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

This blog posting is a collection of little news items, rather than a single large one.

Two Year Delay for LCT

In a very brief announcement, LCT said that it would delay general commercial availability of it's encapsulated pancreatic product (DIABCELL) from 2016 to 2018.  It sounds to me like they hit a problem in their phase-II study (an open label clinical trial in Argentina), and they need to fix that problem before continuing with their testing for approval.

LCT is developing an encapsulated islet cure for type-1 diabetes. Pig beta cells are wrapped in a coating and implanted into people.  The beta cells generate insulin in response to glucose, while the coating prevents the body's immune system from rejecting or attacking the new beta cells.  Several groups are developing technology like this, but LCT is the farthest along, as they are the only company with results from multiple human trials.

News: http://www.irasia.com/listco/au/lct/press/p130829.htm
Press release: http://www.lctglobal.com/html/blob.php/ASX_130829.pdf?attach=0&documentCode=5126&elementId=20084

ATG (Thymoglobulin) is Unsuccessful in a Phase-II Clinical Trial

ATG (non-human sourced, human T cell antibody infusion) is approved in the US for transplant rejection issues (not type-1 diabetes).  This was a phase-II clinical trial involving 58 people to test it's use for type-1 diabetes.  After one year, the C-peptide production in the treated group and the placebo group was about the same.  Here are two summaries of the results:

Our findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes.

We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve ...

Press Release: http://www.sciencedaily.com/releases/2013/08/130827203920.htm
Summary: http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70065-2/fulltext
Wikipedia information: http://en.wikipedia.org/wiki/Thymoglobulin

Phase-I Results of Dapagliflozin as a Treatment

Dapagliflozin is a pill used for treating type-2 diabetes.  It has been approved for use in the European Union, Japan, and elsewhere, but was rejected by the US FDA.  It has been resubmitted for approval in the US, and that second approval is still under consideration.  It is in a family of drugs called SGLT-2 inhibitors.  

Because the drug has already gone through phase-I, phase-II, and phase-III testing for type-2 diabetics, this early trial in type-1 diabetics was a phase-II study.  62 patients from 5 different locations were included.  Half got the drug, half got a placebo.  All had A1c numbers of 8.5% or higher and were treated for 3 months. 

The results were good, for a treatment.  A1c numbers dropped 0.7 to 1.0 for treated patients, and BG numbers were 30-40 points lower. 

Canagliflozin (Invokana) is a similar SGLT-2 inhibitor which is approved in the US, but I don't think it's been tested on type-1 diabetics as yet.

I don't plan to cover Dapagliflozin in the future, because it is a treatment not a cure, but I did think it was an interesting drug for type-1 diabetics who have trouble controlling their BG and have higher than desired A1c numbers.

Press release: http://www.clinicalendocrinologynews.com/news/top-news/single-article/dapagliflozin-explored-in-type-1-diabetes/5b2de5a29aa324691649e6a01768441b.html
Wiki: http://en.wikipedia.org/wiki/Dapagliflozin

Good Sources of News

I know that it is hard to find good news sources these days.  Two sources that I think are worth reading are:

DiaTribe newsletter: http://www.diatribe.org/ 
This is one of my favorite sources of information.  These guys understand type-1 diabetes and all of it's complexities.  They are not just cutting and pasting other people's press releases into their news articles, but actually applying their own knowledge and expertise to their reporting and analysis.

Ellen Ullman's Scoop.it page: http://www.scoop.it/t/diabetes-and-more   
This is a collection of media news stories, but it is a very good collection of media news stories. Unfortunately, the media does not do a good job of reporting on type-1 cures or treatments.  The reasons for this are too complex to discuss here.  But Ellen's page is my favorite way of reading about diabetes in the media.

Note that both of these sources cover both type-1 and type-2 diabetes, so be ready to mentally filter out the type-2 stories, if you only care about type-1.

Donating to Non-Animal Research

I was asked the following question: "I like to donate every year to help find a cure [for type-1 diabetes]. However, I don't want to support testing on animals. Have you come across any research groups that you think are effective but don't test on animals?"

I don't know of any research aimed at curing type-1 diabetes that has never used animal trials. Indeed, it is hard to see how such research could exist, given our current technology, and the technology we expect to have for the foreseeable future.  Curing type-1 diabetes is expected to require both changing the immune system and regrowing beta cells.  Both of these are complex interactions that occur only within actual animals.  There is no way to test either one of these effects in single cell organisms (which don't have separate immune systems or beta cells), or tissue samples, or in computer simulations.  So researchers either need to test on animals, or guess wildly, and then test in humans.  The second path is blocked by the FDA (because it's unsafe), but even if not, it's almost impossible that such guess work could lead to a cure.  

Now, if you want to only donate to research which is not currently using animals (which has already transitioned into human trials) then there are several research projects to choose from.  Any research in human trials would be a good target.  You can see a list from last September here:
http://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html
and I expect to post an updated list for this year in a few weeks.

But to put it bluntly: right now, if you are not willing to fund animal research, you are not going to fund a cure for type-1 diabetes.  For type-1 diabetes, cell cultures, tissue samples, and computer simulations are not good enough for research use.

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.

Results from a Phase-II Trial of Teplizumab in Honeymooners

This blog posting covers the results from a phase-II clinical trial of a drug called Teplizumab.  This trial ran from 2005-2011 and was published on line in July 2013:
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/23835333
(The full paper is not available for free on line, but one of the authors sent me a PDF, so I do have the published details: Thanks very much!)

I have written several blogs about this drug in the past, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab

The sound track for this blog posting is "Wait" by Wang Chung from the "To Live and Die in LA" soundtrack:   http://grooveshark.com/#!/s/Wait/3IYAu1?src=5

Results

The key results are summarized in this graph, which I will explain below:

This graph shows a person's ability to generate their own insulin (as measured by C-peptide production [d1]).  Higher points on the left hand scale show more insulin production, so are good.  The bottom scale is the number of months from treatment, and treatment started about a month after diagnosis.

• In this study, about 55% of the people who were treated, had almost no effect.  This is the green line above, which is right next to the blue line (untreated people).
• However, about 45% of the treated people had a good response to the treatment, and this data is the red line.
• If you look at the responders (the red line), you can see that their insulin generation ability actually went up in the 6 months after their first dose.  And even about 20 months later, they were still generating as much of their own insulin as they were when first treated.   This is in stark contrast to the placebo group, and the non-responsive group, which steadily dropped for that whole time.

Comparing results from different studies is never straight forward, but here is my attempt to compare the recent TOL-3021 results to Teplizumab.  For this comparison, TOL-3021 results are for established type-1 diabetics and include everyone who got the best dosing regimen, while the Teplizumab results are for honeymoon type-1 diabetics, and only include "responders" (about 45% of total):

• Both treatments resulted in a maximum improvement of +20% in the body's ability to produce it's own insulin, as compared to their production at the start of the study.
• The duration of effect (until insulin production dropped back down to baseline) was about 6 months for TOL-3021 and about 20 months for Teplizumab.
• The absolute change was higher for Teplizumab than for TOL-3021.  The Teplizumab patients started out generating higher levels of insulin since they were in their honeymoon phase, so their maximum was 20% of a larger number.

Background

How Teplizumab Works

Teplizumab is a humanized monoclonal antibody [d2] which targets CD3 cells in the immune system in order to lower (or stop) the body's autoimmune response. This drug tries to prevent type-1, or lessen it's severity, by "turning down" [d3] the immune system's attack on the body's own pancreas cells. This basic approach has resulted in treatments (but not cures) for other autoimmune diseases. It does carry the possible risk that the body's immune system will not properly attack a real threat in the future.

The History of Teplizumab Clinical Trials

Teplizumab has a long history of clinical trials, and not all of it successful.  There are 9 clinical trials of Teplizumab either completed or ongoing at this time.  The quick summary is this:  A company called MacroGenics (partnering with Eli Lilly) put Teplizumab through a full round of testing, culminating in two large phase-III clinical trials.  It looked good in the phase-II study, but failed in the first phase-III study.  The second phase-III study was canceled.  In addition to the MacroGenics studies, there were other studies done by universities' researchers that were not directly related to FDA approval.  This study is the most recent of those.

Discussion

There are a lot of interesting issues here, but I'm gong to touch on some of the bigger ones:

Why did previous studies fail, while this study succeeded? This is a major question.  Remember that the study that failed had twice as many people as this one.  On one hand, it is reasonable to expect more accurate results from the larger study.  On the other hand, later trials can learn from the earlier trials, and the successful trial was later.  So should we side with the larger trial that was unsuccessful, or the later trial that was successful?  I think the answer is: we do more research, run more clinical trials.

The researchers in the study suggested that their better results were caused by treating generally younger people, and starting treatment closer to diagnosis [d4].  If these two factors did cause the difference, it is a mixed bag, because on the one hand it suggests that this really is a honeymoon-only treatment, but on the other hand, if approved as a regular treatment, then it is reasonable to assume that it will be given within a day or two of diagnosis, and even better results might be seen.

Could it continue forever? / Did the second dose help?  Another question which is critical to this research is this: Did the second dose help?  Because answering that question is critical to answering the question: can this treatment be extended for longer periods of time?  If the best this treatment can do is extend the honeymoon by 12 extra months, that has some advantages, but it's not an (obvious) path to a cure.  On the other hand if repeated dosing results in longer and longer honeymoons, that might someday lead to a cure.  And even more quickly: a preventative [d5].

Unfortunately, the news here doesn't look too good.  The second dose was given at about 12 months, so pretty close to the second row of dots in the graph above.  You'll notice that there is no improvement at that point.  The C-peptide measures don't change much (i.e. the slope of the line doesn't change at that point).  If the second dose had an obvious good effect, I would expect to see a bump up from about 12 to 18 months, much as there is a bump up between 0 and 6 months. Unfortunately, I don't see that.  An interesting trial would be to randomly give some people one dose, others two doses (as done here), and others three, four, or more doses [d6].  That would give very strong data telling us if extra doses resulted in longer effectiveness.

Is this a preventative, a honeymoon cure, or a cure for established type-1 diabetics?  In a sense, this study extended the honeymoon from one year to two years (approximately) in the 45% of the patients who responded to the treatment.  So right now the biggest question is: can this result be extended for longer periods of time?  If the answer is "yes", then it can be used as an important adjunct treatment.  It would lower insulin use, and presumably lower all sorts of long-term bad side effects of having type-1 diabetes.  Furthermore, if the results can be extended, then this might very well turn into a preventative.

Who is going to respond?  The difference between those who responded to the treatment as compared to those who did not respond, was large.  From a clinical point of view, it brings up a different question: can we tell ahead of time who is going to respond, so we don't even bother to treat people who will not benefit.  From a basic research point of view, this brings up a bunch of interesting questions which boil down to: why do some people respond and others don't?

The researchers did see differences in people who responded versus those who did not.  They do not have a single test that gives a simple yes/no answer, but by combining the results of several tests, they can say that some people are a lot more likely to be responders, and others much less likely. However, if the side effects are small enough, then it might be worthwhile to dose everyone.  We will need to know more about the rate adverse effects to be sure.

We know that many different genes are involved in type-1 diabetes, and several different autoantibodies, so studying Teplizumab may give insight into immunological differences between different populations of type-1 diabetics.

Discussion Footnotes

[d1] When your body makes insulin, it comes with a C-peptide attached, but if you inject insulin, there is no C-peptide.  So measuring C-peptide will measure just the insulin generated by the body.  Neat trick; very useful in all kinds of diabetes research.

[d2] Monoclonal antibodies is a method of creating therapies by finding one cell that attacks the cell you don't want, and cloning it.  You end up with a vast number of identical cells, all of which attack the cell you don't want.  By carefully chooing the starting cell, you can "target" the monoclonal antibody to attack a very specific type of immune cell.  Because of how they are produced, early monoclonal antibodies were targeted at mouse cells, rather than human cells, and this sometimes caused problems.  Later techniques were developed to make the cells more human like, but still not completely human.  These were called "humanised" or "chimeric" monoclonal antibodies.  Finally, techniques were developed to create fully human monoclonal antibodies, and these are called "human" or "fully humanized".

There are scores of monoclonal antibodies (of all three types) approved for use in the United States, for a wide variety of illnesses.  Different monoclonal antibodies have different safety profiles.  Most have names ending in "mab".

[d3] The medical term for this is "modulate".  Teplizumab is said to modulate the immune system.

[d4] The researchers also point out that this trial did not use a placebo and the previous trial did.

[d5] The treatment given here, was given just after diagnosis, and kept insulin production at or above current levels for 24 months or so.   So if we could predict that someone would come down with type-1 diabetes a few months before they actually did, then we could give them Teplizumab, and they would (theoretically, if all worked well) preserve their insulin production high enough to not be diagnosed, for 24 months.  Furthermore, if we could extend this treatment for longer periods of time, we could delay diagnosis for longer periods of time.  There is an ongoing clinical trial called "The Natural History of Type-1 Diabetes" which is specifically aimed at gathering data from one who gets type-1, when, and how to predict it.

[d6] Some patients in this study were given only one dose, while others got two, but it was not random.  The patients who had better initial results got the second dose.  This makes it hard to separate out the effect of one dose versus two doses, from the effect of "responder" versus "non-responder".

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. 

One Year of "Cured In Mice"

At the end of 2011 I started keeping track of all the treatments that were discovered to cure type-1 diabetes in animals.  Throughout 2012 I kept track of all these announcements, so now I have a full year's data on type-1 cures in animals, and this blog posting is a summary of that data and my thoughts on it.

You can see all these potential cures here: http://t1dcuredinmice.blogspot.com/

Summary of One Year of "Cured In Mice"

The big news is this:  Depending on how you count them, there were between 10 and 18 animal cures discovered in 2012.  That's a huge number.  Much more than I expected.

What kind of mouse cures were found?  Everything that I could imagine, and some that I couldn't imagine.  There were animal cures based on growing new beta cells in the pancreas and in other parts of the body.  There are stem cell cures, nanoparticles, parasitic infections, a natural/alternative/complimentary cure, all kinds of drugs, and biologicals.  Even "hyperbaric oxygen" made an appearance.

Here is the full list. More details (including web sites) are on the t1dcuredinmice blog.

Trial	Treatment	Animal	Results
ViaCyte	VC-01: encapsulated stem cells	diabetic mice and rats	Cure
Sheba Medical Ctr.	Ad-CMV-PDX-1	CAD-NOD mice	43% Cure
Feinstein Institute	ISO-1
NJ Medical School	intestinal parasite	NOD mice	Prevention
Karolinska Institutet	M2r macrophages	NOD mice	65% Prevention
U British Columbia	human embryonic stem cells	STZ mice	Beta Cell Creation
U North Carolina	non-depleting antibodies	NOD mice	80% honeymoon cure
U Florida	Adult Stem Cells + Beta Cell Growth Factors	mice	Cure
DRI	Hyperbaric Oxygen	mice	30% Prevention
KU Leuven	proinsulin autoantigen	NOD mice,	Honeymoon Cure
St. Jude  Hospital	Interleukin-35	NOD mice
U Colorado	CD40 inhibitory peptide	mice	Prevention and Cure
XOMA	XMetA	mouse model of diabetes	lower A1C
Hannover Medical School	Hepatic Insulin	IDDM and STZ Rats	Cure
Vanderbilt U	Brown Fat	STZ mice	Cure
U of Tokushima	anti-CD98hc	TZ NOD mice	Cure
Parvus	Nanoparticle	mice	70% Cure
Academia Sinica	Catenarin	NOD mice	Prevention

Notes on Animals

NOD mice have an autoimmune diabetes similar to human type-1 diabetes.  STZ mice have had their beta cells killed with a toxin, and therefore have no autoimmunity issues.  CAD-NOD mice are NOD mice where the type-1 was triggered with a toxin.

The Allure of Animal Research

One of the themes that I repeat over and over in this blog, is that animal research -- even really successful, animal research that sounds like a great idea and a sure winner -- is always a long way away from real success in people.  Reading this paper on Catenarin:
http://www.hindawi.com/journals/ecam/2012/982396/   (especially figure 2A)
really reminded me of the dangers of the siren-song of animal research.  How easy it is to sound really good, like a cure was just around the corner, even when it is not.  This paper shows a graph where untreated animals start to come down with type-1 diabetes at 12 weeks, and by 24 weeks every animal has type-1 (100%).  They give animals the smallest dose of Catenarin, and at 24 weeks only 70% of the animals have type-1; a medium dose results in 30% type-1 diabetes rates, and at full dose, no NOD mice get type-1 diabetes.  Even at 30 weeks, none of the full dose mice have type-1.  On paper it looks like the perfect preventative.  It looks so beautiful, so alluring. There is no reason why it shouldn't work; no reason why we should fund any other research.  So perfect.  And yet, so many treatments have shown this in mice.  Most wildly successful mice treatments never even start a human trial, and most of those that do, fail.   Reality is so hard, sometimes.  This is part of the reason I don't follow animal research very closely.  Too much heart-ache.  Even with human trials, there is too much, but with animals, it is even more.

The Future

How many of these animal cures are going to progress to human clinical trials?  I don't know.  So far the answer is none, but it's only been 8-20 months, and that's not a lot of time to translate into human trials.  But this is definitely the next piece of data to gather: out of the animal cures in 2012, how many turn into human trials in 2013, in 2014, in the next 5 years, or ever?  In looking over the research, I have a sinking feeling in my stomach, that very few of these are ever going to be tried in people.  But I'm really just guessing, and the whole point of gathering the data, is so I don't have to guess.

• The ViaCyte researchers are very specific about planning to start human trials in 2014.
• The lead Feinstein researcher (Dr. Al-Abed) "is now designing clinical trials" according to their press release. 
• I have heard some discussion about a human trial for the intestinal parasite tested at NJ Medical School, but there is widespread belief that very few people will volunteer for this, so there is little enthusiasm for starting the trial.

I'm not planning to continue the "Cured in Mice" blog, because I feel it has served it's purpose, and the extra work involved in keeping two blogs up to date is not worth it.  I may blog on animal research slightly more often here, but I don't think it's worth a second blog.

Joshua Levy -- Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail 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.

Data From A Phase-I Clinical Trial of Polyclonal Tregs

18 Month Data from a Phase-I Trial of Polyclonal Tregs

I previously blogged on this research here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs
so please read that blog posting for details of what is being tested, and who it is being tested on.

A quick summary is this: Dr. Trzonkowski and co-researchers at the Medical University of Gdańsk  remove one specific type of T regulator cell (called "CD3(+)CD4(+)CD25(high)CD127(-)") from a person with type-1 diabetes.  They use these cells to grow a lot more of them, and then put them back in the body.  Since regulatory T cells naturally regulate the body's immune system, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes. 

The previous data was from 10 children, who were treated within 2 months of diagnosis.  But this new data covers 12 children (aged 8-16), also treated within 2 months, and were followed for 18 months.  They were compared to a placebo (untreated) group.

The big news is simple: two of the treated children did not need to inject any insulin at all for 11 months.  The treated patients in general generated statistically significantly more C-peptide than the untreated group, which means they were generating more of their own insulin.  And obviously, two of the treated kids were generating a lot more insulin.  It is important to remember, that some honeymooners do not require insulin for some part of their honeymoon time.  However, I think that 2 out of 10 is far more than would be seen randomly, and I think that 11 months is longer than one would expect naturally.

A pessimist might say "It only works for honeymooners, it worked for less than 20% of the people, and it only worked for 11 months."  But I am an optimist.  I say "If it works for honeymooners now, maybe it will work for established type-1 diabetics in the future, or might work when combined with a beta cell growth factor.  Previously we had a prevention for no one; if this work pans out, we will have something that works for some people, and if we start out with 11 months, maybe we can stretch it longer with more research, or repeated doses.

So I think these results are very interesting, and well worth following.  I'm very happy that at least one other group (Drs. Gitelman, Bluestone, and Herold) also have a 14 person, phase-I trial going into this treatment.  However, that group is not expected to finish their trial until 2016. Hopefully Dr. Trzonkowski and his co-researchers will have a phase-II trial well underway by then; maybe even finished (if their phase-II trial gets funded quickly).   

Abstract: http://app.core-apps.com/tristar_ada13/abstract/9b942b88cb23351f1c62fdf808057354

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

Data From A Phase-II Clinical Trial of TOL-3021

Data From A Phase-II Clinical Trial of TOL-3021 by Tolerion
(Previously known as BHT-3021 by Bayhill)

Tolerion recently reported results from a Phase-I/II clinical trial of TOL-3021.  This treatment started life as BHT-3021 under development by Bayhill Theraputics, so you can read my previous blogging on it under that name:
http://cureresearch4type1diabetes.blogspot.com/search/label/Bayhill

Background

The best results (most positive results) were seen in people dosed 1 micro gram, which was a middle dose in this trial, which tested a range of different doses.  Those are the results I discuss below.  This study was a true phase-I/II study.  The researchers started out dosing a few people to check for safety and to get early efficacy data for a very small number of people (the phase-I part). They then expanded into a larger group, which got four different dose levels (plus a placebo group).  The goal of the phase-II part was to find the best dose for future trials.  The people in this trial had type-1 diabetes for years prior to the start of the treatment.

Results

The researchers reported three interesting results:

1. Treated type-1 diabetics generated more of their own insulin, but only a tiny amount more.
The "top line" results for this study is that people treated with TOL-3021 saw a 28% increase in C-peptide production, which means a 28% increase in the amount of insulin their bodies were naturally producing. (I'm reporting on "spread" here: the treated group went up about 20%, the placebo group went down about 8%, so the spread was about 28%.)  On the one hand, this is a tiny amount.  So little that their insulin requirements did not change noticeably (ie. in a statistically significant amount).  On the other hand, any increase at all in well established type-1 diabetics is big news.  Even ten years ago, it was thought to be impossible.

2. Treated type-1 diabetics generated less autoimmune cells ("bad killer T cells"), targeting proinsulin.  The immune system generates cells ("killer T cells") that attack foreign cells.  In type-1 diabetes a small number of these killer T cells mistakenly attack the body's beta cells in the pancreas, which causes type-1 diabetes.  These are called "bad killer T cells".  These researchers specifically measured "bad killer T cells" (separately from other killer T cells) and found fewer of them in patients who got TOL-3021 as compared to those which got a placebo.  This is direct evidence that the treatment is working in the way the researchers expected.

3. Treated type-1 diabetics did not change their immune response to foreign cells.
One of dangers of immunology in general, is that you might damage the body's immune system. You might cure the type-1 diabetes, but hurt the body's ability to fight off disease in the future. These researchers specifically looked at the effect of TOL-3021 on the body's reaction to foreign bodies (the viruses, cancers, and foreign cells that the immune system is supposed to attack).  They found there was no change in the immune system's ability to do it's job of attacking these foreign cells.  This is interesting for at least two reasons: first, it's unusual.  Most immune treatments end up lowering the immune response across the board.   Second, it's important.  By showing this treatment did not effect the rest of the immune system at all, it puts TOL-3021 in a good position to move forward, because the safety worries will be lower and the potential doses can go higher.

Moving Forward

So what is the next step?  Well money, for one thing.  Or, better yet, a strategic partnership.  Since these are phase-II results, the obvious next step is either a phase-III study or another phase-II study.  Either path requires money.  Of the four phase-III studies I've followed in the past, three were funded via a strategic partnership with a "big pharma" company; only one was funded by a smaller company itself.

What are the problems to overcome?  The small results are a big problem.  They need to see a larger C-peptide production, if they are going to produce a treatment, much less a cure.  A second issue is duration.  The biggest results were seen 15 weeks into the treatment. since the treatment was given for 12 weeks, this is close to the point of longest duration of treatment.  That suggests to me that the treatment might need to be given for a longer duration, or given more often, or improved in some way, in order to be more effective in the long term.

What sort of clinical trial comes next? There are a lot of options here. Since TOL-3021 seems to lower the autoimmune attack, but does not create replacement beta cells.  An obvious trial would be to try it on honeymooners or even pre-diagnosis, high risk relatives of type-1 diabetics. Those people have more surviving beta cells, so the benefit should be more obvious. Another option would be to combine it with a treatment that stimulates beta cell regrowth. Simply repeating the treatment for a longer period of time would be interesting, as well.

Business News

The reason there was no news on TOL-3021, prior to these phase-II results, is that until recently this drug was known as BHT-3021 and was being developed by Bayhill Therapeutics.  Bayhill had all the trappings of a successful little pharmaceutical start up (several drugs in development, a deal with Genentech, about $50 million invested, etc.)  But it collapsed while BHT-3021 was in the middle of it's phase-II trial.  Luckily, the researchers focusing on BHT-3021 were able to rise, phoenix-like, from the ashes, and create Tolerion.

Some Discussion

One question I've heard is "why do they call this a vaccine" or "what is a reverse vaccine", and there is a simple answer to that.  Classic vaccines work by stimulating the immune system.  This product works by regulating (lowering) the immune system, so it acts like the reverse of a vaccine. It is similar to the way food allergies are treated.  For food allergies doctors sometimes give small amounts of what you are allergic to, so your body learns not to attack it.  The difference here, is that they are giving the body a specially crafted molecule, which is designed specifically to teach the body not to self-attack proinsulin.  Other researchers are giving small amounts of insulin to teach the body not to attack insulin, which is a related idea, but the hope here is that TOL-3021 will work better and more specifically than insulin.

Comparing TOL-3021 to BCG (ie. Tolerion's results to Faustman's results)

These two potential cures are similar in many ways.    Medically, they are both immunology based approaches.  They are both being tested on established type-1 diabetics (not honeymooners), and they both started clinical trials in the 2006-2007 time frame.   From a "marketing" point of view, their respective proponents each claimed that they targeted the exact cells that cause the destruction of beta cells in the pancreas.  They are not suppressing a whole class of immune cells, just the ones that are incorrectly attacking beta cells.

So with all those similarities, it makes sense to compare them in three different ways:
1: Effectiveness. The most important comparison would be C-peptide numbers. The BCG treated patients gained 22% of their C-peptide production, while the TOL-3021 group gained 28%. So TOL did slightly better.
2: Targeting.  One of the key advantages claimed by Dr. Faustman for BCG and by the Tolerion group for TOL-3021, is that they selectively target the bad T cells. Here the Tolerion group has published data supporting both sides of their claim: data showing bad T cells are lower when treated, and data showing other T cells don't change.  Dr. Faustman's trial found no difference in the number of active bad T cells, and did not measure the other T cells at all.
3: Research size/analysis. The TOL group was more than three times as large as the BCG group, which is always a good thing.   Finally, Tolerion's results were statistically significant as designed, which is different than Dr. Faustman's group.  They had to move a person out of the placebo group in order to get statistically significant results, and use different comparison groups for different measurements.

In a head to head comparison, TOL-3021 has better results across the board, and both treatments were tested in long established type-1 diabetics.

Note that Dr. Faustman's group reported C-peptide production in absolute numbers, while the Tolerion group reported as a percentage change. I did ask the Tolerion group for the absolute numbers, since that would make the comparison simpler, but that data is not publicly available. Therefore, I have converted Dr. Faustman's numbers into percentages in order to do the comparison. So the comparison is approximate. In my opinion, reporting absolute numbers (as done by Dr. Faustman) is the better way to go.

News: http://www.biospace.com/news_story.aspx?NewsEntityId=301263&source=news-email
http://news.yahoo.com/type-1-diabetes-vaccine-shows-promise-early-study-180404550.html
Press Release: http://www.tolerioninc.com/TOL-3021_press_release.html
Interview: http://www.bizjournals.com/sanfrancisco/blog/biotech/2013/06/type-1-diabetes-vaccine-stanford.html?page=all
Abstract: http://stm.sciencemag.org/content/5/191/191ra82
US Trial Registration: http://www.clinicaltrials.gov/ct2/show/NCT00453375
Company Web Site: http://www.tolerioninc.com/

Summary of ADA's Annual Conference

ADA just finished their annual conference. I enjoyed the summaries below. Remember that ADA covers both type-1 and type-2, so some of the news will be about type-2 diabetes:

http://www.integrateddiabetes.com/Articles/ADA%202013%20meeting%20notes.pdf
http://www.diabetesmine.com/2013/06/its-a-wrap-on-the-ada-scientific-sessions-for-2013.html
http://www.diabetesmine.com/2013/06/ada-scientific-sessions-part-2.html

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

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

Aldesleukin (Proleukin) Starts a Phase-II Clinical Trial

Called DILD1T, this is a 40 person clinical trial.  It started in March 2013, and is expected to finish in January 2015.  It is enrolling adults who have had type-1 diabetes for 3-24 months (so not just honeymooners) in Addenbrooke’s Hospital, Cambridge, UK.  Currently, it is only 12% enrolled, so they have a ways to go.  I'm treating this as a phase-II trial, because of it's size and because Proleukin has already been tested twice in type-1 diabetics (that I know of).

I think that this study involves only one subcutaneous injection (like an insulin injection).

Here is the justification for the study.  The quote is from the researchers, but I've removed some of the medical language:

The vast majority of genes that contribute to susceptibility to type 1 diabetes [are related to] immune regulation and function. In particular, ... the interleukin 2 (IL-2) pathway that regulates T cell activation .... Aldesleukin (Proleukin) is a human recombinant IL-2 product .... There is substantial [research data in tissues/petri dishes, animals, and humans] that ultra low dose IL-2 (aldesleukin) therapy can arrest the autoimmune mediated destruction of pancreatic beta cells by [encouraging] functional T regulatory cells.

The researchers view this study as looking for the optimal dose as a prelude to doing a large phase-III trial.  This is a classic goal of many phase-II trials.  This trial is funded by the Welcome Trust (a big UK operation), JDRF, and the NHS Foundation Trust (which I think is the UK government).

Here are links for this new research:
Web sites: http://www.clinical-trials-type1-diabetes.com  http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=13846
News: http://www.wellcome.ac.uk/News/Media-office/Press-releases/2013/WTP052844.htm
Facebook: https://www.facebook.com/ClinicalTrialsType1Diabetes
Twitter: https://twitter.com/t1diabetestrial
WHO Registration: http://www.controlled-trials.com/ISRCTN27852285/
US Registration: http://www.clinicaltrials.gov/ct2/show/NCT01827735
Wikipedia on IL-2: http://en.wikipedia.org/wiki/Interleukin_2

I also think it is important to remember that IL-2 has been tested in humans twice before, and has failed both times.  I previously blogged on those trials:
http://cureresearch4type1diabetes.blogspot.com/search/label/IL-2
Clinical Trial Records:
    http://www.clinicaltrials.gov/ct2/show/NCT00336674
    http://www.clinicaltrials.gov/ct2/show/NCT00525889


DiaPep 277's Results from an Extended Phase-III Trial:
No Longer a Cure?

I've been following DiaPep 277 for as long as I've been following type-1 diabetes cures.  When I started, it was already in phase-II trials.  Recently Andromeda Biotech Ltd, the company developing it, has published some phase-III results, and (most recently) some extended phase-III results.  These extended results are from people who were in the phase-III trial for two years, and then continued with the treatment for an additional two years.  The two year extension was "open label", meaning that the patients and doctors knew they were getting the treatment; it was not blinded.

Unfortunately, the results are decidedly mild.  People's A1C numbers dropped by 0.6 (from an average of 7.6 to an average of 7.0.  In terms of improvement of treatment, that's not bad.  I think there is a market for a drug that would lower A1C numbers that amount, but it is not a cure.  There is always hope that future improvements in the treatment will lead to even better A1C improvements (which I think is likely), or even improvements so great they lead to a cure (which I think is very unlikely).  But currently, this is an adjunct treatment, not a cure.  So I expect to stop covering DiaPep 277, unless I see results much larger than are seen here.

news: http://www.globenewswire.com/news-release/2013/06/05/552188/10035325/en/Andromeda-Announces-the-Results-of-an-Extension-to-Its-Phase-III-Study.html

The previously announced results from one of their phase-III trials, which I blogged about here:
http://cureresearch4type1diabetes.blogspot.com/2011/11/andromedas-diapep277-succeeds-in-phase.html
were similarly mild, and much more like a treatment than like a cure. 

Phase-I Trial Resets the Immune System in MS Patients

This news comes from a human trial in multiple sclerosis (MS) patients.  Basically, researchers were able to "reset" the body's immune system, to lower the autoimmunity reaction (the body's attacking it's own cells) by  50%.-75%.  This was in a 9 person phase-I trial in Germany.

To understand why that is important, a little background is needed.  Most researchers believe that MS and Type-1 are related diseases.  In both cases the immune system mistakenly attacks the body's own cells.  In Type-1, it attacks beta cells in the pancreas, and in MS it attacks the myelin sheaths of nerve cells, however the underlying autoimmunity reaction is similar.

Prior to testing on people, this method was tested in mice who had MS and in mice who had type-1 diabetes, and worked on both groups of mice.  However, the human trials were MS only.  But obviously, trials in type-1 diabetic people could be done as well.  In my opinion, should be done.

The idea of resetting (or rebooting) the body's immune system has been tried on type-1 diabetics, and it was successful.  Some of the treated type-1 diabetics did not have to inject insulin for years afterwards.  However, the risk involved is high enough, that these treatments have never moved forward.  At least three different teams (in Brazil, Poland, and China) have run similar trials and gotten similar results.  I have blogged about them before:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Although it is hard to draw a direct comparison, it sounds like the procedure being tested here is much safer, but slightly less effective than the procedure used by Burt, Snarski, Li, etc.  Of course, it might be refined over time to make it more effective or safer, or both.

news: http://scienceblog.com/63715/big-multiple-sclerosis-breakthrough/

Personal Note

In the past, I've posted on my blog what I call a "non-conflict of interest statement" which is this:

• I don't work for a company involved in medical research; I never have.
• I don't get paid in any way by any company doing medical research; I never have. And that includes free samples, free travel, or free anything.
• None of the hours that I have put into my blog, or the posts that I make to any web site, has ever been paid for, nor have I gotten anything free.  (Except for some very nice and heart felt thank-you emails, and those are worth more than money.)

I'm now adding a fourth bullet point:

• My daughter has type-1 diabetes and participates in clinical trials.  She usually gets some money for participating. I sometimes report on trials that she participates in.  For several reasons, I don't generally reveal what studies she enrolled in (or tried to enroll).  

Why not, you ask?  A couple of reasons.  First  of all, her participation is a two step process.  My wife and I decide the research is safe and that she can participate, and then she decides if she wants to participate.  Therefore, she selects different studies than I would select.  For example, she prefers studies in the summer, and studies that pay well.  I don't want people coming back to me and saying why did she participate in study X rather than study Y?  Second, I get important information from researchers.  I don't want researchers thinking, "his daughter was in Dr. X's trial, but not mine, why is that?"  (Truthfully, the answer is usually, Dr. X paid better, or required less time, or was more convenient, but I don't want to be explaining that.)  Thirdly, I don't want readers of this blog to be thinking "Joshua's daughter isn't in trial X, why should my child be in that one?" or the reverse "Josh's daughter is in trial X, I should get my kid in there, also!"  Our kids are different, and participating in a trial should always be personal decision.  And finally, even participating in a trial might make public health information about my daughter that I don't want public.  For example, enrollment might only be open to people who have a particular side effect, or don't have that side effect, or who are still generating some insulin, or whatever. 

In the last 5 years, I have only blogged on one study that my daughter participated in.  I would expect to blog on only a couple in the next 5 years, so this is a rare thing. 

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials.  My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

The Root Cause of Type-1

Some researchers in Boston made a big splash recently by claiming to find the "root cause" of type-1 diabetes.  I've gotten at least two emails asking for my thoughts on the research, so here they are.

One thing that I try to do, is to read the original paper, or at least the abstract, and then describe what the researchers did, what they found, and why it is important.  I've found that the original research often contains valuable information that doesn't make it into press releases, news articles, blog postings, etc.  So I try hard to find that original work.

Unfortunately, I can't do that for this paper.  I've read the abstract a couple of times, and I can't make heads or tails of it.  The abstract assumes a level of knowledge way beyond me.  One thing that did make me nervous was this: it looks like this research was done on people and mice who had transplants to treat type-1 diabetes, and they studied how those people's bodies attacked the transplanted cells.  This makes me nervous because the immune system's attack on a transplanted organ is proper.  It's a foreign invader, after all.  This is different than the immune system's attack on it's own pancreas, which is an error.  I'm not sure learning about the causes of one, is going to teach us what causes the other.  On the other hand, I might be totally misunderstanding what they were doing.  The abstract is opaque to me.

How important is this?

I don't know.  I don't think anyone knows, as yet.  It often takes a few years to confirm that a breakthrough really is the big breakthrough that everyone hoped it was at the start.  Even after we know that this is a big breakthrough, we don't know if it will lead to a cure or not.  The discovery of the smallpox virus (for example) did not lead to the discovery of a cure for smallpox  (and the first smallpox vaccine predated knowledge of the smallpox virus).

In the future, if this leads to a cure (or preventative) for type-1 diabetes, then we will be able to look back and say, "this really was that important".  But there is no reasonable way for us to look into the future and know that this discovery is that important right now.

(I know that's kind of depressing.  Some people react to that by not donating money to research, because they never know which research is going to lead to a cure.  I view it the exact opposite, that it is important to give money to research, so that as many different options can be funded as possible, specifically because we don't know which will lead to a cure.)

What does this mean to me?

I care about a cure for type-1 diabetes, so what does this discovery mean to me?  Basically, a lot more research.  In order to get from a discovery of root cause to a cure, at least three things need to happen.  (a) they need to be sure the discovery is correct and use that discovery to figure out a cure. (b) they need to test that cure in petri dishes, tissue samples, and animals. (c) they need to test it in people.  Now (a) often takes a few years, although sometimes less, and (b) can take anywhere from years to decades, and (c) takes at least 10 years.  So making a few reasonable guesses, I would expect any cure that comes from this discovery to arrive in 15+ years (for an optimistic guess) to 25+ years (for a more reasonable guess).  If this discovery pans out as being important.  And that is a big "if".

One last word.

Curtis Lomax said "This one smells like a lot of hype."  I agree, and I couldn't put it better myself.  In fact, I'm linking to the Lynyrd Skynyrd song "That Smell" as the theme song for this posting:
http://www.youtube.com/watch?v=sV_toedW2L0

Links to the news coverage:

• http://diabetes.diabetesjournals.org/content/early/2013/01/10/db12-0242?utm_campaign=Diabetes%20transplant&utm_medium=6/2013&utm_source=vector&utm_content=Transplant&utm_term=Tripp
• http://www.bostonmagazine.com/health/blog/2013/06/13/boston-childrens-hospital-found-the-root-cause-of-diabetes/
• http://vectorblog.org/2013/06/silencing-immune-attacks-in-type-1-diabetes-without/#more-8597

I think this is the paper's abstract:

• http://www.ncbi.nlm.nih.gov/pubmed/23315496

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which I sometimes blog on. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/