Monday, September 18, 2017

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


Catching Up With NNC0114­-0006 (Anti IL-21)

Back in 2015 Novo-Norsk started a clinical trial into a combo treatment of NNC0114-0006 and Liraglutide (which is more commonly known as Victoza).  I ignored this trial, because I thought that NNC0114-0006 was a new form of insulin, and they were testing a treatment for type-1 diabetes. However, I have since found out that NNC0114-0006 targets IL-21 and that Liraglutide may stimulate beta cell growth.  Therefore, this combination could have the effect of stopping the autoimmune attack while at the same time regrowing beta cells, and that would be a path to a cure.

Liraglutide is approved for use in type-2 diabetes and works by increasing insulin production. Recently, experiments in mice have suggested that it works (at least partly) by helping the body grow more beta cells, and preventing the death of beta cells:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418765/

NNC0114-0006 is an anti IL-21 treatment.  IL-21 is a chemical that the immune system uses for communication, and several experiments have suggested that too much IL-21 is important to creating type-1 diabetes:
https://www.ncbi.nlm.nih.gov/pubmed/18779574
https://www.ncbi.nlm.nih.gov/pubmed/19208913
https://link.springer.com/article/10.1007/s00125-015-3509-8
(and there are many more such studies.)

So combining these two treatments provides a possible path to a cure.

The Current Study

The study that started in 2015 is a phase-II? trial (the question mark means that it is a phase-II trial, but there has never been a phase-I trial for this combination of treatments).  The basic study design is four groups: one group gets both treatments, one group gets two placebos, one group gets NNC0114-0006 and placebo, and one group gets Liraglutide and a placebo.  So they have all their bases covered. The study is large: 304 people recruited from 100+ sites all over the US and Europe.

The clinical trial record says that this study is recruiting patients.  However, when I look at the list of locations, every one is marked "Active, not recruiting", "Completed", or "Suspended", so I'm very hopeful that they have recruited all the patients that they need.  That is important, because they expect to collect data for 80 weeks.  Their target completion date is April 2019.

This is actually the fifth study of NNC0114­-0006.  You can see the list here:
https://www.clinicaltrials.gov/ct2/results?cond=&term=NNC0114%C2%AD-0006
The four previous studies were smaller (between 10 and 65 people), and were done on other autoimmune diseases: Rheumatoid Arthritis, Crohn's Disease, and Systemic Lupus Erythematosus.

Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT02443155
Other Study ID Numbers: NN9828-4150
2014-001215-39 ( EudraCT Number )
U1111-1154-7172 ( Other Identifier: WHO )
REec-2015-1768 ( Registry Identifier: Spanish registry )

Metreleptin Fails A Phase-I Trial

Back in the 2008-2010 timeframe there was some hope that Leptin would cure type-1 diabetes, and a clinical trial was started in 2010.  Then in 2015 the trial was canceled by one of the sponsors.  Finally, now in 2017 the results have been published, and the conclusions are:
Metreleptin is safe but may not be efficacious in improving glycemic control in patients with T1DM, although it reduces body weight and daily insulin dose modestly.
You can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Leptin
The abstract is here: http://care.diabetesjournals.org/content/40/5/694?etoc
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01268644

Interesting Treatment for Multiple Sclerosis

I usually do not blog on cures or treatments for other diseases.  However, MS, type-1 diabetes and several other diseases are all from the same family of "autoimmune diseases".  They are all caused by the body's immune system attacking a different organ or internal system.  So in theory, research into curing one of these diseases might help cure the others.

So with that in mind, I thought this study was interesting:
Multiple Sclerosis Therapy NKTR-358 Begins Phase 1 Clinical Trial:

Basically, this company has a treatment which causes a person to generate more Treg cells.  Since Treg cells regulate the immune system, having more of them might prevent the immune system from attacking the wrong cells.  In type-1 diabetes, we have several research programs aimed at increasing Treg counts, but usually by growing more Tregs outside the body, and then infusing them into the body (T-Rex, Stem Cell Educator, and Stem Cells of Arabia are all working on similar ideas). NKTR-358 is a treatment which (they hope) will cause the body to generate more Treg cells, itself.

Also, NKTR-358 works at least partially, by targeting the IL-2 receptor in the immune system, and this receptor is also an active target of research in type-1:
http://cureresearch4type1diabetes.blogspot.com/2016/05/general-update-on-il-2-research.html
(and the IL-2 targeted by NKTR-358 is different than the IL-21 targeted by NNC0114-0006 above.)

Company Information: http://www.nektar.com/pipeline/rd-pipeline/nktr-358
Some animal data: http://www.nektar.com/application/files/6514/9970/7031/Langowski_NKTR-358_WCI2017.pdf

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, September 4, 2017

ViaCyte Clinical Trial News: VC-01 is Fully Enrolled, VC-02 Starts

This blog posting covers two important pieces of news from ViaCyte.

ViaCyte's Phase-II Trial of VC-01 is Not Recruiting
(But What does that mean?)


I missed this news, when it was announced back in May 2017, but ViaCyte's Phase-II clinical trial of VC-01 is not recruiting more people.  I'm not sure if this is a "pause" between their phase-I group and their phase-II group, or if they have finished recruiting all people for both groups.  That's important because they are gathering effectiveness data for six months.  So whatever group they finished recruiting in May, they should have effectiveness data in November.  Effectiveness data for 15 people would be good, but from the full 65 people would be even better.  Since this trial is not blinded (and has no control group), they could publish their data as soon as they have it, if they want to.

Also, they are gathering safety data for two years, so that same group will finish gathering safety data in May 2019.  The same "15 people is good 65 people is better" and "with no control group, they can publish if they wish" applies to this safety data as well.

Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02239354

Differences Between ViaCyte's VC-01 and VC-02 Treatments

ViaCyte has started a clinical trial for their VC-02 stem cell implantation product, but as this treatment is not a cure (by my definition of "cure"), I will not be following it.  Don't mix up VC-02 with their earlier VC-01 product.  VC-01 is a potential cure, and I will follow it moving forward.

I found this confusing: why would a company test a non-cure after they had a cure already in the pipeline, and ahead of the non-cure?  Why even bother with the non-cure?

While VC-01 and VC-02 are encapsulated stem cells, the nature of the encapsulation is completely different.  VC-01 uses a "strong" encapsulation which prevents the body's immune system from attacking the new cells. This prevents both the normal rejection (ie. the foreign organ reaction), and type-1 rejection (ie. the malfunctioning autoantibody reaction) from attacking the new cells.  Therefore, VC-01 does not require anti-rejection drugs.  VC-02 uses a "weak" encapsulation which holds the stem cells together and in one place, and encourages new blood vessels to integrate into the encapsulation, but provides no immune protection.  People getting VC-02 will need to take anti-rejection drugs [d1].

Both VC-01 and VC-02 have the same cells inside.  They both start with ViaCyte's PEC-01 cells. These are created by harvesting human embryonic stem cells from a long-existing culture and treating them so they differentiate into pancreatic cells.  The cells that are inside the devices are these pancreatic cells.   (There are no "raw" stem cells in the device.)  This process is described on ViaCyte's web site here:
http://viacyte.com/technology/stem-cell-engineering/

The obvious question is, why would any person with type-1 diabetes choose to be in the VC-02 trial, if they could be in the VC-01 trial?  The immunosuppression required by VC-02 has known bad side effects, and there are known risks in taking those drugs for decades.

First is that the VC-01 trial is not recruiting right now.  So if you want an encapsulated ViaCyte stem cell treatment right now, VC-02 is your only option.  I don't know if the VC-01 trial is completely enrolled, or if it will open up again, to gather a second group of patients.

Second is this: The ViaCyte team believes that the reason some implanted beta cells work and some fail is "vascularization".  Vascularization is the body's ability to grow blood vessels into the new beta cells so that they can get oxygen, remove waste products, and generally integrate with the host person.   ViaCyte believes that the encapsulation used in VC-01 will allow this vascularization and therefore be successful.   However, they also believe that VC-02 will have even better vascularization, and therefore an even higher chance of success.  So if someone currently has type-1 diabetes, they may choose to have VC-02 because it has a higher chance of success (even if this is a trade off against a known higher risk from the treatment).

The VC-02 Study

Although there is only one official clinical trial of VC-02, there are two patient groups within this trial (which they call "cohorts"), and these cohorts are really separate phase-I and phase-II trials. It's just that one clinical trial registry covers both. The first cohort will be 15 patients, all of whom will get a low dose version of the treatment. The second cohort will be 40 patients, all of whom will get a higher dose version of the treatment. There is no control group. They expect to finish the second cohort in Dec 2020.

They are collecting their primary safety data at 4 months post transplant, and primary effectiveness data (C-peptide data) at 6 months post transplant.

They are recruiting at two sites:

  • University of California San Diego, San Diego, California, United States, 92121
    Contact: Study Coordinator    1-844-317-STEM (7836)    alphastemcellclinic@ucsd.edu
  • University of Minnesota Recruiting, Minneapolis, Minnesota, United States, 55455
    Contact: Study Coordinator    612-626-4993    kreel001@umn.edu

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03163511
ViaCyte's FAQs: http://viacyte.com/clinical/faqs/

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 14, 2017

Possible Cures In The News (August)


The blog posting is a collection of small updates to existing clinical trials.

The TN20 (Oral Insulin) Phase-II Clinical Trial Completes Enrollment 

TN20 is the name of a specific oral insulin clinical trial, which completed enrollment in March 2017. Since this study will follow people for one year, they should finish collecting data in March 2018.

The following blog post:
https://cureresearch4type1diabetes.blogspot.com/2017/07/phase-iii-results-from-oral-insulin.html
covers oral insulin in detail, describing why people think it might prevent type-1 diabetes, and the other clinical trials (and there are several) currently running.

Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02580877

T-Rex Study Is Half Enrolled

I've previously blogged on the T-Rex study (sometimes under the name "Polyclonal T-Regs"):
https://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs

It is currently in a phase-II clinical trial, and that trial is now half enrolled (56 people out of 111).

This study is unusual in that it can enroll kids as young as 8, and is recruiting people at over a dozen different sites in the US: https://clinicaltrials.gov/ct2/show/study/NCT02691247#contacts

News: http://www.diabetes.co.uk/news/2017/jul/pioneering-t-rex-study-reaches-milestone-in-treating-children-with-type-1-diabetes-96973185.html

A quick summary of this treatment is as follows: remove one specific type of T regulator cell (called "CD4(+)CD25(+)CD127(lo)") from a person with type-1 diabetes.  Grow them out so you have about 500 times more, and then put them back in the same person.  Since regulatory T cells naturally regulate the body's immune system, and the patient now has more of them, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.

Results from the previous phase-I trial found that this treatment preserved beta cells.  C-peptide levels remained constant in the treated group.  Since C-peptide levels drop during the honeymoon period, these treated people did better than untreated people would be expected to do.  The previous phase-I study did not have a control group, but the current phase-II study does.

Results of Phase-I Clinical Trial of REMD-477 for T1D

I probably will not cover this moving forward, because it is more treatment than cure. REMD-477 is a  Glucagon Receptor Antibody.  The hope is that giving this to people with type-1 will cause them to produce less glucagon and therefore use less insulin.   This was a 21 person trial, where half the people got the treatment and half did not.  The people spend a few days in a hospital, and then were followed for a few weeks "in the wild".

They found that glucagon levels did go down (20-30%), insulin requirements did go down (about 10%), and people did spend more time in their target BG range (about 15%), for a few weeks after treatment.

Slides: https://professional.diabetes.org/sites/professional.diabetes.org/files/media/2017_press_program_ppt_pettus-final.pdf
Several Press Releases: http://sashayan.edicy.co/new-media
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02715193

They have started a follow up study, which will enroll 75 people and last 24 weeks.  They hope to finish it in Sept-2018: https://clinicaltrials.gov/ct2/show/NCT03117998

I suspect that any treatment which lowers glucagon levels is going to have some impact on people who play sports, and anyone who has an unexpected low (especially if they need a Glucagon injection, but even if not).  This study did not address either of those issues, but I suspect that follow on studies will need to, if they want FDA approval for this as a treatment for type-1 diabetes.

Diamyd Unsuccessful in Phase-II Clinical Trial on Presymptomatics 

This study is another testament to the optimism of researchers.  Diamyd ("GAD Vaccine") has been tested for over 10 years.  None of these trials has been particularly successful.  They culminated in an unsuccessful Phase-III trial years ago.  You can read my previous blogging on Diamyd here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd

However, researchers are natural optimists.  And it is important that they are.  Society needs optimistic researchers so that they will repeatedly attack problems, and not give up, even in the face of adversity.  Previous Diamyd trials had been done on honeymooners, so this trial was done on presymptomatics. Unfortunately it failed.

News Coverage: http://www.diabetesincontrol.com/ada-alum-gad-diamyd-vaccine-fails-to-prevent-type-1-diabetes
Press Release: http://www.diabetes.org/newsroom/press-releases/2017/larsson-scientific-sessions-2017.html
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01122446

Discussion

This trial reminded me that, in the world of type-1 diabetes, if the headline reads "new treatment shown safe" that really means "new treatment is not effective".  Almost all clinical trials aimed at type-1 diabetes measure both safety and effectiveness. This is especially true of phase-II trials, like this one, and phase-III trials. Since effectiveness data is obviously more news worthy than safety data, if the headline talks about safety, that means the treatment was ineffective.

The headline for the press release above is classic that way "Autoantigen GAD-Vaccine is Safe for Children at High Risk for Developing Type 1 Diabetes", while the headline for the news coverage is much more accurate "ADA: Alum-GAD (Diamyd) Vaccine Fails to Prevent Type 1 Diabetes".

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Friday, July 14, 2017

Update On Dr. Faustman's BCG Research

There was some media buzz about Dr. Faustman's BCG research as reported on a poster at ADA 2017.  I can't link directly to it, but you can go to this page:
https://ada.apprisor.org/epsSearchADA.cfm
and search for Faustman to see the poster and the abstract.

Dr. Faustman's research has about 15 years of history, which I've blogged about before, here:
http://cureresearch4type1diabetes.blogspot.com/2014/04/dr-faustman-starts-phase-ii-trial-for.html
http://cureresearch4type1diabetes.blogspot.com/2012/08/summary-of-drfaustmans-phase-i-results.html
And in several other blogs.

But to summarize very quickly: Dr. Faustman's previous research was based on the idea that BCG (a Tuberculosis vaccine) increases the levels of TNF, and higher TNF levels could result in less autoreactive T cells, and this would lead to a cure for type-1 diabetes.  Unfortunately, this did not pan out.  Her phase-I trial showed that BCG did not change the levels of live autoreactive T cells in circulation.  However, using some non-standard data analysis, Dr. Faustman interpreted the phase-I study to show that there was an increase in T-reg immune cells.  T-reg cells get rid of the autoreactive T cells, so increasing the T-reg cell count could also lead to a cure for type-1 diabetes.

What is the New News?

The poster presented at ADA 2017 contained data on a possible mechanism whereby BCG could increase the level of T-regs in a type-1 diabetic.  This mechanism involved changes to how genes are used in the body (called "epigenetic changes").  These changes can be long lasting.  Obviously, a long lasting treatment is better than a short lasting one, so (if this finding is confirmed by more research) this is good news.

Also, although not required, it is nice to have a theoretical basis for why a treatment should work, if you are going to test that treatment. This is particularly true of the BCG research, since the phase-I trial showed pretty clearly that the previous theory was wrong, so having a new theory is good.

How Important Is This?

In my opinion, it is not very important. Why not?  In a nutshell:
1. It's a finding about a possible mechanism of how a cure works, not evidence of effectiveness, for a treatment where effectiveness is the important, unanswered question.
2. It's based on data from 3 people.
3. It's a poster, not a presentation (or a paper).

1. It's a mechanistic finding so it is aimed at answering the question "how does BCG work?", but the important question is "does BCG work?"  That needs to be answered before the "how" question is important.  The results from the phase-I trial were not successful (see discussion below).  Therefore, for me, research into the mechanism of how it might work is less important until we get some evidence that it does work.

2. Dr. Faustman's phase-I study gave BCG to only three people.  It is the smallest phase-I study I have ever covered in the field of type-1 diabetes.  This poster is based on data from those same 3 people, and that is not a large enough foundation to get me excited.

3. As a poster, this is a lesser form of publication, than a journal article or a presentation.  That is not fatal, of course, but it is a handicap.  For comparison, Gleevec and Oral Insulin both merited presentations, so the organizers of the ADA scientific sessions clearly thought that those studies were more important than this BCG result.  (And I agree with them.)

Some Discussion on The Results From the Phase-I Trial

Obviously, Dr. Faustman considers the phase-I trial to be a success, which is why she has started a phase-II trial, so why do I consider it unsuccessful?  For two reasons:

First, the normal definition of success for a clinical trial is successful results from the primary outcome.  Her phase-I trial's primary outcome was autoreactive T cells, and there was no difference between the the treated group and the control group.  So that's an unsuccessful result.

She did report two tiny successful outcomes in her secondary results.  But to get those, she had to do two different data manipulations.  I discussed those in detail in 2012 when the original results were published:
http://cureresearch4type1diabetes.blogspot.com/2012/08/details-of-dr-faustmans-phase-i-results.html
See the section called "Weaknesses in Data Analysis".

A very short summary is:
1. She shifted 1/3 of her control group to be analysed as though it were in the treatment group, after she had seen the results, and saw that would change the outcomes.
2. She did not use a single control group.  Rather, she used different control groups for different outcomes, including (in some cases) pulling data from other studies.

My older blog posting describes in detail how damaging these are to her analysis.  But suffice it to say, if the data shows success, there is no reason to do those manipulations.  And if the data is successful (even at a tiny level), only after those manipulations, then how real is it?

Now, if her phase-II study (which is expected to enroll about 150 people) is successful using standard data analysis techniques, then she can rerun this poster study with data from those 150 people.  She will then have more people and a successful treatment and at that point, a mechanistic study would be interesting. The phase-II study is expected to end around 2023.


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.

Phase-III Results from an Oral Insulin Clinical Trial In Presymptomatics


A Quick Introduction to Oral Insulin to Prevent T1D

Obviously, all type-1 diabetics need to take insulin in order to process carbohydrates. This insulin must be injected, because if it were taken orally it would be digested into smaller pieces and would not work as insulin [d1]. Injecting insulin in this way does not cure or prevent type-1 diabetes, it just treats it.

However, one of the autoantibodies that is associated with type-1 diabetes targets insulin molecules[d2]. Therefore, there is a theory that giving insulin to people with T1D might prevent or delay the onset of type-1 diabetes by training the body not to produce this autoantibody. The process is vaguely similar to giving small amounts of peanut proteins to people with peanut allergies[d3]. Insulin pills may work for this purpose even though they would not work as a treatment for type-1.

The Phase-III Study (Structure and Results)

These researchers started with 10,000s of TrialNet participants, and enrolled 560 people who were "presymptomatic". They showed two autoimmune markers, but no symptoms of type-1 diabetes. All of these people tested positive for one particular autoantibody associated with T1D (micro insulin autoantibody) [d2], but they were further subdivided into four groups based on the other autoantibodies they tested positive for, and how much insulin they were producing.

Each subgroup was split in half. One of these halves got oral insulin twice a day, and the other half got a placebo. They were followed for a year or longer to see how many people in each group developed type-1 diabetes as measured by "classic" symptoms.

If you look at the entire study, oral insulin did not have a statistically significant effect. However, if you looked at one subgroup specifically [d4], that subgroup did show a statistically significant effect. For that one subgroup, about 18% of the treated group came down with T1D, while 34% of the untreated group did. The researchers viewed this as delaying the onset of type-1 diabetes by 2.5 years (on average) for this subgroup.

Presentation Slides:
https://professional.diabetes.org/sites/professional.diabetes.org/files/media/2017_press_program_ppt_greenbaum-final.pdf

News Coverage:
https://www.healio.com/endocrinology/diabetes/news/online/%7Bbdefed06-5c4e-442f-8724-972e380cdbcb%7D/oral-insulin-therapy-fails-to-prevent-type-1-diabetes-but-some-see-disease-delay
http://www.diabetesincontrol.com/ada-oral-insulin-may-delay-type-1-diabetes-onset/

Clinical Trial Record:
https://clinicaltrials.gov/ct2/show/NCT00419562

Discussion Of This Study

The results of this study are clearly "bad news on one hand, good news on the other". If you look at the study as applied to all presymptomatics, it was not successful. On the other hand, if you look at it for one specific subgroup, then it was successful. So the obvious thing to do is to try to replicate the results on the specific subgroup where it was previously successful. If so, this could turn into a delaying or preventative treatment for the 10% of patients who fall into this group. Since this subgroup had a specific combination of autoantibodies, it is straightforward to test ahead of time, and give oral insulin to people with this same combination, but not other combinations (where it did not work).

This trial was the size of a phase-III trial. However, the success was only seen in a subgroup, and that subgroup was the size of a phase-II trial. So I would not think of this as a successful phase-III trial, but rather as a successful phase-II trial (meaning that at least two phase-III trials should be expected before it becomes commonly available) [d5].

It is also important to remember that as group size gets smaller, the chance for accidental correlation gets bigger. With these sorts of subset analysis, it is always possible that the effect seen is cause by luck rather than effect. In this particular case, the results were statistically significant even for the smaller group, which is a good sign, but only larger studies will be conclusive.
The History of Oral Insulin

Oral Insulin has a long, complex history of clinical trials, and the results are very mixed (like this study). Just before I started my blog (so 10+ years ago), the results of an oral insulin for prevention trial were announced, and the trial was unsuccessful. However, the researchers analysed the data in more depth after the study concluded, and realized that it had worked for one subgroup (sound familiar?) That was the micro insulin autoantibody subgroup, and that's why everyone in this study had that antibody.

But the idea that oral insulin might prevent/delay type-1 is a popular one, and there are at least three clinical trials running right now. All three of these studies are similar, except for size: the first is 44 people, the second is 220, and the third is 92.

Oral Insulin Starts a Phase-II Trial In Germany (pre-POINT Early)
Recruiting:
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes der Technischen Universität München, München, Germany, 80804
Started in Aug 2015 and expected to finish in Aug 2017
News: Vaccination against type 1 diabetes may soon be available to young children:
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02547519

Phase-II Oral Insulin Trial In Germany (Fr1da)
Recruiting:
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, München, Deutschland (DEU), Germany, 80804
Anette-G. Ziegler, Prof. Dr., MD +49 (0)800 464 ext 8835 diabetes.frueherkennung@helmholtz-muenchen.de
Started in Dec 2015 and expected to finish in June 2021
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02620072


Phase-II Oral Insulin Trial In The US (TN20)
Not recruiting.
Started in Jan 2016 and expected to finish in Dec 2017.
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02580877
Extra Discussion

[d1] To complicate things, several researchers are working on creating a form of insulin which could be eaten, but which would avoid digestion, so that it could be used to treat type-1 diabetes. This is also called "oral insulin" research. In this blog posting, I'm talking about oral insulin as a cure or preventative for T1D, not as a treatment.

[d2] Autoantibodies are the malfunctioning antibodies which cause the immune system to attack beta cells. There are five autoantibodies associated with type-1 diabetes, and there may be more that we haven't discovered yet. The five we know about are:
* micro insulin autoantibodies (mIAA or just IAA)
* islet-cell antibodies (ICA)
* glutamic acid decarboxylase (GAD) antibodies
* islet antigen-2 (IA-2) antibodies
* zinc-transporter 8 (ZnT8) autoantibodies
The last one was not used in this study, possibly because it tends to show up later in the disease process.

[d3] It is important to realize that type-1 diabetes is NOT a conventional allergy to insulin. It is similar to allergies in that it is the body's immune system overreacting to something that it should not react to, but other than that, is quite different. Allergies involve the immune system overproducing histamines. These histamines attempt to get physical irritants, like pollen, out of your body. You can counter this histamine reaction by taking antihistamines. Type-1 diabetes involves the immune system overproducing malfunctioning killer T-cells (or perhaps under producing regulatory T-cells). These malfunctioning killer T-cells mistakenly kill beta cells, thinking they are foreign cells (ie. living creatures like viruses, that have invaded the body). So the mechanism is different (histamines vs. T-cells), and the mistaken target is different (physical things, like pollen or wheat vs. living organisms, like viruses).

[d4] The subgroup that showed the effect was the micro insulin autoantibody (which everyone in this study had), and either the ICA autoantibody or both the GAD and IA-2 antibodies, and also low insulin secretion at the start of the study.

[d5] As far as I can tell, oral insulin is not approved for the treatment of any disease in the US, and is not available either by prescription or "over the counter". Therefore, it will need to go through full US FDA approval, which requires two phase-III trials. I don't know if the FDA would consider this a phase-III trial for approval purposes.

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, July 5, 2017

Presymptomatics and Two Clinical Trials for Victoza / Liraglutide

First, a new word: "Presymptomatic". This refers to people who have tested positive for two autoantibodies, but who have no other symptoms of type-1 diabetes. Their blood glucose levels are normal (not elevated), etc.

Presymptomatics are not yet diagnosed with type-1 diabetes in the classic way, but current theory is that all of these people will eventually be diagnosed. It is just a matter of time. So in the same way I might say "Drug X starts a phase-I trial in honeymooners" or "Treatment Y starts a prevention trial" or "Drug Z starts a trial in people with established type-1 diabetes", I will also start to report "Drug W starts a phase-I trial in presymptomatics".

You can think of presymptomatics as pre-honeymooners.  They are like honeymooners, but even earlier in the disease process.

I also want to stress that although the JDRF, the ADA, and the Endocrine Society agree that two autoantibodies is the earliest diagnostic for type-1 diabetes, this is not universal agreement, and what agreement there is, is only about 2 years old.  Here are some web sites which describe this view of the stages of type-1 diabetes:
This also changes when "diagnosis" occurs.  In the past, diagnosis occurred when symptoms were seen, and confirmed with a blood glucose measurement.  However, now diagnosis occurs when two autoantibodies are measured, and this is often years before symptoms are seen, or blood glucose levels are noticeably abnormal.

So, moving forward, I will use the term "classic diagnosis" or to refer to people who were diagnosed because they showed symptoms, as was done in the past, so it's obvious what kind of diagnosis I'm talking about.

Discussion

I expect there will be more studies like the two described below, that specifically target presymptomatics. After all, any treatment that researchers thought might work for honeymooners (but did not), should now be retested on presymptomatics. This is especially true of treatments which change the immune system.

In the past, it's generally been understood that to cure type-1 diabetes, you needed to change the immune system (so it stopped generating autoantibodies and stopped attacking beta cells), but you also needed to regrow beta cells.  However, presymptomatics have enough beta cells so that they can regulate their own blood glucose levels.   To cure them (ie. to prevent symptoms from ever showing up), "all" you need to do is change the immune system.  No need to regrow any beta cells.

That sounds important, and it is, especially when you think about treatments that have already been shown to stop the destruction of beta cells.  In the last 5-10 years, several treatments have been shown to "preserve beta cells" meaning that once given, beta cells stop being killed off by the immune system.  Since these studies were typically done in honeymooners, this did not cure anybody, it just extended the honeymoon.

But if those same treatments showed the same results in presymptomatics, then it could be said that they prevented type-1 diabetes.  I very much hope that every treatment which has previously been found to preserve beta cells, will now be tested on presymptomatics. Some of the treatments which have preserved beta cells in honeymoon diabetics (at least to some degree) are: T-Rex (polyclonal Tregs), Abatacept (Orencia), Etanercept (ENBREL), and Teplizumab. 

Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics

About this trial: it's testing the theory that Liraglutide (sold as Victoza) might help people use less insulin or delay their use of insulin, when given to people before they are classically diagnosed with type-1 diabetes.  This is an early phase-I trial.  Only 10 people will be enrolled, and there is no control group.   This trial recruits people who have started to have trouble generating insulin in response to food that they've eaten.  They will be followed for one year.  The trial started in March 2016 and they hope to finish by July 2018.

They are recruiting only by invitation at several nordic hospitals:
  • University of Oulu and Oulu University Hospital, Dept of Children and Adolescents Oulu, Finland, 90029
  • University of Tampere and Tampere University Hospital Tampere, Finland, 33520
  • University of Turku and Turku University Hospital Turku, Finland, 20520
  • Lund University and Skåne University Hospital Malmö, Sweden, 205 02
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02908087

Discussion

The Clinical Trial Record lists this as a phase-II trial, but with only 10 people included and no control group, I consider it a phase-I trial.

I don't see how this trial could ever prove any level of effectiveness.  We don't know how many people eligible to enroll in this study would "naturally" have type-1 diabetes symptoms within the one year study time.   And, this trial has no control group.  So there is no way to compare the results from this study to "normal" results to see if it worked or not.

It could show safety, but the drug being tested has been approved for use in overweight people and also people with type-2 diabetes for years, and is used "off label" by some people with type-1 diabetes, so safety is not really an issue.

Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics

This trial is similar to the one above, except that it is much larger, and recruiting a slightly different population.  This second trial recruits people who have two autoantibodies and one of several different glucose abnormalities, so it's a larger group of people, and also more in tune with the "two autoantibodies means type-1 diabetes" definition of Presymptomatic.  

This is an phase-II- trial which will enroll 82 people with half in a control group and half getting the treatment.  People will be followed for one year.  The trial started in 2016, and is expected to finish in mid 2019.  They are recruiting by invitation only at the same hospitals listed in the previous trial.


Discussion

(As you read this remember that I'm not a statistician, and have never take a college level class in statistics.)
I'm a little worried about the statistical power of this study.  They are going to have 41 people in their treatment group, and will follow them for one year.  The data I've seen suggests that about 10% of the people with two more more autoantibodies will show classic type-1 diabetes systems each year.  So that means that we should expect about 4 from this group to show symptoms by the end of the study. If this treatment were perfect in preventing type-1 diabetes, then 0 in the treated group would show symptoms.   But the difference between 0 and 4 is not that large.   And the treatment is unlikely to be perfect the first time it is tested.  Let's say that 2 people in the treated group get symptoms, but 4 people in the untreated group get them.  Is that a 50% reduction in diagnosis (which would be huge) or is that just a little good luck involving two patients?  It's hard to tell, and that is what I'm worried about.

On the other hand, this is a phase-II study, so will not be the last word, in any case, and Victoza is already approved, so is not a particularly risky drug.  Also, if the results for the first year are good, then it would be relatively easy to extend this trial for another year (or longer) which would increase its statistical power.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Friday, May 19, 2017

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


Phase-I Study of Of Gluten Free Diet In Honeymoon Type 1 Diabetes (Diabglut)

This trial will recruit 160 children, aged 3 to 18.  It started in December 2015, and is expected to end in December 2020. Half of the people will be put on a gluten free diet within one month of diagnosis, and the other half will not (and will be the control group).

This study is being done in Skanes University Hospital, Lund, Region Skane, Sweden, 22185
Contact: Annelie Carlsson, MD PhD    +46768267170    annelie.carlsson@med.lu.se
Contact: Iren Tiberg, PhD, nurse       iren.tiberg@med.lu.se

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT03037190

Discussion

My first thoughts when I saw this study were: "Why do a study like this?  Does anyone really believe that a gluten free diet will cure/improve type-1 diabetes?"

The researchers included four previous studies as references for this work, but I think the one that mattered was this one:
https://www.ncbi.nlm.nih.gov/pubmed/22729336
This is the case study of a single patient (a five year old boy).  He was was put on a gluten free diet a few weeks after diagnosis, and remained off insulin for 20+ months.  That's an unusually strong honeymoon, and I think it is reasonable to say that the researchers are hoping that they can create that kind of honeymoon in other newly diagnosed people.

For me, case studies (like this one) represent a middle ground between anecdotes and scientific studies.  I don't think they are very strong by themselves, but I do think that following them up with a research study is a good way to proceed.

The other three studies cited by the researchers as background for this research were much less dramatic. One study tried delaying introduction of gluten in the diet of babies: no effect. Another tried putting people with two antibodies on a gluten free diet before diagnosis: no effect on eventual diagnosis, but might have a small effect on beta cell survival after diagnosis. The third study was population based, and suggested that introducing gluten earlier (at 4 months, rather than later) might lower the rate of celiac diagnosed at 12 years. As a population study, I don't put a lot of weight on it, and the impact was to celiac and not type-1, in any case.

Minimal Islet Transplant at Diabetes Onset (MITO)

This is mostly a transplant trial, so I don't expect to follow it moving forward, but it is a different type of transplant, so I'm describing it here.

Most transplants are done on the most seriously impacted people with type-1 diabetes.  These people often have a lot of trouble controlling their type-1, they are often already having serious complications, and are generally on the worst side of the type-1 spectrum.  These are the people who often volunteer for transplantation.

This study is targeting the opposite: people who within 6 months of type-1 diagnoses, and are still generating some residual insulin.  The idea is to transplant some islet cells in combination with ATG, G-CSF, and Rapamycin treatments. It's a "kitchen sink" approach.  All of those treatments are in active clinical trials right now, but none of them has been shown effective so far.

I do think that it will be valuable to get data from people who are not so extremely sick when they get their transplant, although I doubt this will lead to a cure in the short term.

They are recruiting 6 people in Italy:
IRCCS San Raffaele Scientific Institute   Milan, Italy, 20132
Contact: Lorenzo Piemonti, MD   0226432706 ext 39    piemonti.lorenzo@hsr.it
Contact: Paola Maffi, MD       paola.maffi@hsr.it
Contact: Emauele Bosi, MD 0226432818 ext 39 emanuele.bosi@hsr.it

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02505893

T-Rex Now Can Enroll People 8 Years Old, and Older

Previously, they could enroll people as young as 12, but they have enough safe results with those kids, so that the FDA will now allow kids as young as 8 to enroll. You can read all about the technique they are using and who is eligible in my previous blogging:http://cureresearch4type1diabetes.blogspot.com/search?q=T-Rex

Also, the last time I blogged, this study was only recruiting in two locations, but now they are recruiting all over the US, from Oregon to Connecticut to Florida to UCSF, not to mention Tennessee, Missouri, Massachusetts, Indiana, and that is not a complete list.  (See the Clinical Trial Record, link below, to get a complete list.)

This is a phase-II trial which is a follow on to the previous "Polyclonal T-Reg" study, which I also blogged about here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs
(Look at all the postings in this link, except the first one, in order to see the history of this treatment.)

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02691247

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.