucose sensitive insulin", or "glucose responsive insulin".  This is insulin which is inactive if blood glucose numbers are low, but becomes active when those numbers are high. A person with T1D would inject a fixed amount of this insulin every day (or maybe every week), and it would become active only as needed.

This would not truly "cure" T1D, but it would result in a disease which did not require measuring blood glucose, counting carbs, or changing insulin doses based on food, exercise, hormones, etc.  It would make treating T1D much more like treating high blood pressure.  Some people (myself included) would consider this a practical cure.

Several different companies have attempted to create glucose responsive insulins, and several university researchers are also working on it.  However, most are still in animal testing.  Only one is being tested on people.  That one is being developed by Novo Nordisk and is called NN1845  (it used to be called NNC0363-0845).

The situation here is a little unusual in that Novo Nordsk has already run one phase-I clinical trial aimed very narrowly at safety and tolerability, and has recently started a second phase-I clinical trial, aimed at how well it works.

Results from the Previous Phase-I Clinical Trial

This is the summary of research results as published in a Novo Nordisk update:

During the third quarter of 2021, Novo Nordisk completed a phase 1 trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administrated glucose-sensitive insulin (NN1845). In the trial, NN1845 appeared to have a safe and well-tolerated profile and demonstrated proof of principle of glucose-sensitive properties. Further development of glucose-sensitive insulin to optimize pharmacokinetic properties is now being evaluated.

First Phase-I Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT04569994

I want to stress that this is not a publication in scientific literature, and it does not include any actual data, just English phrases.  However, they are starting a follow-on clinical trial, which shows that they are optimistic about the results, and want to move forward with the research.

Plans for the Next Phase-I Clinical Trial

They will recruit 30 adults who have had T1D for more than a year.  Participants will receive the "smart insulin" once every 4 hours up to 6 times daily for 3 days.  The study is blinded and has a cross over design.  Each person will be treated with the experimental insulin and Levemir® (at different times) and the results compared.

They will be followed about 6 weeks, up to a maximum of 14 weeks.  The primary end point is blood glucose levels in the hours after a simulated meal.  Secondary outcomes include adverse side effects and several additional measures of blood glucose levels during different time periods after a simulated meal.

This study is recruiting in Graz, Austria:
Contact: Novo Nordisk     (+1) 866-867-7178     clinicaltrials@novonordisk.com     

Second Phase-I Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT05134987

Discussion and Opinions

I like the fact that this study should be quick.  Classic cure-focused trials usually gather data for 2 years, but these researchers will gather data for 14 week at most.  Also, since they are recruiting people with established T1D, it should be easier and quicker to recruit the 30 people they need.  Together, these should lead to quick results.

Two things I don't like about this trial are the use of Levemir® and the lack of any background or fasting data.  Levemir is long acting insulin.  But is that the right comparison for effects after a meal?  It depends on Novo Nordsk's goal with this insulin.  If their goal is a better, safer long acting insulin, then this is a good comparison.  However, that is not a practical cure.  A practical cure would require the glucose sensitive insulin to cover a meal much like fast acting insulin.  I'm worried that this comparison telegraphs Novo Nordsk's opinion that this is not a practical cure, but just a better long acting insulin. 

Of course, the optimist in me thinks that even if this particular "smart insulin" is not fast enough to be a practical cure, maybe the next one will be.  Or maybe an improvement to this one will make it faster in the future.

Both of these studies are phase-I so an obvious question is: how are they different?  Let me summarize the major differences:  

  • The biggest difference is in end points.  In the first study people were only monitored for adverse effects and to see how the experimental insulin is absorbed by the body.  In the second study most of the monitoring is aimed at blood glucose results.
  • The first study includes 68 people in three parts, and each part is quite different.  The second study is 30 people all together, which is a much more common design.   Phase-I studies in T1D often have 10-20 people, so both of these studies are big for phase-I.
  • In the first study, people get treated once with the experimental insulin and once with the control.  In the second study, people will be treated for 3 days and given the control for 3 days.

Obviously, I'm excited to see this research progressing.  Unfortunately, because the research is run by a commercial company, there is no requirement that they publish results quickly, and so far, they have not published at all.  Therefore there is no way to know the results from the first phase-I study.  They think there is a chance of a product there (commercial success) and the evidence is strong enough for them to put more money into the research, to fund a second phase-I trial.  So that suggests good results, but there is no way to independently confirm it.

The Real Publication Requirement

A lot of people seem to think there is some rule that says you must publish the results of clinical trails.  Twenty years ago, the answer was simple: no.  There was no law saying anyone had to publish anything.  Sure, academics built their reputations by publishing, so there was pressure for them to publish.  But for commercial companies, there was no reason to publish anything that would not increase their profits.  Then the USA passed a law saying that any clinical trial that was part of a new drug application must be listed on the FDA's clinical trial registry.  That was enforced as part of drug approvals, so suddenly there was a trial registration requirement, but no requirement to publish results.  (Companies had to submit results for FDA approval, but not publish them in the scientific literature or make them available to anyone else.)  

Years later the law was updated to require results be added to the clinical trial registry.  However, there was no enforcement, and therefore few researchers did.  Even researchers who published results rarely added them to the clinical trial registry.  Years later, a news service published a series of articles describing the legal requirement, the fact that it was widely ignored, that there was no enforcement, and that most of this research was funded by US taxpayers via government agencies.  Finally, there was some movement.  Over the next few years many old clinical trial registries were updated with results, and now more results are posted when the studies are completed.  But the number is still low.

So the summery right now, in the US, is that there is a paper rule that researchers must make results of clinical trials public, but, in fact, this data is not available for many clinical trials, including many focused on T1D.  I think the situation is worse in the rest of the world, but I've never investigated in depth.

For example, in 2015 none of the research results previously funded by JDRF were available in the FDA's clinical trial registry.  The publication of this information by Statnews resulted in several JDRF funded clinical trials posting results to the clinical trial registry, in some cases years after the research finished.  I'm sure JDRF funded researchers are doing better now, but I don't have any more recent data.

As of 2019, the two local (to me) universities who do the most T1D research were University of California San Francisco (reporting less than 50% of results) and Stanford (reporting less than 75%).  These numbers are for all the clinical trials done at those universities, not just their T1D trials.

More to read:


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, April 5, 2022

ViaCyte and CRISPR start a Phase-I Clinical Trial (VCTX210A-101)

For many years, it has been clear that one possible path to a cure is to transplant new beta cells and also in some way prevent the body from rejecting those new, transplanted cells.  Since the 1980s many different companies have tried encapsulated beta cells as a path to a cure.  The idea is that beta cells cure T1D and encapsulation means both that the person does not need to take anti-rejection drugs and that the person's autoantibodies cannot destroy the new beta cells.  Unfortunately, even after 40 years of research done by many different companies, this line of research has not been successful.

The JDRF has a good timeline of their support for stem cell therapies here:
https://www.jdrf.org/blog/2021/11/29/jdrf-timeline-stem-cell-therapies/
Note that they have funded several different research projects, and ViaCyte is just one of them. 

ViaCyte is one of these "old school" beta cell transplantation companies.  They have developed an infrastructure to grow large numbers of beta cells from stem cells.  However, recently they have partnered with a CRISPR company (called CRISPR Therapeutics).  CRISPR is a technology to edit genes.  In this case, they are editing genes in their newly grown beta cells, so that the beta cells are invisible to the patient's immune system.  The hope is that this is going to have two important effects:  First, the body will not reject the transplanted beta cells.  Second, the bodies' autoimmune attack will not be able to target the transplanted beta cells.

Obviously, either one of these effects would result in a huge step forward on the path to curing T1D, and both of them together could result in an outright cure.  This combination is what they have just started testing in a Phase-I clinical trial.

The Phase-I Clinical Trial

This is an open label (no blinding) clinical trial with 10 participants who are adults (18-65 years old) and have established T1D (diagnosed at least 5 years prior).  All 10 people will get the treatment; there is no control group.

The gene edited, stem cell derived beta cells are loaded into a device and then implanted into a person.  The person is then followed for 6 months.   The trial's end points involve safety and several scientific measures of transplant success.  The researchers will check for bad side effects, if the body is generating antibodies against the transplanted cells, and new autoantibodies related to T1D.  They will also see if the stem cells are growing properly.  However, none of the end points measure success in treating or curing T1D.  There are no measures of C-peptides (the body generating its own insulin) or lowered requirements of insulin, or improved A1c. This study is really focused on testing safety and ability to be tolerated, not effectiveness.

Because patients are only followed for 6 months, they hope to run this study from January 2022 to December 2022.  This includes the time needed to recruit the patients and the time to actually run the study on each patient.

This trial is being run in Canada, and you can get more information on participating here:
Contact: Clinical Trials     +1 (877) 214-4634     MedicalAffairs@crisprtx.com

The study locations include:

  • University of Alberta,  Edmonton, Alberta, Canada
    Contact: Parastoo Dinyari    +1 (780) 407-1501    parastoo@islet.ca   
  • University of British Columbia, Vancouver, British Columbia, Canada    
    Not yet recruiting
  • LMC Manna, Toronto, Ontario, Canada
    Enrolling by invitation

Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT05210530

Discussion and Opinions

I'm very happy that a company is testing a combination cure, which (in theory) will both generate new beta cells and prevent the autoimmune process from destroying the new beta cells.  This is something I've been hoping for for 10 years. 

Normally, I'd would be happy with the speed of this trial.  Finishing this year means we will get our first data very quickly.  However, this clinical trial is only measuring safety outcomes, not effectiveness results.   Although phase-I trials are sometimes safety only, in T1D research it is normal to include some effectiveness outcomes.  They can give an early signal of success.  Not having effectiveness measures makes the short duration and quick results of this study less important, because (at best) it can only show us the treatment is safe, and not that it actually works (much less, works well).  We might need to wait to the end of the phase-II trial to see if it works, which will be very frustrating. 

Here are two very good articles which cover this clinical trial:

And here is the official press release:

Some notes on names and terminology:

  • ViaCyte refers to this product as PEC-QT, but CRISPR Theraputics calls it VCTX210 in the press release and VCTX210A in the clinical trial record.
  • The stem cells are created using CRISPR/Cas9, which is an improved form of CRISPR gene editing.
  • The clinical trial is called VCTX210A-101 by the companies running it, and has the clinical trial registration number NCT05210530.
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, March 21, 2022

Update On Teplizumab from Provention Bio

Teplizumab is a proposed treatment which, if given to someone at-risk for type-1 diabetes (T1D), can delay or possibly prevent the onset of T1D symptoms.  At-risk has a specific meaning here: it is someone who has tested positive for two or more autoantibodies for T1D, but has not yet shown symptoms of T1D (i.e. a lack of blood glucose control).  These are people not yet in their honeymoon phase.  In TrialNet terminology, they are in stage 1 of T1D.  Teplizumab works by targeting one specific part of the immune system which is involved in the attack on beta-cells which leads to T1D.

Scientifically, Teplizumab is a monoclonal antibody targeting CD3.  What does that mean?  It means Teplizumab starts out as an antibody aimed at neutralizing a specific part of the immune system called CD3.  Because CD3 is part of the process that leads to type-1 diabetes, the hope is by neutralizing it, T1D can be delayed or maybe even prevented.  Provention Bio starts out with one of these cells, and clones it repeatedly to create a large number of cells, all of which target CD3 (and only CD3) in exactly the same way.  This is a very common way to create new medicines.  Roughly 1/3 of the new medicines approved in recent years have been monoclonal antibodies.  If you see a treatment with a generic name ending in "mab" that is a Monoclonal AntiBody.

The full history of Teplizumab is long and complex, and I covered it in a previous blog:
https://cureresearch4type1diabetes.blogspot.com/2019/09/teplizumab-phase-ii-results-for.html

As very quick summary is as follows: Teplizumab was developed in the 1990s, and had its first clinical trial 1999-2005.  In 2008 it started a phase-III trial, which could have led to approval, but was unsuccessful, and was stopped in 2010.  A similar treatment, also targeting CD3, was also in phase-III trials at the same time and was also unsuccessful.  Other clinical trials on Teplizumab continued however, and in 2018 a different company, Provention Bio, restarted clinical trials.  Provention believed that the previous phase-III trials had failed because of a poor choice of primary end point (i.e. they measured the wrong thing to prove success).

In 2019, Provention Bio announced plans to submit Teplizumab for FDA approval based on three sets of data: 1. from the long ago completed studies. 2. from the long running, recently completed study, and 3. from their own recently completed study.

Recent History
  
November 2020 
Provention Bio finished submitting their application to sell Teplizumab.  This was (and is) huge news.  It is the first time, to my knowledge, a company has asked for FDA approval for a drug that will fundamentally change the course of type-1 diabetes [d1].  It is not a cure, or a preventative, but it is (potentially) able to delay the onset of T1D.  Obviously, this treatment will not directly help people who already have type-1 diabetes, but it will directly help their younger relatives, and I'm hopeful it will lead to better treatments over time which may lead to a cure.

Press Release: http://investors.proventionbio.com/2020-11-02-Provention-Bio-Completes-Rolling-Submission-of-the-Biologics-License-Application-BLA-for-Teplizumab-for-the-Delay-or-Prevention-of-Clinical-Type-1-Diabetes-in-At-risk-Individuals

April 2021 
The FDA reports on a serious problem in the Teplizumab application, which will require Provention Bio to address it before their application can move forward.

So what happened?  Teplizumab has been tested by several different companies over 15+ years.  The Teplizumab from the earlier, longer studies was made by Eli Lilly, while the Teplizumab for the later, smaller study (and for future sales) is being made by AGC Biologics.   Provention submitted data to show that these two Teplizumabs were the same as absorbed by the patients [d2].  However, the FDA did not accept that the data showed this.  This problem could (in the worst case) cause a long delay because it might imply that studies done with Eli Lily made Teplizumab may not be used to approve a treatment based on the AGC Teplizumab.  Or, it might mean that more "bridging study" data is needed.  This is data to show that the two Teplizumabs are not as different as first thought.  There are other solutions to this problem as well.

Press Releases:

http://investors.proventionbio.com/2021-04-08-Provention-Bio-Provides-Regulatory-Update-on-Biologics-License-Application-for-Teplizumab-for-the-Delay-or-Prevention-of-Clinical-Type-1-Diabetes-in-At-Risk-Individuals

http://investors.proventionbio.com/2021-04-27-Provention-Bio-Provides-Additional-Regulatory-Update-on-Biologics-License-Application-for-Teplizumab-for-the-Delay-or-Prevention-of-Clinical-Type-1-Diabetes-in-At-Risk-Individuals

May - Sept 2021
Provention Bio and the FDA exchange various communications and have meetings to discuss this issue.  Also the FDA's committee of experts recommends approval of Teplizumab, even with the issue found in April.

These proceedings are described from Provention's point of view by various press releases here:
http://investors.proventionbio.com/news?l=100&year=2021

I'm not going to describe the back-and-forth, except to point out that it lasted 9 months.

January 2022
At this point, the FDA decided (and Provention Bio agreed) that the company can resubmit their application to specify dosing based on the earlier clinical trials, rather than on the last clinical trial.  This means that no new clinical trials will need to be done.  Provention will change the dosing given to patients so that it matches the dosing used in the previous clinical trials, taking into account the differences between the Teplizumab used in older vs. newer studies.
 
Discussion and Opinions
This is, in my opinion, the best possible outcome for the T1D community and for Provention Bio.  Faced with two different absorption profiles from different manufacturers, The FDA could have required Provention Bio to run more clinical trials in order to generate enough data for approval for Teplizumab based solely on the current absorption profile.  That would have cost a lot and caused a many years delay (if Provention did it at all).  The solution proposed by the FDA, to tailor the dosing schedule to the absorption curve used by the previous clinical testing, only requires a change in application paperwork.  This is vastly cheaper and should only take months rather than years. 

I view this as a good call by the FDA, but remember, they are trading off a little safety in order to get this treatment to market sooner.   The most conservative (i.e. safest) path forward is to require all testing on new medicines to use the exact same product as will be sold.   However, the FDA already has a lot of experience in allowing slightly different formulations (especially in the context of "generic" drugs and "biosimilar" biologics), and so I think this safety trade off is a reasonable one to make.   More discussion here: [d3].

Press Release: http://investors.proventionbio.com/2022-01-27-Provention-Bio-Resubmitting-Biologics-License-Application-for-Delay-of-Clinical-Type-1-Diabetes-in-At-Risk-Individuals-Following-Type-B-Meeting-with-the-FDA

Why Is This Important?

I'm going to discuss why the approval of Teplizumab is important from two different points of view.  First the "tactical", how it would change the life of families with T1D right now, and second the "strategic", how it would change the research landscape of trying to cure T1D.

For the tactical part of the discussion, I'm going to assume that Teplizumab does exactly what the existing research says it does: delay the onset of T1D by about 3 years on average.  I think that will have two important good effects.  First, I think, in some cases, delaying the onset, even for just 3 years, is a good thing all by itself.  In practical terms, that means that someone who would normally be diagnosed in college, might actually be diagnosed after college.  Or someone in high school might be diagnosed in college.  Everything I've heard from families diagnosed in the teenage years, is that later diagnoses would be better.   I don't think this would be true for everyone.  My daughter was diagnosed at 18 months, and I actually think it would have been worse to be diagnosed at 4 years, but for many families, a delay would be a good thing.  If approved, Teplizumab would give families and patients that choice.

Second, I think that a 3 year delay may cushion the psychological impact of diagnosis.  Right now, a person goes from healthy to having a chronic, incurable disease in a week or two.  As a parent, I experienced this shock, and it was very jarring, but I'm sure it is much worse for the patients themselves.  Teplizumab would give people a few years to transition from not-T1D to T1D.  We have no experience with this, but I'm hopeful that it will lead to better psychological outcomes, because people will have more time to adjust.

The approval of Teplizumab will also have a huge impact on future research aimed at curing T1D.  For example:

Right now, there is a lot of uncertainty, in terms of getting drugs approved to cure T1D.  Since no drug has been approved, no one knows (for sure) how much evidence the FDA will require in order to do the approval.  We can read generic FDA policy documents, but it is not the same thing.  But if Teplizumab is approved, then from now on, everyone will know how much data is required and what results are good enough.  This makes the whole approval process less risky.  And less risky means more companies will try.

Second, the first drug approved to treat a disease, is almost never the best drug.  Once one is approved, improvements follow.  So I think it is fair to view Teplizumab as being the first in a series of improving drugs.  Having one drug, makes the development of other drugs easier in several different ways.  It shows researchers where to focus their efforts, it encourages more researchers to enter this field, and it shows companies how much money is available.

Third, I think it will encourage people to participate in trials like TrialNet.  One of the things I hear over and over is parents who say "Why should I participate in TrialNet, even if they tell me my son/daughter will get T1D, there is nothing we can do."  Right now, that is not true because they can participate in research, but if Teplizumab were approved, then it would be even less true, because they would have the option of delaying their T1D.

What Next?
Provention Bio has announced that they will resubmit their application using the new dosing data as soon as possible (no exact date has been publicized).  At that point the FDA has 30 days to review the application, and we will all see what they find at that point.
 
Of course, everyone wants an estimate for when this will happen.   You won't get one from me.  Why not?  Because the availability of Teplizumab is based on two things, and I don't know either one of them:  First, when will Provention Bio put together its updated application, and second, when/if the FDA will approve it.  Considering all the back and forth between the FDA and Prevention Bio over the last year, I have to believe that it will get approved, eventually.  However, I have no insight on the exact time.  And, since this is the first treatment which changes the progression of T1D, and no one has ever been through the approval process before, there could always be a last minute issue. 

Definitions

[d1] The technical term for this is "disease-modifying" treatment.  This is very different from a treatment like insulin which treats the symptoms, but does not change the underlying cause of the disease.  Teplizumab has the potential to change T1D itself in ways that insulin does not.

[d2] This is called "pharmacokinetics/pharmacodynamics" (or PKs/PDs) which refers to how quickly a medicine is absorbed into the body, how quickly it is distributed to different parts of the body, and how quickly it is used up.

[d3] To over simplify a little, the FDA regulates three things: drugs, biologicals, and devices.  Drugs are chemicals, biologicals are cells and parts of cells, devices are electromechanical objects.  Since Teplizumab is a cloned cell, it is a biological.  The rules for approval for drugs and biologicals are similar.  The rules for devices are different and generally "looser".  The concept of a "generic" applies only to drugs, since the 1960s.  The same idea for biologicals is called "biosimilar" and has been in use only since 2015.  Devices do not have anything similar to generics or biosimilars for other companies, but do have a simplified approval system for newer versions of a previously approved 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.

 

Wednesday, February 16, 2022

Verapamil Starts A Phase-II Trial (Ver-A-T1D)

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  Some researchers believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. Verapamil has already undergone phase-II trials for T1D in the United States, which I discuss below.

The Ver-A-T1D Study

This is a 138 person study, randomized, controlled, and double blind.  It is for adults in the honeymoon phase (within 6 weeks of diagnosis).  Half the participants will get Verapamil for a year, the control group will get a placebo.  All will be followed for a total of 2 years, so one year while they get the drug, and then one additional year.  The study started in Feb-2021 and is expected to end in May-2023.

The primary outcome is a measure of C-peptide generation, which measures how much insulin a person is naturally generating.  There are 10 secondary outcomes, mostly measurements of C-peptides, but also insulin use, proinsulin generation, BG in range, and A1c.  There are a few tertiary (or "other") outcomes, which are quality of life questionnaires. 

This trial will recruit in 22 different locations, at least.  These sites are all over Europe and the United Kingdom.  There is a list in the clinical trial registry below, but the exact status of each site might be out of date.  If you are unsure if one of the listed sites is actually recruiting, you can contact the study organizers here:

Martina Brunner  +43 316 385 ext 72841 martina.brunner@medunigraz.at
Karin Brandner  +43 316 385 ext 72800 karin.brandner@medunigraz.at

Clinical Trial Registry:
https://www.clinicaltrials.gov/ct2/show/study/NCT04545151
The European Clinical Registry number is 2020-000435-45.

This study is being funded by the JDRF, among others.

Discussion

There are a couple of interesting discussion points here.

What happened last time?

This is the second phase-II trial for Verapamil.  I blogged on the previous phase-II trial here:
https://cureresearch4type1diabetes.blogspot.com/2018/09/results-from-phase-ii-verapamil-trial.html

So, for me, the most important question for any T1D cure that has been tested previously is, how did it work before, and why do we think it will be better this time? This is especially true for a trial like Ver-A-T1D, where the dose and duration of the study is the same as the previous study.

The results from that trial were definitely interesting.  The visual summary of that study is here.  Remember that people in the study were given the drug for 12 months:

My summary:

  • For three months after treatment, C-peptide number went up, and this is great news.  That is on the path to a cure.  However, after three months, C-peptide numbers went down and did so at basically the same rate as the untreated (placebo) group.
  • The treated group started out at a noticeably higher C-peptide level than the untreated group.  That is not a good thing.  The two groups should start out the same.

Clinical Trial registry for the earlier study:
https://clinicaltrials.gov/ct2/show/NCT02372253

INNODIA and T1DUK

This study is part of the INNODIA and T1DUK networks.  INNODIA is a European collection of research universities, commercial companies, and patient organizations aimed at fighting T1D.  Their research goal is "to advance in a decisive way how to predict, stage, evaluate and prevent the onset and progression of type 1 diabetes (T1D)."  T1DUK is a UK collection of research universities focused on Immunotherapy research.  Its principal aim is "To help get immune therapy into the market as part of the management for type 1 diabetes".  Both networks are funded by JDRF.  T1DUK is also funded by Diabetes UK (and others) while INNODIA is funded also funded by the Helmsley Trust (and others).

I plan to blog on both of these research networks in the future, but in the meantime, I view them as similar to TrialNet in the US.

Recruiting Issues
(Children vs Adults. Honeymoon vs Established. Money and More Money)

This study is using 22 different sites to recruit 138 people.  Think about how expensive that is.  Each site must be staffed, trained, and supported.  They are expecting to be able to recruit about 6 people per site (on average).  Why so few people?  Well, they are recruiting adults because of safety concerns and a general regulatory assumption that clinical trials should be run on adults when possible.

But these assumptions create problems for T1D research.  Most people with T1D go through their honeymoon phase as children, so if recruiting for a honeymoon treatment is limited to adults, most people are excluded.  And if most people are excluded, then you need to cast a very wide net to get the people you need, and that adds to the expense. 

For this trial, there is the question of, why limit it to adults?  The drug they are testing is already approved.  Although the disease it is approved for affects adults, there are no age restrictions on the approval.  It can be prescribed to children.  More specifically, it has already been tested in people with T1D, so it would be quite reasonable to test it on children in this, the second, T1D study done.  But they chose not to do this.  That decision is going to result in a more expensive and slower clinical trial, which is too bad. 

The study will not finish in May-2023.

Although the plan is for the study to finish in May-2023 (as listed in the clinical trial registration), we already know that it will not.  How?   Because the study is still recruiting people now, and once those people are recruited, it takes 2 years to gather the data.  Therefore, the study can't possibly finish before Feb-2024. (Unless they have finish recruiting and just forgot to update the clinical trial registration.  That is possible, but unlikely.)

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.

Wednesday, January 12, 2022

No One Was Cured Of Type-1 Diabetes in 2021

You might have seen a headline like one of these: Ohio man appears to be first in the world to be cured of Type 1 diabetes or this: A Cure for Type 1 Diabetes? For One Man, It Seems to Have Worked.  That last one is from The New York Times. 

Don't worry.  You (or your kid) is not missing out on a cure.  

So what did happen?  Vertex corporation issued a press release hyping the fact that the first person who got a beta cell transplant as part of their clinical trial uses much less injected insulin in the 5 months since the transplant, than he used before the transplant.  But there are three important facts to put this into context:

  1. The patient still takes insulin.  His insulin requirements have dropped 91%, which is a huge drop, and I don't want to belittle it, but he is still injecting insulin; just much less.
  2. The patient now must take immune suppressive drugs for the rest of his life.  Currently, he is taking a combination of 10 pills a day.  These drugs have serious side effects (including risk of death).  The very best that can be said of this treatment, as used on this patient, is that he traded high insulin therapy for low insulin therapy and immune suppression. Some people might  consider this an improvement, but I would not.
  3. These results have been seen before, many times over the last 10 years.  In fact, a JDCA report found that over 75% of people receiving Edmonton protocol transplants (first available in 2001) did not need to inject insulin for a year after the transplant:
Data from the Clinical Islet Transplantation Network Annual Report 2017
Graphic by the Juvenile Diabetes Cure Alliance 

 

In short, the result which generated all the recent buzz is actually worse than transplant results over the last 20 years.  All of these transplant "cures" (to date) require immune suppression and (in my opinion) are not cures at all.

Also, notice that by year five, 85% of the people who got a transplant were back to injecting insulin. These people still must take the immune suppression drugs for the rest of their life, even if transplant is not working any more.

Now, as a research milestone, this is solid.  Vertex should be happy with these results, because it is the first time their product has been tested in a person, and they specifically started with a low dose.  So the fact that the results are worse than other transplant results should be expected.  As the research progresses, they will be able to use larger doses, and (hopefully) get better results.  From a corporate point of view, this is very good news.  If everyone in their phase-I trial has results this good, it will surely move to a phase-II trial. 

Also, I don't want to minimize the impact this has had on this one person's life.  His insulin usage has gone from 30-40 units a day down to about 3 units a day.  His A1c has gone from 8.6% to 7.2%.  Perhaps most importantly,  his T1D was previously "brittle".  He had seizures and ambulances had to be called for him many times.  Now he reports much better control with vastly fewer seizures and emergencies in general.  These are all important benefits from the transplant.  There is no doubt that he is very happy with the outcome, and I'm sure there are others who would be very happy with these risks and results.

Additional Reading

Overview of islet transplantation with data on success rates and duration:

  • http://thejdca.org/ict-survey-2021
  • https://www.jdrf.org/blog/2021/11/29/progress-toward-cures-thoughts-from-jdrf-ceo-aaron-kowalski/
  • http://thejdca.org/islet-transplanation-overview

Press Release from Vertex:

  • https://news.vrtx.com/press-release/vertex-announces-positive-day-90-data-first-patient-phase-12-clinical-trial-dosed-vx

Just some of the news articles which reported on this "cure":

  • https://spectrumnews1.com/oh/columbus/news/2021/12/09/ohio-man-cured-of-type-1-diabetes--at-least-temporarily-
  • https://www.nytimes.com/2021/11/27/health/diabetes-cure-stem-cells.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.

Monday, August 30, 2021

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

This blog is a collection of short updates, mostly from the ADA conference.

Diet (Macronutrients) Does not Impact T1D Risk

Macronutrients are carbohydrates, protein, fat, sugar, and fiber (things that you eat large amounts of).  This study also looked at glycemic index and glycemic load.  It did not look at micronutrients, such as vitamins and minerals (things that you eat small amounts of).  This study enrolled people who already tested positive for autoantibodies to see how long it took them to show symptoms of type-1 diabetes.  

This study covered 881 people divided into four groups by age: 1-4 years old, 5-12 y/o, 13-22 y/o, and 23 and over.  Here is the summary of their findings:

Given multiple comparisons, there was no significant association between rate of progression from IA to T1D and daily dietary intake of any macronutrients analyzed, after adjusting for [confounders]. ... Baseline dietary macronutrient intake does not appear to influence rate of T1D diagnosis in children, adolescents, or adults with IA.  

This study is strong evidence that feeding low carb, low sugar, low fat, or any other type of macronutrient based diet cannot prevent (or even delay) the onset of type-1 diabetes, at least among people who have autoantibodies.

Abstract: https://diabetes.diabetesjournals.org/content/70/Supplement_1/1116-P

Maternal C-Peptide Generation

It has been known that women with T1D often have increased levels of C-peptide when pregnant, and especially later in pregnancy. In the past this has been considered a hopeful sign that pregnancy caused beta cells to regrow (generating the C-peptide) and that perhaps research into this phenomena could lead to a way to regrow beta cells in others with T1D.

Unfortunately, a study at ADA2021 implies that beta cells are not regrowing.  Rather, the fetuses C-peptides are moving across the placenta so they are found in the mother.  To quote the abstract:

... This suggests transfer of C-peptide from fetal to maternal serum and is inconsistent with pregnancy-related β-cell regeneration.

Tweet: https://twitter.com/ClaireMeek5/status/1409028250450509824
Full Paper: https://care.diabetesjournals.org/content/early/2021/06/05/dc21-0028 

Leptin

Leptin is a hormone generated by fat cells which helps the body regulate hunger and energy use, and may regulate other body processes as well.  Back in 2011 there was hope that it might become a cure for T1D, but clinical trials were unsuccessful.  However, there is still hope that Leptin (in addition to standard insulin use) might end up helping to treat T1D by lowering insulin spikes after meals, resulting in better control.

A poster at ADA reported on a phase-I study (7 treated people, 3 in a control group).  Basically, they gave a small dose of Leptin to people with T1D who were fasting, and then cut their pump basal insulin by 50%.  The control group's blood sugar and glucagon levels went up (as expected), but the treated group's levels went down, even though they were getting less insulin.  The effect lasted less than 3 hours.  This is a good result, if you are positioning Leptin as a "take with meals" drug to lower blood sugar spikes caused by eating.  However, this is not a cure, and I don't expect to cover it in the future.

ADA 2021 had results for a 10 person study: https://www.hcplive.com/view/oral-leptin-formulation-offers-short-term-benefit-type-1-diabetes-patients
Abstract of poster: https://diabetes.diabetesjournals.org/content/70/Supplement_1/121-LB

Viacyte Update

Viacyte was in the news this summer because they released some data at ADA (American Diabetes Association) 2021 Scientific Sessions.  Unfortunately, the data they released was from one person who was part of their "PEC-Direct" study.  The PEC-Direct study still requires people to take immune suppressive drugs for the rest of their lives.  Therefore, I don't consider this to be a cure, because it swaps one drug regimen (insulin replacement) for another drug (immune suppression).  Immune suppression has serious long term side effects, possibly worse than T1D itself.  Furthermore, I don't put much stock in single person results, so their press release had two reasons for me not to get excited.

The data showed that one person's transplanted beta cells were working well 9 months after the transplant.  Her A1c was 6.6% (compared to 7.4% before the operation) and her time within range was 84% (up from 54%).  She was still injecting insulin, however.

Viacyte is also running another study called PEC-Encap.  This study will use encapsulated stem cells and so these people will not need to take immune suppressive drugs for the rest of their lives.  I do consider that a cure.  Last I heard (from the JDCA) they were hoping to have interim results from this study in the second half of 2021 (soon!)  Those are the results I care about.

JDCA update on Viacyte from early 2021: http://thejdca.org/viacyte-2021
Viacyte press release on PEC-Direct: https://viacyte.com/press-releases/viacyte-reports-compelling-preliminary-clinical-data-from-islet-cell-replacement-therapy-for-patients-with-type-1-diabetes/
Viacyte press release on PEC-Encap: https://viacyte.com/press-releases/viacyte-announces-initiation-of-phase-2-study-of-encapsulated-cell-ther-apy-for-type-1-diabetes-patients/
News coverage: https://endpts.com/after-years-of-failure-viacyte-shows-off-first-proof-of-concept-for-diabetes-stem-cell-transplants/

Viacyte is part of a long line of attempts to cure T1D by encapsulating beta cells.  This sounds easy: just wrap the implanted cells in a membrane that lets sugar and oxygen in, insulin and carbon dioxide out, and does not allow T-cells to enter).  Seems straightforward.   For all of the last 25+ years there have been companies working on this, and none has succeeded yet.  So it is clear to me that there is something more complex and difficult about this path than we currently know.  At the moment, I think there are 3 companies working on this approach that are in human trials, or close to it.

BCG News

Dr. Faustman's lab released their most recent BCG result as a poster at the ADA 2021 conference.  They reported on demethylation of signature Treg genes.  BCG (Bacillus Calmette–Guérin) is a biologic which has been given to over a billion people (in low dose) as a tuberculosis vaccine, and is also approved (in much higher doses) as a bladder cancer treatment. It is a generic drug with a very long record of safety. 

BCG was tested as a T1D cure or preventative several times in the early 2000s (including once by this same lab), and all those clinical trials were unsuccessful.  However, Dr. Faustman's continues to run clinical trials with BCG.

In my view, these results are another step in the collapse of BCG as a possible cure. When this research started 20 years ago, it was based on curing mice. Then, the first results in people (in a tiny phase-I trial) showed very small progress to a cure in people. Later, a follow on trial showed no progress to a cure in people, but maybe small progress to treatment. Now we have these results which don't show any progress to treatment, but instead are looking at demethylation, a type of gene expression change.  The particular change they report certainly does not cure T1D, and may have nothing to do with T1D at all. By itself, it does not show progress to either a cure or treatment.

Press coverage: https://www.fiercebiotech.com/research/ada-tb-vaccine-repurposed-type-1-diabetes-restores-gene-expression-key-immune-cells?fbclid=IwAR0Jhuk8gC-IjQG6qyoX7u8UYDuP00hRtjrF5TT33RVIqnG91FnR84jazmM

Poster: https://diabetes.diabetesjournals.org/content/70/Supplement_1/1142-P

 

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, July 17, 2021

TrialNet In General

I have blogged dozens of times on clinical trials run by TrialNet, but I've never discussed TrialNet as an organization, so this blog contains some information on TrialNet, starting with their web site:
 
A Little History
 
The pre-history of TrialNet traces back to a large study called Diabetes Prevention Trial of Type 1 (DPT-1) which started 1994, which was testing oral insulin as a prevention of T1D.  TrialNet was formally founded in 2001, and (for me) is best known for their huge study now called "Pathway to Prevention" (previously called "Natural History Study").  This study is central to the mission of preventing T1D, by both (a) studying what is the normal progression of T1D and (b) creating a large pool of people in the process of developing T1D, which makes prevention focused clinical trials much easier to run. 

Kevan C. Herold of Yale University became chair of TrialNet on June 1st, 2021.  Prior to that, from 2015 to 2021, Carla J. Greenbaum of the Benaroya Research Institute was the chair, and before that, Jay Skyler.  Carla Greenbaum continues to direct the TrialNet Clinical Hub.
 
In writing this, I searched for a concise history of TrialNet, but was not able to find anything.  So if you have an interest in the history of science, this might make a great paper, or even a thesis.  Also, I was not able to find any public organizational or governance materials, so can't include any information on how TrialNet decisions are made.

Goals and Methods

TrialNet's goal is to prevent, delay and slow the progression of the T1D.  I would describe their basic method as a research funnel:
  1. They start out screening relatives of people with T1D, looking for those who have autoimmune antibodies.
  2. They then follow those people to see if the number of autoimmune antibodies increases, if they start having higher than normal blood glucose after eating carbohydrates, and if they are diagnosed with T1D.
  3. For those who develop T1D, they follow them to see how the disease evolves over time.

Throughout this whole process, they are recruiting people for more specific studies to test preventions or cures appropriate to their stage in the disease. 

Without TrialNet, if a researcher wanted to recruit 50 people at-risk for type-1 diabetes from the general population, they would need to test thousands of people to find the 50 they were looking for.  That process alone would likely take years and cost hundreds of thousands, if not millions, of dollars.  Even if they could focus on the relatives of people with T1D, they would still need to test 100s of people, and it would still cost a lot and take a long time.  But TrialNet has already found many people who can participate in those studies.

Research Achievements

I consider the following items to be TrialNet's three biggest achievements in chronological order: 
 
First: showing the normal progression of T1D.  In particular documenting the length of the honeymoon period, and what should be expected during that time.  To understand why this is important, consider the saga of BCG.  In the 1990s there was a small clinical trial which gave BCG to six people with newly diagnosed type-1 diabetes (no control group).  One of them went a few weeks without injecting insulin.  At the time (before the TrialNet results), this triggered a lot of optimism, including at least three follow-on studies.  The follow-on studies all had control groups and all failed, because (in fact) that result is pretty normal for the honeymoon period without any treatment at all.  With the TrialNet information, researchers do not waste their time following up these "normal, but we didn't know it was normal" results.  Also, there is now much more and much better information on what should be expected during the honeymoon period, which is a very stressful time for everyone involved.
 
Second, showing that a person who tests positive for two autoantibodies would later develop T1D in nearly all cases.   This process might take up to 10 years, but it would eventually happen.  Without TrialNet we would not know how number of autoantibodies related to chance of being diagnosed with T1D, or how long it would take on average.  The whole idea of using number of autoantibodies to predict chances of being diagnosed with T1D is based on TrialNet data.

I know that many people are unhappy with this knowledge, especially when their kids test positive for those first two autoantibodies.  However, this knowledge has opened up a wide range of research to try and prevent this diagnoses which would never have been possible without it.

Third,  Teplizumab, which I've blogged on before:
TrialNet did the earliest research into Teplizumab, and they continued researching Teplizumab even when clinical trials run by commercial companies were unsuccessful.  This dogged determination led directly to Teplizumab's current status. In November 2020, Teplizumab was submitted for marketing approval by the FDA for preventing or delaying the onset of T1D when given to people at-risk of the disease.  (Obviously, I'll blog if it is approved.)  If approved it will be a huge breakthrough: the first treatment to delay the onset of T1D.  More than that, the first treatment to change the immune reaction which causes T1D.  First treatments are rarely perfect, but even if not perfect, they often point the way to better treatments, and TrialNet was key to Teplizumab's research success.

Current Research

List of TrialNet's honeymoon research:
    http://www.trialnet.org/our-research/newly-diagnosed-t1d
List of TrialNet's at-risk research:  

In addition to TOPPLE T1D, which is for adults within 4 years of clinical diagnosis, TrialNet is
also running trials on Abatacept and Hydroxychloroquine (HCQ) for at-risk individuals.  In the past, TrialNet and has run multiple trials in honeymooners, most recently on ATG/GCSF, and also run two and oral insulin trials in people at risk of T1D.

By far the largest research project is TrialNet’s Pathway to Prevention which is focused on Risk Screening and Monitoring.  These are cooperative large scale monitoring trials, involving tens of thousands of people.  Relatives of people with T1D are tested for autoantibodies, and then monitored or enrolled in prevention trials if autoantibodies are found.  If they develop T1D, its progression is followed through the LIFT study. TrialNet's prevention studies are open to anyone who has  autoantibodies, no matter if they have relatives with T1D or not.

In the past, I know that some people did not want to participate in risk screening style research, because they "didn't want to know if there was nothing they could do".  However, that thinking is now out of date.  Because of several clinical studies underway to prevent or delay T1D, there now is something you can do, if you know ahead of time.  Furthermore, if Teplizumab is approved, then there will be a treatment available to delay the onset of T1D.

Also, these risk screening projects have been critical to learning how T1D naturally progresses, and also to finding people to participate in the more specific prevention and delay studies mentioned above.  So participants are helping to move forward important parts of T1D research, no matter how much they personally benefit during the study.

A final word about terminology: TrialNet uses a four stage timeline of T1D progression described here:
The basic summary is that stages 1 and 2 are people who have two or more autoantibodies [definition], but no symptoms that a patient would notice.  Stage 3 is honeymoon, and stage 4 is established type-1 diabetes.  However, this is not the terminology used (or understood) by most people effected by T1D, which is why I use more informal terminology: "at-risk" meaning people with 2 or more antibodies, but no symptoms (stage 1 and 2 in TrialNet terminology), and then "honeymoon" for stage 3 and "established" for stage 4.

More Reading


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.