Results from a Phase-II ATG and GCSF Combination Trial

I'm embarrassed about this blog posting, because it is very late.  It reports on news announced about 18 months ago.  I was digging through some old emails, and found it.

ATG is Anti-Thymocyte Globulin, a biological agent used to lower immune reactions.
GCSF is Granulocyte Colony-Stimulating Factor, a biological agent which causes bone marrow to generate more stem cells and more immune cells, and put them into the blood stream.

So the two of them together could make an effective combination therapy against type-1 diabetes. ATG would lower the autoimmune attack, and GCSF would help the body regrow beta cells. At least, that is the hope. I wrote about the start of this trial here, and it contains a lot of background material:
https://cureresearch4type1diabetes.blogspot.com/2010/08/atg-gcsf-starts-phase-i-clinical-trial.html

In brief: this study took 25 people, 2/3s got the treatment, and 1/3 got a placebo.  The treatment was spread out over 12 weeks.  The primary result was C-peptide results after 1 year, but this paper reported on extended results after 2 years.

Results from a Phase-II ATG and GCSF Combination Trial

The following graph is from the paper, and you can see that for the first year the treated group did noticeably better.  (Meaning they generated the same C-peptide at the end as at the beginning, while the placebo group dropped over time.)  The 3 to 6 month time period was particularly strong, with the treatment group generating more C-peptide while the control group generated less.  The first year change was statistically significant.  However, during the second year, C-peptide numbers continued to drop for both the treated and placebo groups, and the separation between the two of them shrunk, so that the difference was not statistically significant.

Research Paper:
http://diabetes.diabetesjournals.org/content/65/12/3765?etoc
http://diabetes.diabetesjournals.org/content/early/2016/09/26/db16-0823?papetoc

Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01106157

Discussion

This is one of several studies which preserved beta cell function for a year during the honeymoon.  Early on, these studies gave me a lot of hope that they could be improved on, and eventually even lead to a cure.  However, so far I haven't seen any movement in that direction.  Treatments that preserved beta cells for one year, have (so far) not been extended to last longer.

Earlier results from this trial were strong enough so that this team started a follow on trial for honeymoon type-1s (people in their first 4 months after diagnosis):
Recruiting Site: http://www.diabetestrialnet.org/ATG-GCSF/index.htm
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02215200

There are two obvious questions in this research:
1. If this treatment were started prior to diagnosis (in people who had several autoantibodies, for example, but were not showing any symptoms of type-1 diabetes), would it prevent the onset of symptoms?
2. If this treatment were repeated on a yearly, or every two year basis, could it prevent type-1 diabetes completely?  And would the hassle and side effects of the retreating on a regular basis be worth it?

Unfortunately, the new study (in honeymooners) will not answer these questions.  But it is three times as large, so it will confirm that this study was not a fluke, and the results should be available very soon.  Recruiting was completed before July 2016, so primary data should have been collected by July 2017, and publication should be imminent.

Since this study started, there is now a new hope for this level of result ("preserving beta cells for one year").  Those results could be applied to presymptomatics: people who had two or more autoantibodies, but no symptoms of type-1.  Preserving beta cells for these people would have the effect of delaying the diagnosis of type-1 diabetes.  That would be great.  However, identifying presymptomatics to test this on has just happened in the last few years, and few studies have looked into this.  But I will be looking forward to seeing the results of these studies (as prevention).

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.

ATG and GCSF Combination Starts a Phase-II Trial

ATG is Anti-Thymocyte Globulin, a biological agent used to lower immune reactions.
GCSF is Granulocyte Colony-Stimulating Factor, a biological agent which causes bone marrow to generate more stem cells and more immune cells, and put them into the blood stream.  It is sometimes called G-CSF, and the exact product being used is Neulasta.

So the two of them together could make an effective combination therapy against type-1 diabetes. ATG would lower the autoimmune attack, and GCSF would help the body regrow beta cells.  At least, that is the hope. I wrote a more detailed blog entry on this combination four years ago, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/2010/08/atg-gcsf-starts-phase-i-clinical-trial.html

ATG and GCSF Combination Starts a Phase-II Trial

This is a three armed study.  Each group will have at least 28 people.  The first will get ATG.  The second will get ATG and GCSF.  The third will get a placebo.  The ATG will be given twice, one day apart.  The GCSF will be given six times, two weeks apart. They started recruiting in December 2014, and hope to finish collecting their data in October 2016.  The primary outcome (the most important result they will measure) is C-peptide generation after a meal as measured a year after treatment.  There are no secondary outcomes listed, however I've been told they will track A1c, insulin usage, low BG, adverse effects, and infection rates as secondary outcomes.

They are recruiting in at least six different locations, all over the United States.  Although it's not listed on the clinical trial site, Stanford is recruiting for this trial, and they are planning on adding UCSF soon as well.  The list (with contact information) is in the Clinical Trial Record below. Patients must be between 12 and 46, and have been diagnosed within a 100 days,so this is a honeymoon trial.

Recruiting Site: http://www.diabetestrialnet.org/ATG-GCSF/index.htm
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02215200
Press Release: http://jdrf.org/2015/01/unlocking-a-combination-therapy-for-new-onset-t1d/
Wikipedia: http://en.wikipedia.org/wiki/Anti-thymocyte_globulin http://en.wikipedia.org/wiki/Granulocyte_colony-stimulating_factor

Funding for this trial comes from several US government agencies, JDRF, ADA, Helmsley, and two commercial companies: Sanofi and Amgen.

Discussion About Previous Results

For me, the most important question in a phase-II trial is: "What happened in the phase-I trial?"  If there was a phase-I trial.  For this treatment, there was and it included a placebo group.  The results were good, but not great, from the point of view of curing type-1 diabetes.  Over the years of the trial, the placebo group had lower C-peptide levels (meaning they lost the ability to make their own insulin). This is what would be expected during the years after diagnosis.  The treated group's C-peptide levels stayed about the same.

Obviously, an optimist will look at those results, and say "they stopped the loss, this is good, and the earlier we can use this, the better it will be".  A pessimist would say "they had type-1 when the trial started; they had it when it was over; there was no real improvement".

My blog on their previous results is here:
http://cureresearch4type1diabetes.blogspot.com/2014/07/ada-2014-type-1-diabetes-cure-research_14.html

And here is the most important graph from those results, you can see that treated people stayed the same (dark line at top) while untreated people got worse (lighter line below):

The full paper is here: http://www.jci.org/articles/view/78492.
Thanks to the The Journal of Clinical Investigation for making the whole paper available on line.

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

Possible Cures for Type-1 in the News (late Sept-2012)

Prochymal Failed Phase-II Trials

I missed this, when it was published back in May, but luckily Kelly Close (of Close Concerns, who publishes DiaTribe) reported on it:

At 1 year, intravenous infusions of Prochymal were reportedly well tolerated, with no differences in adverse event rates between the Prochymal and placebo groups. 

With regard to efficacy, no significant differences in stimulated C-peptide levels were observed between the two arms (the primary efficacy endpoint), although a trend towards fewer hypoglycemic events in the Prochymal arm was observed. 

A full analysis will be performed following an additional year of follow-up (for a total of 24 months)

My translation is this:

• The trial failed its primary endpoint.
• The researchers are trying to be optimistic about a small, vague result in one of the secondary endpoints.
• The study will get more data after another year, and they are hoping for better news.

Obviously, I'm hoping for better news next year, too.  But I'm not expecting it.

Scientific Press Coverage: http://onlinelibrary.wiley.com/doi/10.1111/j.1753-0407.2012.00197.x/full

DiaTribe is a free on line newsletter (http://www.diatribe.us/), which is is a great source of info on diabetes research, technology, etc.

NI-0401 by NovImmune Failed a Long Time Ago

Years ago a company called NovImmune started a phase-II trial for their drug NI-0401 aimed at type-1 diabetes.    After that, no news.  This drug was targeted at CD3, and all the other CD3 drugs failed, so I always assumed this one had, as well.  But there never was any news, and I never saw an official announcement.  However, NovImmune updated their entire web site, and NI-0401 is still there, but diabetes is not listed as a target at all.  Also, I found a European clinical trial registry, which showed that the long ago study had been canceled just months after it started.

So NI-0401 is dead, as far as I'm concerned, until I hear otherwise.

European clinical trials registry:
http://apps.who.int/trialsearch/trial.aspx?trialid=EUCTR2009-012988-34-AT
https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-012988-34/AT

Corporate web site:
http://www.novimmune.com/products/ni-0401.html

DiaPep277 by Andromida is Fully Enrolled

This is the only treatment that I'm following that is currently in phase-III trials.  The results from previous work suggest it might be a "longer, strong honeymoon" type treatment, rather than a cure. they have already finished one phase-III trial, and this is their second.  The FDA requires two, so when this one completes, if it is successful, they will be ready to move into "marketing approval" phase, which takes a year or two.

Why is this important? For two reasons.  First, because it is now possible to predict when they will finish collecting data.  (Since this study gathers data for 2 years, it will finish about Sept 2014.) Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants.  It is often unclear how hard it will be to recruit people, and long it will take.   But that this point, all that cunertainty is behind the researchers.  From now on, it is just gather data, then analyze data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.

News: http://www.marketwatch.com/story/andromeda-biotech-successfully-completes-patient-recruitment-in-phase-iii-confirmatory-trial-for-its-lead-drug-diapep277-for-type-1-diabetes-2012-09-12

How Doctors Weigh Clinical Trial Funding

This was a very interesting study of doctors.  Basically, the researchers gave doctors summaries of research results.  These summaries breifly described a study's results, methodology, and source of funding.    The doctor was then asked questions to determine how much they trusted the results, and how willing they were to proscribe the medicine being tested, based on the trial.  (The research described was fictional, so the doctors did not have any prior knowledge of the drugs in question.)

Here is a summary of the results:

The study found that physicians weighted their assessment of the rigor of a trial based on pharma funding, and that they were half as willing to prescribe those disclosing industry sponsorship as they were those disclosing NIH funding, regardless of methodological rigor.

Discussion

I think these results are good in two separate (but related) ways.  First, they suggest to me that doctors properly "discount" clinical trials funded by industry.  Second, it suggests to me that when a doctor recommends a treatment, they are already taking into account who funded the studies suggesting its use.  The recent problems with pharma PR guys "ghost writing" research articles, and withholding placebos from some researchers has made some people nervous about the accuracy of studies they do fund.  I think it is proper that doctors are also nervous, and I feel good that the average doctor in the study took into account the funding source of clinical trials they read about.

Interestingly, the researchers who ran this particular trial are a little unhappy about their own results.  They seem to think that when comparing two studies, if the methodologies are equally rigorous, that the results should be weighted the same, no matter who did the funding.  They are specifically worried about doctors undervaluing what the researchers consider large scale, well designed, industry funded studies.   I disagree.  I think the prescribing doctors are doing the right thing by undervaluing (or "discounting") equally rigorous studies that are funded by industry.  I view the attitude of these researchers as being very "old school" (and in this case, out of date).  Sure, in the 1950s the idea was that rigorous trial methodology and peer review together were all that was needed to ensure accurate results.  The idea was that the scientific method was so good that who funded the trial was not critical to the quality of the results.  But 60 years later, I don't think that's the consensus opinion.   Now we know that quality starts with good methodology and peer review, but those alone are not enough.

News coverage: http://www.mmm-online.com/docs-downgrade-results-of-pharma-funded-clinical-trials/article/259981/

Symlin as a Treatment

Not for a cure, but of interest, are the results of two studies testing symlin in type-1 diabetics.  Only one was placebo controled, and it found:

analysis of 248 patients from a 29-week, placebo-controlled study, measurements in the normal range based on ADA criteria increased from 37.3 percent to 43.9 percent for SYMLIN-treated patients (n=115), compared to an increase from 38.2 percent to 40.9 percent in those receiving placebo (n=133). The percent of measurements in the normal range based on AACE criteria increased from 22.6 percent to 27.8 percent for SYMLIN-treated patients compared to an increase from 24.1 to 25.0 in those receiving placebo. The percentage of readings in the hypoglycemic range remained relatively stable.

Discussion

I'm not sure I'd take a second injection with meals (or a first injection for pump users) for that level of improvement, but it's still interesting.  I also think that A1c improvements would be a better measure of goodness than % inside of guidelines.   But you gotta start somewhere.

Maybe we'll end up with a tri-treatment artificial pancreas.  It will dose insulin for highs, glucagon for lows, and symlin with meal boluses.

Press Release: http://www.businesswire.com/news/home/20120609005027/en/SYMLIN%C2%AE-Helped-Patients-Type-2-Type-1

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (early Aug-2012)

Prologue: Why Completing Enrollment is an Important Milestone for Clinical Trials

For two reasons.  First, because at that point it is possible to predict when the researchers will eventually finish collecting data.  The experimental design will say how long data will be collected for each person, so you can just add that duration to the date they finished enrollment, and that tells you when the final data will be collected.  Second, because much of the uncertainty that surrounds clinical trials involves recruiting participants, it is often unclear how hard it will be to get people, and long it will take.   But at this point, all that cunertainty is behind the researchers.  Once enrollment is complete, it is just gathering data, then analyzing data, and then publishing the data.  Researchers have a lot more control over those later stages, than over recruiting people in the first place.

Put another way, a clinical trial is made up of five tasks:
1. Do research to figure out what clinical trial should be done.  During this phase, the researchers are at the mercy of the science.  If they science doesn't pan out, then the experiment never gets done.
2. Get FDA approval for the clinical trial.  During this phase, the researchers are at the mercy of the FDA (or similar regulatory agency).  If they don't get approval, the experiment never gets done.
3. Recruiting patients.  During this phase, the researchers are at the mercy of the patients (or their parents).  If they can't get enough people to enroll, the experiment fails.
4.  Gathering the data.  During this phase, the researchers pretty much control their own destiny, unless a huge number of people drop out, or there is some unexpected safety issue.
5. Writing and publishing the results.  During this phase, the researchers are subject to editors and peer review (to some degree).  However, there are so many journals and web sites, that the researchers have many choices; they can even self publish, if all else fails.  They are not at the mercy of any one person or committee.

Completing enrollment is the end of phase 3 / start of phase 4, and you can see that researchers have a lot more control of their own destiny in phases 4 and 5, then in 1, 2, or 3.  

"REPAIR-T1D" (Lansoprazole and Sitagliptin) phase-II Study Completes Enrollment

This study finished enrolling in May 2012 and they plan to gather data for two years, so we should have results soon after May 2014.  This trail gives two currently approved drugs (Januvia and Prevacid) to type-1 diabetics within six months of diagnosis.  The hope is that it will restore or at least preserve beta cell function.

Press Release: http://www.newswise.com/articles/the-sanford-project-reaches-milestone-in-quest-to-cure-type-1-diabetes
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01155284

GCSF/Neulasta phase-II Study Completes Enrollment

Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Haller

This study finished enrolling in March 2012, and they plan to gather data for two years, so we should have results soon after March 2014.  (Their clinical trial record says December 2014.) GCSF, also known as Neulasta or Pegfilgrastim, causes the body to generate it's own stem cells from bone marrow. These might rebalence the immune system or they might retrain it, but in any case, the hope is they will help cure type-1.

Burt's trial (the most successful so far) uses GCSF, ATG, and CZ. CZ is, by far, the most toxic of the three, so this trial can be viewed as "Burt ultra-lite". GCSF and ATG together would be "Burt lite" and there is a trial for that also ongoing.
Clinical Trial Record:   http://www.clinicaltrials.gov/ct2/show/NCT00662519

Thymoglobulin (ATG) Phase-II Study Completes Enrollment

Please read about Thymoglobulin (ATG) here: http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html (scroll down the page until you see the section on ATG)

This phase-II study of ATG has completed enrollment.   It took them about 2 years longer than expected, so that's not good, but we can expect data collection to be complete in 2 years, and hopefully results will be published soon there after.  The ATG link about has complete information on why the researchers hope ATG might cure type-1 diabetes or be part of a cure.

Clinical Trial Record:  http://www.clinicaltrials.gov/ct2/show/NCT00515099
Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman

Combo (Diamyd, Lansoprazole and Sitagliptin) Trial Fails

This trial has a long and not so good history, which you can read in my previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Combo

This Phase II study combined regenerative agents (lansoprazole and sitagliptin) and also Diamyd. The regenerative agents are both marketed drugs in the US. Diamyd is a vaccine like drug which trains the body's autoimmune system not to attack it's own cells.

This study's clinical trial record updated to show that it was terminated on 20 March 2012, although I think it had actually ended earlier.  Dr. Harlan, who started this study, had left the NIH, and the phase-III studies of Diamyd alone had failed or been canceled, so they decided not to pursue it.  

Obviously, it's too bad that it was canceled.  This was the first study that I knew of that attempted to combine a drug to stop the autoimmune attack and drugs to encourage the regrowth of beta cells.      I think that combining treatments like that is still a good thing to try, even if this specific combination did not work out.

Clinical Trial Record:  http://www.clinicaltrials.gov/ct2/show/NCT00837759

More Stable Glucagon

This is only vaguely related to a cure, but I thought I'd mention it.  Xeris is trying to create a form of glucagon which can be stored at room temperature for long periods of time.  From a cure point of view this is useful for an artificial pancreas (if you consider that a cure).  Simple APs are based on insulin alone.  However, there are more complex APs, which are based on insulin and glucagon.  Having a glucagon which was approved to sit in the pump for days, maybe weeks, would be important to these "bihormonal" APs.

As a nice side effect, it would mean that emergency glucagon needles could be preloaded, just like insulin pens, which would make them much easier to actually use in an emergency.  It also would make mini-glucagon doses much easier to administer, for those who use them.

You can think of an insulin only AP sort of like a car with a break but no accelerator.  The engine "revs high" and you run along.  You use the break to slow up.  A bihormonal AP (insulin and glucagon) is more like a car with a break and an accelerator.  More control.  The analogy is not perfect, but that's the basic idea.

Press Release: http://www.marketwatch.com/story/xeris-pharmaceuticals-awarded-phase-i-ii-nih-sbir-fast-track-grant-to-advance-stable-non-aqueous-glucagon-for-bi-hormonal-artificial-pancreas-2012-07-31

Why Pharma/Med Device Co's Apply for Approval in Europe FIRST

If you haven't read this blog posting by Scott Strumello, you should!  It compares the approval process for medical devices in the EU to the same process in the US:
http://blog.sstrumello.com/2012/08/why-pharmamed-device-cos-apply-for.html

Next Up: Results from Dr. Faustman's Phase-I BCG Trial

She published in PLoS last week, so I hope to blog about it in a week or two.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (late-Aug)

 
GCSF (Neulasta/Pegfilgrastim) Starts a Phase-I Clinical Trial
This is straight forward trial where GCSF is given to people in the honeymoon phase of type-1 diabetes.  It is interesting for many of the same reasons that the ATG+GCSF trial is interesting (see older post on ATG+GCSF).  Both of these trials are being done at the University of Florida, and Dr. Michael J. Haller is involved in both.

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00662519

There is a second GCSF clinical trial being done at the University of Padova (Padova, Padua, Italy), but it is not aimed directly a curing type-1 diabetes.  Although I don't understand it fully, it appears to be more basic research into GCSF effects on people with type-1 diabetes.  Clinical trial record is here: http://www.clinicaltrials.gov/ct2/show/NCT01102699

A Little Discussion: Why a GCSF only Trial?
One obvious question that came to mind when I saw this GCSF only clinical trial, done at the same place and time, and by the same researcher as doing the ATG and GCSF trial, was: why do both?  I mean, if GCSF works, then certainly ATG and GCSF will work, and clinical trials are a lot of work and expense.

The answer to this question (for me) has to do with with three separate, but related goals:

1. We want to cure type-1 diabetes. (Cure Product Development.)
2. We want to learn how drugs effect type-1 diabetes, so we can find a cure.  (Basic research.)
3. We want the FDA to approve clinical trials which lead to points 1 and 2.

If you only look at point 1, then a GCSF-only trial (when a GCSF+ATG trial is also ongoing) might sound like a waste of time.  As a parent of a child with type-1 diabetes, I often focus only on point 1.  However, product development flows out of basic research, so points 2 and 3 are also important.  It may turn out that studying GCSF alone will help create a cure in the future, or that the FDA might require more knowledge of GCSF alone before it will approve some future clinical trial, which leads to finding a cure.

In the past I have blogged about not understanding how  Sitagliptin alone, or Sitagliptin and Lansoprozole combined, could cure type-1 diabetes.  However, it may be that these clinical trials will be valuable, because of points 2 or 3 above.  They might be the basic research or FDA required background that eventually leads to a cure, even if they are not the cure themselves.

LCT Announces Completion/Extension of their Phase-II Trial
LCT has announced these things in August:

1. Their phase-II trial has been extended with 4 new patients who will get dose 20k u/kg dose.  The phase-II study now includes 4 who got 10k u/kg, 4 who got 15k u/kg and these 4.  This is a 50% expansion of their study, at 33% higher dose.
2. The first four patients have seen a benefit of fewer (or elimination) of low BG episodes.  Only two such events, compared to nineteen, so almost a 90% drop.
3. They plan "commercial launch" in 2013, and "global reach though partnership".  They seem to be assuming that the operation will cost about $150k (I think this is US$, but not sure.)
4. They have also laid out the following time line for getting to commercial availability, which is the most detailed that I've seen:

• 2011: Continue phase-II trials, get approval for phase-III trial (They use the term "pivotal".)
• 2012: Complete phase-III, report on results.
• 2013: "Approval and revenue"

That's their plan, and I hope they make it.  I see the following issues for them to overcome.  First, they need to have a cure.  Right now, the longest they have had anyone insulin-free is 32 weeks, and only two people (out of twelve) have been insulin free for any number of weeks.    Obviously they need to improve both of these numbers.  (Although, if you view them as a treatment to help brittle diabetics, then their results might be good enough already - depending on how long they last - but that wouldn't be a cure.) Second, they need to treat enough people to get their approvals.  Right now, they have treated a total of 16, with 4 more on the way.  That is far fewer patients than any other phase-II trial that I know of.  A more common count is 20-30 in the phase-I trial, 80-120 in phase-II, and 300 in a phase-III "pivotal" trial, and then a second phase-III trial for confirmation.  (Basically all the drugs in phase-III trials have followed that path.)  LCT is running at about 1/3 the size in their phase-I trial, and 1/10 the size in their phase-II.


Press release: http://www.blogger.com/post-edit.g?blogID=5472921328078253036&postID=548554300707664816
Corporate Overview: http://www.lct.com.au/downloads/cms_latest_news/2010-08-26-Presentation%20August%2010.pdf
This corporate presentation contains a lot of information on where they are, what they plan to do in the future, and how they plan to make money.  It is targeted at investors, after all.


NovImmune has started a phase-II for NI-0401
This company is very hard for me to follow, because they don't issue many press releases, don't have the clinical trial records, that most other researchers have, and it is just generally hard to find information on them.  The  are a small, relatively new company and their lead product (the one farthest along is the drug development process) is NI-0401 which is and anti-CD3 drug, generally similar to the Teplizumab and Otelixizumab. 

Their recent corporate literature makes it clear that NI-0401 has started a phase-II clinical trial for type-1 diabetes.  Unfortunately, I have not been able to find clinical trial records for either the phase-I or phase-II trials, so I have no ideas how many patients are involved, if they are honeymoon or not, or any other of the most basic information about the study.  Even worse, I can not find any published results for the phase-I study in type-1 diabetics.  (I did find results for their phase-I trial on Crohn's disease, but not tyoe-1.)


Corp presentation: http://www.swissequitybiotechday.ch/media/biotechday/downloads/novimmune.pdf


AP News: Faster Insulin
Below is a link to a JDRF press release on their project to created faster acting insulin (mostly to help their Artificial Pancreas project):
http://www.eurekalert.org/pub_releases/2010-08/jdrf-jlr081610.php
I normally would not cover it, because it doesn't talk much about results or progress, however I did want to mention it because it is much broader and contains more context than your usual press release.

Most press releases just cover one piece of news for one line of research, but this press release gives a lot more useful context to the search for faster acting insulin.  Basically, it starts out with a goal.  The goal is to get faster acting insulin, mostly because it will make creating an artificial pancreas easier, and make the resulting pancreas better.  (Obviously,  it will also help everyone who uses insulin with meals, which is basically all type-1s.)  The simplest way to speed up insulin (and the way done in the past) is to create a new form of insuilin which is faster than the currently available forms.  And JDRF is funding Dr. Buckingham at Stanford to test one of those.  Another way is to find a faster pathway into the body.  So JDRF is funding Dr. Zisser testing of AFREZZA, which is inhaled insulin; the hope is that inhaled equals faster.  A third idea is to use microneedles to deliver insulin faster (JDRF is working with BD on this one).  A fourth is a port-system which puts insulin from a standard pump directly into a person's liver.  Since insulin mostly effects the liver, this could speed up the effectiveness of pumped insulin.  (JDRF is working with Roche on this.)  Finally, there is a post-pump insulin warmer which might also speed up insulin effectiveness.  (JDRF is funding Dr. Tamborlane of Yale to test this for InsuPatch.)

My Opinions.....
The whole point of research is that you don't know which projects are going to pan out and which are not.  This press release shows how JDRF is trying many different possible paths to faster insulin.  Some of those paths seem like good ideas to me.  Others seem very inventive, if a little strange.  Others don't strike me as unlikely to succeed.  I'm sure other people looking at the same list will expect different research to fail and succeed than I do.  That is why JDRF is funding all of them.  No one knows which will pan out.  I believe that this whole project is part of JDRF's "glucose control" research area, and that whole section includes about 6% of their funding.  So even though it sounds like a lot of different research projects in different areas (and it is!), all together it is only a few percentages of JDRF's total investment.   It doesn't even begin to touch the 33%+ aimed at immune therapies or the 40% aimed a regrowing beta cells.

JDRF Page on Spending: http://www.jdrf.org/index.cfm?fuseaction=home.viewPage&page_id=0B36CA86-9128-4C49-B7D8F55955507931




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. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

ATG + GCSF Starts a Phase-I Clinical Trial

ATG + GCSF Starts a Phase-I Clinical Trial
This is a very interesting study, which is why I'm giving it, it's own blog posting.  The official title of this study says it all, optimistically: "Reversing Type 1 Diabetes After it is Established".  It builds on three separate lines of research: Burt's ATG/GCSF/cyclophosphamide trial, a separate line of ATG-only trials, and NOD mice trials on ATG and GCSF (all discussed more below).

The basic idea behind this research is that ATG modulates the body's immune system, while GCSG  causes the body to generate more t-cells directly from it's own bone marrow.

ATG is a mixture of different antibodies that target T cells, including the anti-CD3 antibody.  The hope is that this multi-faceted approach will be even more successful and have a longer lasting effect than with anti-CD3 alone, and may treat diabetes by several mechanisms. First, it lowers the number of T cells, so there are fewer to attack the beta cells. It also seems to alter the T cells remaining behind, rendering them less likely to be destructive. Following this depletion, the T cells that grow back in the following weeks may be reset and have a healthier balance (meaning that a special type of T cells, called regulatory T cells, will help keep the destructive T cells in check).

GCSG  is essentially a growth factor that helps the body repopulate the cells after ATG depletes them.  So, if ATG fixes the immune system by getting rid of the destructive cells, and the GCSG can cause the body to generate more t-cells afterwords, and presumably a healthier balance of these cells, then the two together could stop the autoimmune defect that causes type-1 diabetes.  (Regrowing new beta cells might still be required for some people.)  And, this process has already been used successfully to cure type-1 diabetes in mice, so that is always a good first step.

But the really positive thing about this research is it's relationship to previous research by Burt.  You can read my previous blog entries about Burt's research at the URL below, but the quick summary is this: Burt has -- by far -- the best results in people of any researcher.  That study used a combination of 3 drugs, ATG, GCSF, and cyclophosphamide.  Some patients went into remission (no need for injected insulin) for a period of years, others for months, and all of these people used much less insulin after the trial.  Only two patients in the study did not go insulin free for at least a few months.  This research also has a serious weakness, which is safety.  Although none of the people in Burt's had serious side effects, the process involves "rebooting" the immune system.  So while this is happening, the patients are in an isolation ward, because their immune system is highly compromised.  Also, there were "hints of toxicity" seen in the trial: a few people had unusual infections, and some of the males had reduced sperm counts afterward.  Burt's research was in honeymoon diabetics, only.

A second line of research that has been going for years uses ATG alone to try to preserve beta cell function in honeymoon type-1 diabetics.  This research has already completed a phase-I study, and a phase-II study is underway right now.  The phase-II study is called START and they hope to finish recruiting patients in 4-6 months.  ATG alone is very good in curing mice, but in combination with GCSF the success rate is nearly 90% for the mice, and hopefully that will translate to people.

Oversimplified a little: Burt's research involves using three drugs (ATG, GCSF, and cyclophosphamide), and reinjecting the patient's own precursor bone marrow cells (previously removed). Dosing with just ATG and GCSF can be viewed as a "kinder, gentler" Burt. Especially since the cyclophosphamide is the one that really hammers the immune system and requires the isolation ward. 

In the past, I've been asked who was following up Burt's research, and this is a pretty direct follow up. Most phase-I trials are aimed at minimum effect and maximum safety, so minimal doses are used.  The follow on research usually involves more drugs.  However, in this case the effectiveness is high, while the safety is the issue.  So the follow on research involves less drugs.  In this case it involves removing the most toxic drug from the treatment.

They are enrolling 25 people who have had type-1 diabetes for more than 4 months, but less than 2 years.  Planned completion date is April 2013.  They are recruiting at the University of Florida, which is in Gainsville.  UCSF (San Francisco, California, USA) and also the Davis Center (Denver, Colorado, USA) will be participating in this study, but they are not listed in the clinical trial record.  The coordination is through University of Florida by Dr. Michael Haller (who is running several other clinical trials aimed at type-1 as well).  The email contact is listed as hallemj@peds.ufl.edu, so I would start there if you are interested.


Previous blogging on Burt's research:  http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
Previous blogging on ATG: http://cureresearch4type1diabetes.blogspot.com/search/label/ATG

Description of study: http://diabetes.ufl.edu/research/clinical-trials-and-studies/established-type-1-diabetes/atggcsf-clinical-trial/
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01106157
Abstract of animal study: http://www.ncbi.nlm.nih.gov/pubmed/19628781?dopt=Abstract
Wikipedia for GCSF: http://en.wikipedia.org/wiki/Neulasta
Wikipedia for ATG: http://en.wikipedia.org/wiki/Anti-thymocyte_globulin

I'd like to thank Dr. Steve Gitelman (who is a Principal Investigator in the ATG START study) for his thoughts on this research.  All mistakes here are my own.


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. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Haller Cord Blood trial, results from Phase-I and Starting Phase-II

Haller at University of Florida is running a research program to transfuse into honeymoon diabetics their own (previously frozen) umbilical cord blood. Umbilical cord contains stem cells and also a lot of a specific type of T-cell (part of the immune system) called T-regulators. These cells help to regulate the immune system, and since type-1 diabetes is caused by a lack of immune regulation, this seems like a reasonable thing to try. Especially since more and more people are "banking" their children's umbilical cords at birth. The Phase-I study was focused on two possible paths to a cure: adult stem cells would migrate to the pancreas and help grow new beta cells, and/or T-regulators would help suppress the bad immune response. It appears that the adult stem cells path did not pan out, and the phase-II trial only discusses the T-reg mechanism, and not the adult stem cell mechanism.

So the basic status is that Haller has completed a phase-I trial, and gotten good results, and has started a phase-II trial.

The Phase-I Trial
It is supposed to involve 23 patients and run from April 2005 to July 2010, however the data I've seen covered 8 patients and was published in June 2007, so it is an interim result.

That said, the results were good: a few months after the transfusion, the treated kids had an average A1C 1 point lower than untreated (7 compared to 8), they used about 2/3 as much insulin per kg of body weight as the untreated patients, and they generated more C-peptide in response to food (meaning they generated more of their own insulin).

For the phase-I trial:
http://cordblood.cryosite.com/UserFiles/File/Cord%20Blood%20and%20Diabetes.pdf Nice summary
http://www.ncbi.nlm.nih.gov/pubmed/18358588 Phase-I Results Abstract
http://cordblood.net/cbrblog/haller-abstract.pdf Phase-I Results Whole Paper
http://clinicaltrials.gov/ct2/show/NCT00305344 Phase-I US Clinical Trial Record

The Phase-II Trial
It involves 15 patients (10 get treatment, 5 are the control group), and is scheduled to start March 2009 and finish collecting data by March 2012.

More details are described here:
http://clinicaltrials.gov/ct2/show/NCT00873925 Phase-II US Clinical Trial Record

My thoughts on this line of research are here; these are all personal opinions:
First, I think it is pretty limited in direct application, since it requires banked cord cells and is a honeymoon treatment. But I'm always hopeful that they might learn something that could be applied more broadly.
Second, I'm very interested in how long the effect lasts. Is it permanent, or does it go away over time?
Third, I think their "phase-II" experiment is tiny. Only 15 patients makes it smaller than some phase-I experiments that I've followed, and that's not a good sign.
Forth, this research "feels" to me like basic research where they're trying to better understand how adult stem cells and T-regulator cells might help type-1 diabetics, by experimenting on people. Rather than research on a short, straight line path to a cure.

Thanks to Ellen over at www.childrenwithdiabetes.com for pointing the phase-II trial out to me.

Joshua Levy