Saturday, April 12, 2014

Dr. Faustman Starts a Phase-II Trial for BCG

Dr. Denise Faustman, of Harvard, has filed the paperwork to start a phase-II trial testing BCG (Bacillus Calmette–Guérin) as a cure for type-1 diabetes.  She is not recruiting patients quite yet, but should start very soon.  This study will be done in Boston.

Background

The essence of Dr. Faustman's theory on how to cure type-1 diabetes is:
  1. BCG causes the body to generate TNF
  2. TNF causes fewer autoreactive T-cells
  3. Fewer autoreactive T-cells results in natural beta cell regrowth and more insulin generation
  4. More insulin generation is the path to curing type-1
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.

TNF ("Tumor necrosis factor" or TNF-alpha) is a naturally occurring protein that can cause cells to die. It is involved in the natural regulation of immune cells.

"Autoreactive" refers to immune cells which mistakenly attack the body's own beta cells. The destruction of these beta cells leads to type-1 diabetes. This is sometimes referred to as an "autoimmune attack" because the body's own immune system attacks the body itself.

A timeline for Dr. Faustman's research can be found here:
http://cdn.knightlab.com/libs/timeline/latest/embed/index.html?source=0AgnCSepg2XrIdGNMY3FVTy1UTHc4WW1MaklhdUxaVkE&font=Bevan-PotanoSans&maptype=toner&lang=en

But the important milestones are:
  • Dr. Faustman announced cures for NOD mice in 2002-2003
  • Dr. Faustman ran a phase-I trial in people from 2007 to 2012
  • Dr. Faustman is starting a phase-II trial, now (in 2014)
This Trial

With all that as background, here are the key design points for the phase-II clinical trial, all taken from the clinical trials record:
  • 120 people involved.
  • Some will get BCG, some will be part of the untreated, placebo group.
  • Double blind (meaning neither the patient nor the researcher will know who got what).
  • Randomized (meaning people will be randomly assigned BCG or placebo group)
  • Patients will get two doses of BCG, one month apart in the first year, and one dose per year for four years after that.
  • Primary end points (most important outcome measure):
    • A1c
    • C-peptide after a meal
  • Secondary end points (other important outcomes):
    • Targeted death of auto reactive T cells (ie. "bad" killer T cells)
    • Autoantibody levels
    • Urinary C-peptide levels
  • The trial is expected to finish collecting data in 2019, and complete in 2022. 
Here are the two key paragraphs from the clinical trials record:
The purpose of this study is to see if repeat bacillus Calmette-Guérin (BCG) vaccinations can confer a beneficial immune and metabolic effect on Type 1 diabetes. ... 
Eligible volunteers will either be vaccinated with BCG in a repeat fashion over a period of four years or receive a placebo treatment. The investigators hypothesize that each BCG vaccination will eliminate more and more of the disease causing white blood cells that could offer relief to the pancreas for increased survival and restoration of insulin secretion from the pancreas.
Discussion

There is a lot to like about this trial (as described in the paperwork).  It's much stronger than the phase-I trial.  Its size (120 people) is large for a phase-II trial for type-1 diabetes, and certainly it will run long enough to see if there is any result at all.  It's double blind and randomized, and is measuring things important both to people with type-1 and to researchers into type-1.

For me, the important numbers being gathered are the C-peptide data after a meal.  That's what the FDA looks for in type-1 drug approval, and that is the most direct measure that the treatment is helping.

But, it's going to take a very long time.  The current plan is to complete data collection in 2019, and finish the study in 2022.  That means it is reasonable to expect publication in the 2022-2023 time frame.  I specifically asked if they were going to publish interim results (for example: after one or two years), and the answer was no.  But they certainly do understand that 2022 is a long time to wait.

I'm also worried about the BCG dose they are using.  It is only very slightly different than the dose on their previous phase-I trial.  The phase-I trial (which saw only tiny results, and maybe not even that) dosed twice, a month apart.  This trial does the exact same, then waits a year, and doses once more, repeating the one dose per year for a total of four years.  They hope to see improvements after each yearly dose.  Some recent work in using BCG to treat multiple sclerosis (another autoimmune disease) gives them optimism about this dose.  But in the phase-I trial, the results after 2 doses were so tiny that even if they saw 5x that size result, it will be no where near a cure.  Still far to small.  To repeat: if the two doses a month apart did little/nothing the first time, why should they do more now?  And the additional one dose per year, seems like a small difference for large hopes.

There is another worry as well, which comes directly from Dr. Faustman's phase-I trial.  That trial (as first described in their clinical trials record) was quite different than the actual trial (as published).  The paperwork included 25 people and a standard placebo group.  However, the completed trial only involved dosing 3 people, and several different comparison groups (used for different end-point measurements).  Hopefully we will not see that kind of downsizing or design change in this clinical trial.

Other Data Relating to BCG and Type-1 Diabetes

In 2012 an article was published showing correlation between more BCG immunizations (for Tuberculosis) and a lower risk of type-1 diabetes.  I did not report it at the time, because it was not indexed in pubmed (the huge US government database of medical publications), and so I did not know about it. The paper itself is in Turkish, and so I have not been able to read it.  However, there is an English abstract, and that is the basis of this summary.

TB vaccinations with BCG leave a mark, which is usually visible for many years.  The researchers simply counted these marks for patients who had type-1 diabetes, and for a matched control group that did not.  What they found was that the people who had type-1 diabetes had fewer BCG vaccinations:

Type-1 Diabetes: 2.3% zero scars, 55.4% one scar, 37.7% two scars, and 4.6% three scars
No Diabetes:          0% zero scars, 17.7% one scar, 74.2% two scars, and 8.19% three scars.

Obviously, this supports the idea that BCG could prevent type-1 diabetes (although it does not directly support BCG as a cure for established type-1).  However, it is important to realize that at least three previous studies have reported that TB vaccinations do not impact type-1 diabetes rates:
http://cat.inist.fr/?aModele=afficheN&cpsidt=11111587
http://care.diabetesjournals.org/cgi/content/abstract/20/5/767?ijkey=de477936685fbc95cfd98bc52cb120be655acd09&keytype2=tf_ipsecsha
http://care.diabetesjournals.org/content/28/5/1204.full

None of these four studies (the three negative and the one positive) was identical to each other, and there is no way for me to tell if the positive one was a better study than the three negative ones.  In general, I think it's safest to go with either the most recent study (positive, in this case), or the largest number of studies (negative, in this case).

But that summary of studies treats all BCG trials together, assuming that all BCG used everywhere is the same.   But that's not strictly true.  BCG is a biologic, and there are different strains.   It's not a chemical were all batches are identical.  Some researchers believe that some strains of BCG will be effective in treating type-1 diabetes, while others will not.  They tend to view previous failures as caused by using the wrong brand of BCG, together with other experimental designs which minimize BCG's effectiveness.  I tend to view these arguments "backwards", meaning that if some experiments fail while other succeed, then there will be discussion of BCG strains and experimental designs.  Right now, for type-1 diabetes, there aren't any clear successes at all, so no need to discuss strains or experimental design.

Summary

My summary is simple: all we have to do is wait, and see what data comes out of Dr. Faustman's study.

More information:
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT02081326
Dr. Faustman's Lab: http://faustmanlab.org/
Facebook: https://www.facebook.com/FaustmanLab

Dr. Faustman's recently published book on BCG, TNF and Autoimmunity:
http://www.amazon.com/Value-BCG-TNF-Autoimmunity-ebook/dp/B00JB4ZC6I/ref=sr_1_1
(I have not read it, yet.)

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

Monday, March 31, 2014

Possible Cures In The News (March)

Here are some bits and pieces of research, that I found interesting:

GAD65 Not Effective for LADA

GAD65 is one of the molecules targeted in the autoimmune attack which leads to type-1 diabetes.  A company called Diamyd, developed it as a honeymoon cure for type-1 diabetes.  The hope was it would train the immune system not to attack pancreas cells, and that would stop type-1 diabetes. It looked OK in phase-II trials, but failed phase-III trials a few years ago.

However, there were a few other studies underway when the phase-III data came in, and this is one of those studies.  The researchers were giving GAD65 to people who had LADA (Latent Autoimmune Diabetes of Adults).  LADA is a not separate form of diabetes, but a name given to people who have type-1 diabetes, but are diagnosed in adulthood (usually over 25).

In this trial, GAD65 treatment had no effect.

Abstract: http://care.diabetesjournals.org/content/early/2014/03/04/dc13-1719.abstract?papetoc


Non-Cure Research

When Does Type-1 Diabetes Start?

Currently, type-1 diabetes is diagnosed when symptoms are seen.  Usually, those symptoms are signs of high blood sugar: excessive urination and thirst, unexplained weight loss, lack of energy, etc.  More recently, some people have been diagnosed because their after meal blood sugar spikes above 200, even before the other symptoms are seen.

But now, there is some discussion that maybe we should change the definition of type-1 diabetes even earlier.    You can read about that in the link below:

JDRF News: http://bayarea.jdrf.org/blog/redefining-diagnosis/

Another Veo Safety Study

The Medtronic Veo is the first (very small) step to an artificial pancreas.  It shuts off for a few hours if blood sugar levels go low for too long.  This could be a huge step forward in preventing "dead in bed" fatalities, which are a significant cause of death for people with type-1 diabetes.

Anyway, there was a clinical trial to find out what would happen if the Veo cut off insulin incorrectly, when the BG levels were high (instead of low).  This is the exact opposite of what the Veo is supposed to do, and it has not been seen to happen in actual use.  However, the idea was to test to see what would happen, if the pump failed in this way.

The researchers found that even if this failure occurred, nothing bad happened to the person using it.  So that gives an added level of safety for this product (and presumably similar products, when they come to market in the future).

Abstract: http://care.diabetesjournals.org/content/37/3/773.abstract?etoc

Future Postings

I'm currently working on three blog postings, which I hope to get out in the next month, but obviously, I'm way behind, so no promises.  And I don't know what order they will come out in:

  • Dr. Damiano's Bihormonal Artificial Pancreas
  • Dr. Faustman's Phase-II study of BCG
  • General Update on AAT 


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

Monday, March 3, 2014

Imatinib ("Gleevec" / "Glivec") Finally Starts a Phase-II Clinical Trial

A year ago, researchers (Drs. Gitelman and Bluestone) at UCSF filed the paperwork to start a clinical trial testing Gleevec on people.  Now, they can finally start enrolling people in the trial.  The generic name for this drug is Imatinib.  It is sold as Gleevec in the US and Glivec in most of the world.

Gleevec is a drug already approved for treating cancer.  Patients will take a daily pill, will visit the clinic at 2 weeks, then monthly for the first year, and after that twice per year.  The researchers will measure C-peptide (to see if patients are generating their own insulin) as well as how much injected insulin the person needs, and their A1c numbers.

I've previously blogged on this trial here:
http://cureresearch4type1diabetes.blogspot.com/2013/02/possible-cures-for-type-1-in-news-mid.html

I also created a "Timeline of Gleevec as a Potential Cure for Type-1 Diabetes" that you can look at.  This timeline is experimental, so if you have any suggestions on how to make ti better, please email them to me.

They are hoping to finish collecting data in 2016 and complete the trial by 2018. It is a 66 person trial (44 will get the treatment, 22 will be in the placebo group). But this is a honeymoon trial, only people within 100 days of diagnosis will be included. Imatinib is a relatively new cancer drug, which is popular because it targets an enzyme that only cancer cells have, so it is relatively non-toxic to non-cancer cells. (The buzzword is "targeted".) The obvious question is, why would it be expected to work on type-1 diabetes?  It's not clear (at least to me) exactly why Gleevec should stop type-1 diabetes.  It does target parts of the immune system and it does lower inflammation, so either one of those (or both) could be it's mechanism of operation.  Or, it could be something completely different.  The work done in mice suggests that it might be the last option: a completely different mechanism, but there is not enough data to be sure.

Unfortunately, right now, they are only recruiting patients 18 years and older (an FDA limitation). Since this is a honeymoon trial, that is a serious limitation, and will make it hard to find people to recruit. The hope is that after some adults are successfully included in the study (and no safety issues come up), they will be able to lower the recruitment age for future patients, and fill the rest of the trial more quickly.

They are recruiting at several locations:
San Francisco: Contact: Chrinstine Torok, RN 415-502-9089 torokc@peds.ucsf.edu
Denver Contact: Jennifer Smith 303-724-8272 jennifer.e.smith@ucdenver.edu
Indianapolis Contact: Jennifer K Terrell 317-944-2584 jkramey@iu.edu
Omaha Contact: Chris Smith 402-280-4319 christosmith@live.com
Philadelphia Contact: Charles Isaacs 215-590-7222 isaacsc@email.chop.edu

Wikipedia: http://en.wikipedia.org/wiki/Imatinib
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01781975
Orange Book Entry: http://www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm

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

Saturday, February 22, 2014

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


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

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

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

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

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

A Little Discussion

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

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

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

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

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

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

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

Opinion

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

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

Abatacept

Abatacept is a treatment that prevents T-cells from becoming activated. Presumably, for type-1 diabetes, it works by blocking the "bad" killer T-cells from activating. ("Bad" killer T-cells are those which target the body's own beta cells rather than the foriegn invaders they are supposed to target).  This drug is already approved for use in rheumatoid arthritis when other treatments have failed, and is marketed as Orencia. It regulates (or modulates) T-cells, rather than depleting them, so the hope is that it will have fewer side effects than other immunosuppressives.

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

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

Results

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

Discussion

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

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

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

Saturday, January 18, 2014

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

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

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

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

Here are the most important parts of their results, from my point of view:
The rate of decline of C-peptide was parallel between groups [treated and untreated], but shifted by 8.2 months in Rituximab treated subjects.
In recent-onset T1DM, Rituximab delays the fall in C-peptide, but does not appear to fundamentally alter the underlying pathophysiology of the disease.
Discussion

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

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

Vitamin-D Not Associated with Type-1 Diagnosis

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

Here is the title of the paper, which makes a good summary, as well:
No Difference in Vitamin D Levels Between Children Newly Diagnosed With Type 1 Diabetes and Their Healthy Siblings: A 13-Year Nationwide Danish Study
Abstract: http://care.diabetesjournals.org/content/36/9/e157.extract.html?etoc
Full text: http://care.diabetesjournals.org/content/36/9/e157.full

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


Teplizumab Commentary

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

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

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

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

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

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

Wednesday, January 8, 2014

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


This posting covers two news items and discussion to go with each.  I'm about 4 months behind on blogging about current events that might lead to a cure or prevention of type-1 diabetes.  Even after this posting, I'll still be several months behind.  I hope to catch up by end of January.

As you read these summaries, remember that C-peptide is generated when your body makes it's own insulin, so more C-peptide means your body is generating more of it's own insulin.

Results from Alefacept in a Phase-II Trial ("T1DAL")

Alefacept is a drug that has been used to treat the skin condition, psoriasis.  Psoriasis is generally considered to be an autoimmune disease, similar to type-1 diabetes, but with the body attacking it's own skin cells, rather than it's own beta cells.  So trying a drug already approved for Psoriasis on type-1 diabetes seemed like a reasonable thing to do, and these researchers did it.  You can read my previous blogging here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Alefacept

This was a honeymoon trial.  33 people got the drug and were compared to 16 who did not.  The treated group got a dose a week for 12 weeks, then a 12 week break, and then weekly doses for 12 more weeks.  They will be followed for 2 years, but these results only cover the first year.

Results

There were six results:
1. A two hour after eating C-peptide test: Treated generated about 0.130 nmol/L more than untreated, but this was not statistically significant.  However, all the rest of the results were statistically significant:
2. A four hour after eating C-peptide test: Treated generated about 0.171 nmol/L more than untreated.
3. Daily amount of insulin used: Treated people used about 25% less insulin.
4. Number of low BG events: Treated people had 10 such events vs. 17 in untreated.
5. No difference in A1c numbers between treated and untreated groups.
6. No serious adverse effects occurred.

Discussion

This is a good news / bad news kind of study.  I'll give you the bad news first:
* Because the first measure was the primary end point, this trial failed it's primary end point.  The others were secondary end points, some of which were successful.

Good news second:
* In for both of the C-peptide numbers, the treated group actually went up (a tiny amount) in the year after diagnosis, while the untreated group went down. So it is possible, that using this drug earlier in the process will preserve more beta cell function.
* Using 25% less insulin (with no difference in A1c numbers), and having half the low BG events both seem promising to me as well.

But the important thing to remember about this study, is that Alefacept is no longer on the market.  When this study started, it was being sold as an anti-Psoriasis drug.  However, the manufacturer withdrew it from the market while this study was running.  (The study was a little smaller than planned, because of that.)  The drug was not subject to any kind of recall prior to the withdrawal.

Because the drug is no longer on the market, I'm not sure if this research will move forward or not.

News: http://medicalxpress.com/news/2013-09-psoriasis-drug-results-diabetes.html
Abstract: http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70111-6/abstract
Web page: http://www.immunetolerance.org/news/2011/04/itn-announces-enrollment-first-participant-t1dal-trial-people-recently-diagnosed-type-1
Recruiting web site: http://www.t1dal.org/
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/study/NCT00965458
Official Notice of Withdrawal: http://www.amevive.com/Patient%20letter.pdf


Results from Extended AAT (Glassia) Phase-I/II Trial

There are two pieces of news on AAT.  One is the results of an extension to their phase-I clinical trial, the other is informal news of a specific case study.  In this blog posting, I'm only covering the phase-I trial.  I'm gathering more information on the case study, and will present that in a future blog posting (probably at the end of January).

AAT is an anti-inflammatory chemical which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own.  There are several clinical studies going on, which use AAT.  In October, one of those studies released data on 20 people who were followed for 20 months after diagnosis.  There was no control group for this phase-I study. You can read more about AAT here:
http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html
Results

Three results were reported:
* 60% of the patients where generating more than 0.2 nmol/L of C-peptide.
* 75% of the patients had an A1c of 7.5 or lower.
* No safety issues were found.

Because there was no control group, I can not directly compare these results to an untreated group of people.  However, my understanding is that both of these numbers are better than expected without treatment.  So this looks like good news, although not cure-type news, and without a comparison group, it's hard to tell.

Next Steps

Kamada is planning a phase-II/III study with 190 people.  The plan is for a double-blind, placebo-controlled, multicenter study on honeymoon type-1 diabetics.   The study will follow people for two-years measuring C-peptide parameters, HbA1C levels, hypoglycemic events, insulin daily dose, safety/tolerability, etc.  They will start in Israel, and expand elsewhere later.

Press Release: http://www.kamada.com/press_item.php?ID=73
The new study: http://clinicaltrials.gov/ct2/show/NCT02005848

Factoid: Type-1 Prevalence in USA Might be 1 in 500

Ten years ago, when my daughter was diagnosed, we were told that about 1 in 250 or 300 people had type-1 diabetes.  Over the years I've seen those numbers repeated many times for the US population, and they seem to fit in with what we see in schools.  Many with a few hundred students have zero or one type-1 diabetics, and those with several hundred often have one or two.   So it all makes sense.

However, a study recently published suggests that the actual number might be just under 1 in 500.  You can read the details at the link below, but they found a prevalence of 1.93 per 1000 in kids 20 and under:

Abstract: http://care.diabetesjournals.org/content/early/2013/09/11/dc13-1838.abstract.html?papetoc


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

Sunday, December 1, 2013

One Study Shows BPA Safety


Bisphenol A (BPA) is a chemical that is used to soften plastics. It has been used in many flexible plastics (such as water bottles, baby bottles, pacifiers, and the plastic inner liners on some food cans).

Over the last few years, I've seen repeated questions about BPA triggering type-1 diabetes. These worries were not fueled by direct evidence, but rather by indirect evidence. Some researchers consider BPA to be an endocrine disruptor and since insulin is part of the endocrine system, it might be possible that BPA was triggering type-1, or making it more likely to be triggered.

Also, until now, there were no intervention studies that looked specifically at BPA's effect on type-1 diabetes. There had been some general safety testing, but nothing specifically targeting type-1 diabetes.

Recently, however Bodin and team reported on their intervention safety study. This one study found that BPA does not effect type-1 diabetes diagnosis in humans in the amounts that people are exposed to. Although, by itself, this is not proof of safety, it is very reassuring.

The Study

The basic format was this: NOD mice were divided into four groups of 20. One group got no BPA, another got the equivalent of 20 times the amount that humans consume (more on this later), the third group got 200 times, and the forth group got 2000 times as much as people do. Each group was studied both for overall type-1 diabetes rate and the timing of type-1 onset, and also for a variety of internal immune changes.

Obviously, this was a mouse study, and mice are not people. However, when it comes to safety studies, they are the best we have. No one is going to test a chemical on people to see if it is safe. ("Parent, we'd like to give your children a chemical to see if it causes them to get type-1 diabetes, please sign here!") That's unethical. So we are stuck with animals; and NOD mice are the best animal model for type-1 diabetes that we have. [d1] Obviously, I pay little attention to cure results in animals, but for safety results, for intervention studies, there really is no choice.

I discuss the dose levels more below, but for now, the important thing to remember is that the only two dose levels that matter in the real world, are the zero dose, and the 20x normal level. Obviously, if a chemical shows no bad effects, even when 20x the normal dose is consumed, then it's pretty safe.

Results

When measuring rates of type-1, the zero group, the 20x group and the 200x group all had the same overall levels of type-1 diabetes [d2]. The 2000x group was slightly higher.

Also, in terms of when the NOD mice got type-1 diabetes, the zero, 20x, and 200x groups all were diagnosed at about the same time [d2], while the 2000x group was a little earlier.

For the various immunological markers, the results were all over the place. Some markers showed a dose-response change, while other showed no change, and others had peaks in the middle of the dosing range. There might be some work here for immunologists, but I think a more likely results is going to be "if you take a massive overdose of BPA, strange things happen". The same is true of aspirin, salt, water, insulin, meat, water, indeed just about every substance there is. [d3]

Discussion

How much BPA are real people exposed to?
When I described the tested doses, I described them in comparison to the normal human consumption. However, there is some controversy about exactly what is the normal human consumption. The European equivalent to the EPA has estimated this at 1.5 ug/kg, and that's the number I used. However, this is an estimated exposure, not a measured exposure, and not everyone agrees with it. Some researchers think this estimate is too low to explain the levels commonly seen in blood tests.

So, the most important thing to remember is this: my opinion on this test is based on the European EPA's estimate of human exposure being accurate (or at least within 10x of the right number). If future research shows that the actual human exposure is wildly different, then this research will need to be reevaluated, based on the real dose. But in the meantime, this study shows safety even well above the currently estimated dose.

Is More Research Warranted?
I am fond of saying that one clinical trial never answers a question, because even if the results are very clear, it is still just one study, and more are needed to be truly persuasive. And I think that is true for this research. So in the perfect world, another group would do a similar study, and that second study would confirm these results, and that would be the end of it.

But we live in a world with limited resources, and a huge number of artificial chemicals. So, if someone has money to study chemicals that might cause type-1 diabetes, should they say "well, these other guys suggest that BPA does not cause type-1 (at the exposures that people actually get) so I'll spend that money to do a confirmation study" [d4] Or should they say "With one study showing BPA safety, I'll investigate some other chemical".

There is an "opportunity cost" here. There are 100s or 1000s or even 10000s of chemicals out there. We now have one animal study showing that this one does not affect type-1 diabetes in doses even 100s of times bigger than people actually get. If we get funding for another study, why not put it into a chemical that has zero animals studies done on it?

For BPA specifically, there is an even more pressing question: how much BPA are real people exposed to? Maybe a better place to put funding is to determine the real human exposure level, rather than run another test on a dose which might be way off?

What are the ethics of using mega-overdoses in safety testing?
To give you some idea of the scale of this research, consider that a normal dose of aspirin is 1 pill. Now, if someone did a safety study and told you that aspirin was unsafe, because they had given the equivalent of 2000 pills to a mouse and the mouse had problems, your reaction might be to ask them why they gave the animal such a huge amount [d5]. You probably would not be worried about the safety of Aspirin, nor should you be, especially if they told you Aspirin was safe at 20 and even 200 pill doses. Yet, that is exactly what these researchers did, and many reporters are trumpeting the danger, based on the mega-overdose they gave.

For me, a huge question in this research is, why did the researchers choose such a silly dosing level? I mean 20 times actual dose is high, but reasonable because it gives a big safety margin.  But 200 times and especially 2000 times average exposure seem so high as to be a joke.

What troubles me about this experiment's design is the following: Everyone (including researchers) should know that headline writers ignore dose levels. So a researcher can manipulate a headline writer (and often the reporter, as well), by including a dose level so high that something bad is bound to happen. Then the headlines will scream that there is a danger, even if the researcher knows the danger only exists with exposure levels so high they never happen.

In future, does type-1 diabetes drop in countries that ban BPA?
If using BPA increases the type-1 diabetes rate, then removing BPA would decrease the type-1 rate.

Another type of research which might be interesting here, would be to see if type-1 diabetes cases start to drop, or the average age goes up, in countries were BPA has been banned. Data from those countries could be examined for 10 to 20 years after the ban. This type of study (a population-based study) is not as well controlled as an intervention-based study, but it is done in people, so (if type-1 numbers continued to go up or stayed the same), it would provide some support that BPA is not involved. Comparing different countries' consumption of BPA over different years might provided a range of interesting data.  Conversely, if the numbers go down, that would suggest that maybe BPA was involved, especially if they went down the same number of years after BPA stopped being used in each country.

Summary of BPA Safety

The one intervention study we have, where BPA was directly tested in animals for type-1 diabetes, found no increase in type-1 diabetes, nor any earlier diagnosis of type-1 diabetes, even when given in doses hundreds of times higher than estimated human exposures. This was just one study, and there is some controversy about how much BPA people consume. Of course, it is always possible that BPA might be dangerous in other ways; this discussion is focused on type-1 diabetes. 


Extra Discussion

[d1] This is a general problem with all safety research: we want to know safety in people, but are forced to test safety in animals.

[d1b] The difference in outcome was not statistically significant, in both these cases.  With only 20 NOD mice, the numbers were usually not exactly the same, nor would they be expected to be exactly the same.  However, the differences were never statistically significant, which is what matters in these kinds of tests.

[d1c] Even water would be toxic at 2000x a normal amount.  If a normal amount of water is 1 gallon a day, then 2000 gallons a day could easily cause death.

[d4] For safety testing in general, people who don't like the results, often want to rerun the test in a different animal. (No matter which side they are on.)  But in this case, there are very few animals that get autoimmune-based diabetes (ie. a diabetes similar to human type-1), so there are not a lot of choices, and NOD mice are generally considered the closest.

[d5] For another comparison, the FDA wants us to eat about 2 grams of salt per day. The actual average is 3 grams per day. Would you do safety studies based on 6 kilograms per day? Would that study have any connection to reality at all? 6 kilograms is over 13 pounds.

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