Friday, May 30, 2014

Research In The News (May)

This post is a collection of interesting items that have not yet made it into clinical trials, or which were unsuccessful in previous clinical trials, but are still being worked on.  These are not aimed at a cure.

Comparing Three Continuous Glucose Monitors

This is the summary of a study aimed at comparing CGMs:
The Navigator and G4 Platinum had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 12.3 ± 12.1% and 10.8 ± 9.9%, respectively. Both had lower MARDs of all paired points than Enlite (17.9 ± 15.8%). Very large errors (MARD > 50%) were less common with the G4 (0.5%) than with the Enlite (4.3%) while the number of very large errors with the Navigator (1.4%) was intermediate between the G4 and Enlite.
Full Study:

New Treatment Option for Type-1s?

LX4211 is an experimental drug designed to cause people to pee out more sugar than normal.  It is designed to cause people to need less insulin at meals, because they can get rid of more sugar by urinating it out.

Quote from the news:
Lexicon said the drug, codenamed LX4211, reduced the total dose of insulin taken by patients at meal times by 32 percent, compared with a 6 percent reduction in patients given a placebo.

When I first heard of this I thought it was a "cheap trick" and not particularly important.  But using 32% less insulin at mealtimes (which is probably about 16% less in total), is a pretty big effect, so it is at least interesting.  I would be even more interested if it improved A1c or BG numbers, since those are directly correlated with better health.  Also, the people in the study had "poorly controlled" type-1 diabetes, but the exact level of control was not stated in the clinical trial record. So it is important to see what happens with people whose control is normal or average.

This drug has been (or is being) tested in a total of 12 clinical trials; one of which is on type-1 diabetics specifically.  The type-1 test was on 36 people.  The study says that people in it must be "willing to refrain from using carbohydrate counting to adjust insulin during the study".  I'm not sure what is going on with that, but if they require people to change their insulin dosing regime as part of the study (and especially to not count carbs), that is certainly something where details matter.

There is a diagram describing how this drug works on the company's web page (but the rest of the page is mostly about type-2):

Enzyme Based Artificial Pancreas

This is another way of making an artificial pancreas that uses chemistry rather than electronics. Unfortunately, it looks to me like they are many years away from even starting human tests, and once those start, they are still many more years away from availability.  Still, it is a good idea, and the more different paths to a cure that are being worked on, the better.


Bi or Tri Hormonal Artificial Pancreas
The link below is to a company trying to develop a tubeless bi or even tri hormonal artificial pancreas.  Sounds interesting, but I can't tell when the website was last updated.  One of the items is a job listing, and it contains the following two quotes:
The CoreMD and "wedges" electronic hardware designs have already been completed. You will work closely with hardware and software engineering senior management in fine-tuning and prototyping (SLA) its pumping mechanism design, making re-design suggestions to save power/space, and capturing that design in SoliWorks. You will then test the SLA and re-design it if needed.  [Which sounds pretty good.]
We are looking for volunteers willing to work "pro bono" (free of charge) [Which does not sound good at all.]


Below is an update on Serova's Cell Pouch.  It looks like they had good results on the very early testing, and expect to spend the rest of 2014 getting more, similar data.  They are still testing with immunosuppressive drugs, and obviously, this gets a lot more interesting when they stop using those.

New Delivery Mechanism

The link below reports on another "cured in mice" experiment. This was done by combining GAD-65 IL-10, and an anti-CD3.  (I'm not holding my breath on that getting into human trials; not with the problems GAD65 and anti-CD3s have already had.)  However, I was interested in the dosing method.  They modified (possibly via genetic engineering) a safe bacteria, which is commonly found in the gut, to generate two of the drugs they gave.  This sounds like a very interesting and broadly useful technique, if they can control the dosing sufficiently.

INGAP Continues

INGAP is a beta cell growth hormone.  It was tested on type-1 diabetics and did not have positive results.  The news article below, which reports on a high school science project, reminds me of two things:

First, some researchers never give up.  Some of them are so committed to their discoveries, that they will continue to work on them even after there have been significant failures in clinical trials. This probably is a good thing; we want researchers who are "all in" and willing to push things as far as they can possibly go, even in the face of failure.  Those are the kind of researchers who will get the eventual cure into our hands.  However, it is important to remember just how committed they can be, when evaluating what they say.

Second, it is always shocking to me just how far technology has gone, in terms of letting younger people do more serious research.  Lab equipment has gotten easy enough to use, and cheap enough to use, so that high school students can do more serious research than they ever could before, and that has to be a good thing.

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

Saturday, May 17, 2014

Secukinumab and Ustekinumab each start Phase-II Trials

Secukinumab and Ustekinumab have a lot in common, including both starting phase-II trials in the last few months, so I'm covering them together.  Both of these drugs are monoclonal antibodies, meaning they are specifically targeted at one kind of immune cell.  (Approximately 1/3 of all new drugs in the US are monoclonal antibodies, so this is not unusual.)  In both cases the drugs have already done phase-I trials for other diseases, so the phase-II trials described here are the first times these drugs have been tested on type-1 diabetes.

Soundtrack for this blog posting:!/s/The+Chain/1Ty1wz


This drug has been submitted to the FDA for approval for treating moderate-to-severe plaque psoriasis (an autoimmune disease), but has not yet been approved.  It has also been tested for some other autoimmune diseases.   Secukinumab is thought to work by blocking inflammation, specifically blocking IL-17, an immune molecule.  Secukinumab was known as AIN457 during development.

The trial has started recruiting, and is expected to run until April 2019, enrolling 100 people.  Half will get the drug, half will be in a placebo group (randomized, double blind).  The primary end points are safety and C-peptide generation after a meal.  Secondary end points include A1c, insulin usage, etc.  This study is funded by Novartis Pharmaceuticals.  They are recruiting people at least 15+ locations all over the US.  Unfortunately, none of them are in the San Francisco bay area.

Ustekinumab (Stelara)

This drug was approved in the US in 2009 for treating psoriasis, which is an autoimmune disease (where the immune system self attacks skin cells rather than pancreas cells, as with type-1).  It has also been tested on multiple sclerosis, Crohn's disease, and sarcoidosis (also all autoimmune diseases).  Ustekinumab is thought to work by blocking inflammation, and specifically blocking two immune molecules called IL-12 and IL-23.

This trial will run from July 2014 to March 2016, and will enroll 20 people, in 4 groups of 5 people. There is no control group; each group will get a different dose of the drug.  The primary end points are all safety related, the secondary endpoints are all immunology related, but there are "exploratory" endpoints which are the results a person with type-1 would care about: C-peptide measurements, insulin usage, and A1c.  The study is being done at the University of British Columbia, by a professor in their dermatology department.  I assume he has experience with the drug's use on psoriasis. It is funded by JDRF.


These studies brought up two points for me:

First: They show the power of money and capitalism in getting research done.  The JDRF (a non profit) is funding the Ustekinumab study, and they can only afford to dose 20 people (no placebo group).  On the other hand, the Secukinumab study is funded by industry, and they are dosing 50 people and in addition have a full placebo group.  It is nice to have money.

Second; conspiracy theorists will need to ignore the Secukinumab study, because it doesn't fit with their "corporate America is making too much money to cure type-1" theory.  That study is being funded by Novartis Pharmaceuticals, which makes a huge amount of money off diabetics.  It is a classic "Big Pharma" company, yet here it is funding a drug that might be a cure for type-1.  Why?  Because they think they can make more money faster by curing type-1, than by treating it.  And they are afraid that if they don't, someone else will, and they'll be left with nothing.  The other company will get all the money from the cure, and they will be left with no one to treat.  Die hard conspiracy  theorists will say "they're funding the trial just to bury it", but if that were true, why fund it at all?  Running a human trial in the US right now, requires public disclosure.  If they really wanted to run some secret trial, they'd be doing it in Russia, China, or some country that didn't have public registry requirements.

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

Friday, May 9, 2014

Four Months of New Studies (Jan-April 2014)

The FDA requires registration of all clinical trials done in the US, or used to get approval for the US market.  Since just about everyone wants to get their drugs sold in the US, this is pretty much a list of all clinical trials.  It is a public database, and I searched it for all new trials starting in the first four months of 2014.  Here is a quick summary:

60 Studies Total
15 - Management of type-1 diabetes carb counting, exercise, etc.
 9 - Artificial Pancreas research and testing
 8 - Insulin testing
 8 - "Interesting" Possible cures for type-1 diabetes.  I will blog on each of these.
 6 - Basic or genetic research
 6 - Complications (this includes 2 tests on Glucagon)
 4 - Equipment (Pump or CGM)
 4 - Non-insulin treatments for type-1.  I might blog on these, if I have time.

This is actually pretty good news because about 13% of the studies are "possible cures".  In the past this number has been closer to 4%, so that's a noticeable improvement.  The interesting trials include these:
  • AAT - Follow on to previous studies (Pathway 5: Inflammation)
  • Beta-O2 - Follow on to a previous case study (Pathway 4: Encapsulated Beta Cells)
  • Secukinumab - First in type-1 study (Pathway 1: Blocking Autoimmunity)
  • Ustekinumab First in type-1 study (Pathway 1: Blocking Autoimmunity)
  • Stem Cells - Implantation of bone marrow stem cells
  • AbATE - Extended data collection for teplizumab trial (Pathway 1: Blocking Autoimmunity)
  • BCG - Dr. Faustman's trial (Pathway 1: Blocking Autoimmunity)
  • ORMID-801 - Oral Insulin (Pathway 1: Training Immunity)

The "Pathway #" come from a report that I worked on with JDCA, which you can read here:  It provides a basic overview of how type-1 diabetes might be cured.

The non-insulin treatments include Liraglutide (Victoza) and PF-06342674.

Also, in the past, there has sometimes been a trial so silly it was worth mentioning.  But this time I did not see anything really silly.

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

Friday, May 2, 2014

Update On AAT

I'm about four months behind on reporting on AAT (Alpha 1-antitrypsin)
AAT is an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that treating inflammation can cure/prevent/treat the disease.

Here is a link to my previous blogging:

Recent Clinical Trial Results

Results of a phase-I clinical trial of AAT were recently published.  This trial included 12 people and had no control group (so was not blinded nor was it randomised).  The 12 people were recently diagnosed, and when the study started, were generating some of their own insulin.  The abstract is included (in full) below.  My summary is that the study found several changes to immune cells, when comparing the situation before and after dosing with AAT.  However, no differences were reported in the abstract for A1c numbers or amount of injected insulin.   They did report that C-peptide generation went up or stayed the same for 4 patients; the implication is that it dropped for 8 patients.  To me, that seems pretty normal for honeymoon diabetics, so the effects for C-peptide seem to be very small (or nonexistent).  Because there was no comparison group, it's hard to tell if the treatment improved C-peptide generation or not.

My summary of these results are that they might be important to immunologists who are trying to learn more about curing type-1, but it's not the kind of result that's directly applicable to curing type-1 diabetes.  Particularly: there is no mention of anyone going insulin free for any length of time.  Remember that.  In terms of "clinical results" (ie. the kind of results that would matter to a person with type-1 diabetes: C-peptide, A1c, and insulin usage), the results are either tiny, tiny, or nonexistent.

This result is similar to previously released results from other studies, showing very modest results.  I've blogged about those before, at the link above.

Recent Publicity from Anecdotal Results

Additionally, there have been two "anecdotal reports" on AAT effectiveness, both sourced from Dr. Eli Lewis, who is one of the researchers involved.  One was several months ago, the other just a month or two ago.  I call these "anecdotal" because they are not reported in the scientific literature and have not been peer reviewed.  In general, the media reports far less data than a medical journal would report.  Obviously, none of them can be used to get FDA approval.

The Oct 2013 Report

The first anecdotal report was in the news in October 2013.  It reported on a family where the son was diagnosed with type-1 diabetes.   Six month later, the daughter was diagnosed with type-1 diabetes, but the family contacted Dr. Lewis and was able (with some difficulty) to get an off-label prescription for AAT.  The daughter was given AAT, and was cured of type-1 diabetes.   The daughter did not use insulin for years afterward.  Just recently, after about 3 years without using insulin, the daughter has started to use some, but at an extremely low level.

Obviously, that sounds wonderful; what every newly diagnosed type-1 diabetes patient wants to hear.  The father believes that the AAT helped delay the time when insulin had to be used.

The Feb 2014 Report

Later, in February 2014, Dr. Lewis was quoted in news articles as follows:
Following treatment of eight to 12 weeks with AAT, in several patients, it allowed proper glucose levels to be controlled without the need for any insulin injections for more than two years
We believe we will see similar results in a number of U.S.patients who recently received this treatment outside the trials within several months of diagnosis and are still completely insulin free.
Again: sounds like exactly what a honeymoon cure would be.

You may ask, if this drug is in phase-I trials, how can people in the US get it, outside of the clinical trial?  The answer is that those people are being treated "off label".  Because AAT is approved for one illness (alpha 1-antitrypsin deficiency) a doctor can prescribe it for any illness, even if it is not specifically approved for those other illnesses.  This is a quirk of the USA's drug regulations, but it is an important one.


I suspect that we might be seeing a conflict between two different ways of diagnosing type-1 diabetes.  The historical method, which I'll call "method A" is that a child starts peeing a lot, and/or drinking a lot, and/or losing weight (often while being hungry all the time), and generally feeling awful.  The doctor checks BG, which is very high, and the person starts using insulin.  Things get much better relatively quickly.  However, there is another way of being diagnosed, which I'll call "method B".  In method B, the child is showing relatively minor symptoms, or maybe none at all.  But they are given a blood sugar test after a meal, and their BG numbers are over 200, which means they have diabetes.  It used to be that type-1 was diagnosed using method A only.  But now, thanks to TrialNet, and heightened awareness, a few people are diagnosed with method B.    But people diagnosed with method B may not need to start using insulin right then.  We don't know a lot about the natural disease progression in people who are diagnosed via method B.  It may be normal (or at least common) for them to go months or years without insulin even without AAT treatment.

Because I've spoken with the father of the child in the first anecdotal report, I know that child was diagnosed using method B.  She did not use insulin before AAT treatment nor did she need it for years afterwards.  But the key question is: was that because she got the AAT, or was that the normal progression of someone diagnosed with method B?

I don't know if that also happened with the second anecdotal report.  One of the problems with scientific results reported via researcher's quotes in the popular media, is that we don't know the most basic information about what was going on.  In this  case: how were the people diagnosed with type-1 diabetes, and were any of them using insulin before AAT treatment?

The difference between these results (the clinical trials vs. the anecdotal results) is very troubling to me.  Going insulin free for years is huge news.  But it's not mentioned in the journal article.  Why not?  If those results were seen in the people in the clinical trials, they would certainly be in the paper.  But if they were not seen in the clinical trial patients, then why did the non-trial patients do so much better than the clinical trial patients?

For me, there's no question which source of information to weigh more heavily, right now.  It's got to be the clinical trial results.  Those are the results where we know more details.  Those are the results that were peer reviewed.  Those are the results that the research community will examine.  And, those are the results that the FDA will eventually use to approve new drugs, or (in the case of AAT) new uses for existing drugs.  Unfortunately, for AAT, the clinical trial results are much smaller than the anecdotal results.

I was able to talk with Dr. Lewis about this research, and heard him speak about it to a lay audience.  He believes that the "off label" patients had better results because their doctors could be much more flexible with the dosing.  When you're in a clinical trial, you get the dose that the trial says you get.  That's it.  However, in "off label" use, the doctor can tailor the dosing to each individual person, and how they react to the treatment.  Dr. Lewis believes that this customization of dosing resulted in the much better results he talked about.

Dr. Lewis also made two other points which bear repeating:  First is AAT's great safety profile.  It has been used on a wide variety of people, over a long time, and has a record of safety.  Second, although AAT is an anti-inflammatory, it may work differently than "classic" anti-inflammatories.  Classic inflammation works like this: some cells are damaged, and those cells and nearby cells chemically signal the immune system for help.  The immune system responds with inflammation.  This information attacks foreign and dead cells, but it also damages nearby cells (a sort of "collateral damage").    Dr. Lewis believes that AAT works by helping to save these "bystander" cells from this inflammatory damage, without lowering the entire response.  Classic anti-inflammatories lower the whole inflammation reaction.

What Next?

Kamada, the company that produces AAT is starting a phase-II/III clinical trial in Israel, which I will discuss in a future posting.  This is very good news, of course, because if those anecdotal reports mean what we hope they mean, then the data from the phase-II trial will show it.  The phase-II trial will have a placebo group, and will be much larger than the phase-I trial, so any effect as large as a cure (even a temporary one) will be obvious.

Also, there are several other AAT clinical trials already underway.  The recent publication was one of three similar studies.  So the publication of the other studies, which should happen shortly, will also be informative.


Below are links to abstracts and press releases on the clinical findings, and news articles on the anecdotal reports.  I did speak with the father of the first anecdotal report, and included some information from him.  He did review this posting to ensure that the information from him was accurate, and that he was comfortable with the amount of information I was making public.  I also emailed with Dr. Lewis, and heard him speak.   As always, all mistakes are my own.

Clinical Trial Results:

Below is the complete "Results" section of the abstract:
Results: No adverse effects were detected. AAT led to increased or unchanged levels of C-peptide responses compared to baseline in four patients. The total content of TLR4-induced cellular IL-1β in monocytes at 12 months following AAT therapy was 3-fold reduced compared to baseline (p < 0.05). Furthermore, at baseline, 82% of monocytes produced IL-1β, but at 12 months post-therapy the level decreased to 42%. Similar reductions were observed using TLR7/8 and TLR3 agonists in monocytes and mDCs. Unexpectedly, the reduction in cellular IL-1β was observed only 9 and 12 months post-treatment but not in untreated diabetics. Improved beta cell function in the four AAT-treated individuals correlated with lower frequencies of monocytes and myeloid DCs producing IL-1β compared to subjects without improvement of islet function (p < 0.04 and p < 0.02, respectively). Conclusions: We hypothesize that AAT may have a beneficial effect on T1D in recently diagnosed patients that is associated with downmodulation of IL-1β.
Researcher's Web Page:

Oct 2013 Reports:

Feb 2014 Reports:

Phase-II/III Trial:

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