Friday, October 2, 2015

Summary of EASD 2015

EASD is the European Association for the Study of Diabetes.  Their conference is the largest diabetes research gathering in Europe.  I did not attend, but reviewed all the abstracts, posters, and 100s of tweets sent with the EASD2015 hashtag.  This posting is my summary.

Unfortunately, as with ADA 2015 earlier this year, there was not much research aimed at a cure which had reached human trials.  I've divided this posting into four areas: news on human trials aimed at a cure, artificial pancreas research, high buzz research, and other research I found interesting.  But there was only one abstract dealing with a cure in human trials.  Disappointing.

Research In Human Trials Aimed At A Cure

Proinsulin peptide immunotherapy in type 1 diabetes: safety data of a first in new-onset type 1 diabetes phase 1b trial || Abstract #503
These researchers are testing a type-1 diabetes vaccine made from part of an insulin molecule.  They are testing it for safety in newly diagnosed type-1 diabetics.
The poster is not on line, but you can see the abstract.  It appears that the study was strictly safety-only, and there were no safety issues, but no data on effectiveness, either.

Artificial Pancreas Research

There was a lot of AP research.

This was a presentation by the Cambridge group:
33 adults used an AP for 12 weeks "free range".  Trial was open label, cross-over design.  (Meaning that all patients were both treatment group and control group at different times.)  AP did not handle meals.  AP did better than non-AP in terms of average BG, and no worse for lows.  AP also did better on A1c.  This research was published in the New England Journal of Medicine:
and is also discussed here:
and here:

This was a presentation by groups in France and Italy using the University of Virgina AP:
35 adults used an AP overnight for two months. Trial was cross-over design.  AP did better than non-AP in terms of time in target, with less time in both high and low BG.
One patient dropped out of this study because he was not able to trust the device enough to participate in the study.  This patient was a professor of mathematics.  (This got a laugh during the presentation.)
These researchers are now testing 24 hour use of the device.

This presentation was by Steven Russell on the Bionic AP (same project as Dr. Damiano works on):
This presentation included previous data from adults and camp kids, but also new (to me) data from younger children (6-11 years old).  This was also at camp, and was 5 days on, 5 days off (cross-over design).  The BG improvements seen in these younger kids was better than seen in adults or in camp kids.  In my opinion, the improvements seen in these kids were striking.

He then presented data from a "free range" trial of 40 adults for 11 days on, and 11 days off (cross-over) study.  This data was also very good.  The whole presentation was well done, and well worth viewing, but if you just want some quick data: fast forward to slide 25 (usual care) and then compare it to 26 (AP); this is for one selected patient, but you can see the huge improvement.

He then presented data from a comparison of glucagon vs. no glucagon study.

Finally he presented their target (hoped for) timeline:

  • Transitional Studies: 2013 - 2016
  • Production of a fully integrated device (prototype already made via private donations).
  • Bridging Studies: starting in 2016
  • Pivotal Studies: 2017 - 2018
  • Review by FDA: 2018
  • Commercial availability: late 2018 or early 2019

Dr. Russell said that the FDA had indicated that this device and long term glucagon use, could be approved based on a single pivotal trial of 450 patients for 6 months, with a 6 month extension for 100 of the patients.  (And this length and size is due to the needs of the glucagon approval.)

Also, Tidepool is collaborating with this research team in creating the user interface for their AP.

High Buzz Research

The research which generated the most buzz, by far, was the results of the EMPA-REG study.
However, this was a huge study of a SGLT2 drug in type-2 diabetes, so I won't comment.

There were also a lot of "Insulin vs. Insulin" and "New Insulin" papers and posters.  These are studies which show that one type of insulin is better than another, or that a new type of insulin is safe and effective.  I didn't count, but suspect there were over 20 of them, but this kind of research does not excite me.  There was some early work on a weekly shot basal insulin, and that is interesting to me. The research was on people, too.  But it is still years off, I think.

Glucagon nasal powder: an effective alternative to intramuscular glucagon in youth with type 1 diabetes (Abstract #42) generated some buzz:
You can watch the 15 minute presentation or read the abstract, at this web page.
Slide #5 shows clearly that glucagon nasal powder is similar to glucagon injection.
This tweet contains a one chart summary:
Patients in this study were between 4 and 17 years old; a previous study had focused on adults.
The nasal formulation was much easier to use, and (of course) no needle was needed.  Also the same nasal dose can be used for youth of all ages, so no more "half shots" for younger/smaller kids.
One patient sneezed immediately after getting the nasal glucagon, and this patient's BG levels did not rise, but the researcher wasn't worried because glucagon is usually given to unconscious people, who don't sneeze.  The company involved (Locemia Solutions) is "in discussions with regulatory agencies".

There was a phone app (I think called "gocarb") where you took a picture of a plate of food, and it estimated carbs.  Here are some of the tweets for that:
I'm a little dubious about this whole idea, but it did generate a lot of positive tweets.

Dexcom's G5 will soon be available in Europe:

The Google/Dexcom tiny BG sensor also generated some buzz:

Other Research I Found Interesting

The talk by Andrew Hattersly:
This is a one hour talk given by Dr. Hattersly, who basically discovered monogenic diabetes (often called MODY).  I really enjoyed it, even if I did not understand all of the science.  The talk is good because it shows how different scientific work comes together to make important discoveries, and how science is a team effort, and patients are involved.  Monogenic diabetes  is caused by a single genetic mutation.  There are several different types of monogenic diabetes , each involves the mutation of a different single gene.  This is quite different than classic type-1 diabetes, where there are many genetic features, some of which make type-1 more likely, some less likely, plus environment triggers, all of which come together to cause type-1 diabetes.  Monogenetic is binary: you have the gene, you get the disease.

The key points from this talk are two fold:

  1. Anyone diagnosed with type-1 diabetes when they are under six months of age, actually has neonatal diabetes (one form of monogenic diabetes ).  Neonatal diabetes can be treated with insulin, but can also be treated with a much cheaper pill (no shots!)  If you, or someone  you know, was diagnosed when less than six months old, and uses insulin, you (or they) may want to talk to your doctor about trying to switch to the pill.  More information:
  2. Dr. Hattersly estimates that between 1% and 3% of the people diagnosed with type-1 diabetes actually have some form of monogenitic diabetes. Except for neonatals, these people generally must be treated with insulin, just like type-1s, but it's still valuable knowledge.  He has an experimental web page to calculate a person's chance of having monogenic type-1 diabetes:

Autoimmune diseases in children and adults with type 1 diabetes from the type 1 diabetes exchange clinic registry || Abstract #499
This link has an abstract, the poster, and a 5 minute discussion by the author.
The Type 1 Diabetes Exchange is a huge project, funded by the Helmsly trust, to gather all kinds of data on over 25k people who have type-1 diabetes.    Some findings:
The #1 additional autoimmune disease found in type-1s is thyroid disease at 19%.
Celiac's is #2 at 6%.

Sustained glycemic control and less nocturnal hypoglycemia with new insulin glargine 300 U/ml versus glargine 100 U/ml over 1 year in Japanese people with type 1 diabetes mellitus (EDITION JP 1) || Abstract #4
ADA 2015 had at least one paper (which I found interesting) suggesting that higher density insulins were better for type-2 diabetics.  Some extremely obese type-1 diabetics need to refill their pump every day with standard u100 insulin, but only every other day with u300 insulin.  This is a money and convenience issue.  But additionally, there was evidence that higher density insulins were more effective; that fewer units were needed for the same carb or basal situations.  This study found that type-1s used more insulin, but had lower nocturnal numbers and at the same time, fewer lows.  That's still a good outcome.

I found the comparison to u100 to higher density insulins interesting, especially if we get sets that can last longer than 3 days, the pressure for high density will become stronger.

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

Wednesday, September 23, 2015

AAT Completes a Phase-I Trial (No Strong Results)

AAT is an anti-inflammatory / immunomodulatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that one of AAT's effects (lowering inflammation, immune modulation, or wound healing) can cure/prevent/treat the disease.

Kamada (makers of one form of AAT) recently published the results of a Phase-I trial in honeymoon type-1 diabetics.  There are several AAT clinical trials going on, and I've reported on different results before:

AAT Completes a Phase-I Trial (But No Strong Results)

This study was open label, with no control group.  A total of 24 people were divided into three groups and each group got a different dose [d1].  Primary end points were safety related, but effectiveness was measured in secondary end points.  The study lasted 37 weeks.  The patients got a total of 18 doses of AAT, spread out over the first 28 weeks of the trial.

The results were:
  • No serious adverse events occurred, and non-serious adverse events were not dose dependant.
  • Average hemoglobin A1c decreased from 8.4% to 7.1% [my rounding]. 
  • C-peptide levels dropped during the study, but the researchers felt that they dropped less than seen in untreated people from other studies.  At the end of the study, 18 subjects (75%) had a peak C-peptide ≥0.2 pmol/mL. 
  • At the end of the study 1/3 of the subjects met the definition of "possible responder" meaning their C-peptide numbers had gone down 7.5% or less.
Opinions of Results

First, no serious adverse events is a good safety result, and having non-serious adverse events be non-dose dependent is also a good safety result.  If there were safety issues, they would likely get stronger as the dose gets higher, since that did not happen, it is likely that these adverse events were not related to the treatment.   So it looks like it passed the safety part of the trial.

Because this study was done on youth between 10 and 18 years old, showing a good safety profile is particularly important.  It is likely to open up future trials to youth.  Recruiting youth speeds the clinical trial process (especially in the honeymoon phase) because type-1 is so often first diagnosed in children.  The safety profile might also lower barriers to "off label" use of this drug [d2]. 

Now an optimist would say "phase-I tests safety and safety is OK, so trial is a success". However, they did measure effectiveness also, and so I do think it is important to look at the effectiveness numbers that we have.  I have noticed that if the phase-I is not effective, it makes it less likely that the phase-II will be.  So with that in mind:

The most important thing to remember is that this study did not have a control group, and that makes interpreting the results difficult.  The A1c group, the C-peptide group, and the "responder" group all have the same fundamental difficulty: we know what happened to the treated people, but there is no untreated group to directly compare them to.  Therefore the researchers compare these people with untreated people from other studies; and I'm doing the same.   

I think that the drop in A1c levels was meaningless.  This was a honeymoon trial; people were recruited within 6 months of diagnosis.  That first A1c number covers either the early months of type-1 diabetes self treatment or the weeks just before diagnosis (or some of each).  These are both times of high A1c numbers.  Conversely, the second A1c number covers a time when the patient has between 6 and 12 months of experience with type-1, and is therefore better at treating their type-1. So of course the A1c numbers are better.

The researchers compare these A1c numbers to average A1c numbers in adults, and note that the first is above average while the second is below.  However, for the reasons described above, I don't think this is a case where comparing to average is an appropriate thing to do.  

For the C-peptide data, I think the data is hard to interpret, but disappointing.  The researchers summarized their findings this way:
subjects treated with AAT showed less of a decline in C-peptide levels as compared with historical controls.  However, in the absence of a randomized control group, these findings should not be interpreted as showing a beneficial effect on beta cell preservation
and glycemic control.
For me "less of a decline" is the very smallest sign of success a researcher can talk about.  I'd put these results below results from TOL-3021 and Alefacept  (both which held C-peptides constant), and maybe even Teplizumab (which held C-peptides constant in some people).

Each person has to decide for themselves which results excite them, and which don't.  For my part, in honeymoon trials, results where the C-peptide numbers go up (after a year) excite me.  Results where they stay constant are unexciting.  And, results where they go down are disappointing.  Here the average went down.

People in this study will be offered a chance to participate in a long term (3 year) follow up study. Those who still generate C-peptides [d3] will be kept on their current dose of AAT.  Those who don't (or who don't want to continue, will not get AAT, but will be followed as a comparison group.

Overall Status of AAT As A Cure For Type-1

AAT is unusual, in that there are two different types of information on it.  There are results of previous clinical trials.  But there are also anecdotal reports from the popular press.  The anecdotal reports are far more positive.   Unfortunately, these phase-I reports are clearly in line with the previous clinical trial results.  They are lackluster and will not lead to a cure without a large improvement in effectiveness.

The good news is that there are two phase-II clinical trials of AAT already underway, so there is nothing to do but wait.  Especially since one of those phase-II trials is being done by the same company as did this trial: they have incorporated what was learned from the older trial into the design of the newer trial.  If there are good results from the phase-II trials, then AAT is in good shape.   Mediocre results in phase-I mean nothing if the phase-II results are good.  If those results are as good as the anecdotal results, then AAT is in great shape.  But if those phase-II results are similar to these phase-I results, then that would be bad news for AAT.

Opinionated Discussion of Footnote 30

Because this study did not have a control group of it's own, the researchers used control group data from other studies.  In particular, some control group data from the phase-II trial of DiaPep 277, and this reference was provided in footnote 30.   In my opinion, using this data raises a red flag.  One of DiaPep's phase-III trials was canceled because of serious scientific misconduct [d4].  The article reporting the results of the other phase-III trial was retracted because the same misconduct was found in that study as well. To my knowledge, no misconduct has been found in the phase-II trial, but none was particularly looked for, either.  And there are authors in common between the retracted phase-III paper, and the cited phase-II paper [d5]. Finally, the manipulation that was done in the phase-III paper changed both the treated group and the control group [d6].  So if that same manipulation was done to the phase-II trial, (that is a big "if" of course) then it would effect the exact data that these AAT researchers are using.

For all these reasons, I think using data from the DiaPep 277 phase-II study is a mistake.  The AAT researchers were using control group data.  Lots of studies have control groups.  Why use potentially tainted data, when untainted data is available?


I want to specifically thank the author of this paper who sent me a copy of the full paper, so I could comment on all of the paper, and not just the abstract.

More Discussion

[d1] The researchers listed this trial as "Phase-I/II".  Generally I consider phase-I to be less than 20 people, and phase-II to be larger than that, but I also expect a Phase-II to have a control group, which this did not.  So based on the whole trial, I consider this a phase-I trial.

[d2] In the USA once a drug or device is approved, a doctor can prescribe it in situations different than it was originally approved for.  As an example, a doctor may prescribe it for a different disease, at a different dose, or for a different type of person than it has been approved for.  In the world of type-1 treatments, drugs or devices that have been approved for use on adults are often prescribed for children.  This is a classic "off label" use.  Off label use is based on the professional opinion of a doctor, and consent of the patient.  Therefore safety data (such as from this study) can make doctors more willing to prescribe "off label", and patients more interested in trying it.

[d3] Specifically, patients who have C-peptide levels of ≥ 0.2nmol/L will be able to continue their AAT regimen.  Note also that I refer to the other group as a "comparison" group and not a "control" group.  These two groups start off different, so I don't consider one to be a good control for the other.

[d4] Hyperion used the term "serious misconduct" in describing the situation, and Globe News used the term "fraud".

[d5] I want to stress that there were authors who only worked on the phase-II paper, and there were authors who only worked on the phase-III paper.  And, there were authors who worked on both papers.  To my knowledge, there has never been a public naming of who was involved in the misconduct, so there is no way to know if one of the authors was involved or if it was someone else in the organization, or even how many people were involved.

[d6] A more complete discussion of the misconduct alleged in this case is in my previous blog posting:


Press Release:
Clinical Trial Record:
Follow On Study Clinical Trial Record

Joshua Levy 
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.

Tuesday, September 1, 2015

Background Information: "Adverse Events" In Clinical Trials

This blog posting applies to all clinical trials, not just those for type-1 diabetes.

I try to avoid using technical jargon when I describe clinical trials.  I think one of the values of this blog is that I turn technical jargon in to plain English.  (I sometimes joke about providing "researcher to patient simultaneous translation", but it's not really a joke.  It's important.)  However, one technical term that I do use is "adverse event".  "Adverse event" generally means "bad side effect".  Serious adverse event generally means "really bad side effect".  But the truth is more complex than this simplified version, and so I thought I would make a post describing exactly what "adverse event" and "serious adverse event" means, because these terms are defined by the US FDA, and their meaning is the same no matter which clinical trial I'm discussing.

The Basics

The basic definition of "adverse event" and "serious adverse event" comes from the US FDA:
for lots more details:
  • An "adverse event" is any bad effect seen in the study.  The FDA uses the term "undesirable experience".  It does not have to be caused by the treatment!
  • A "serious adverse event" is an adverse event that causes death, hospitalization, persistent or significant disability, or a birth defect.  Or one which requires immediate medical attention to prevent one of these outcomes.
For example, a mild allergic reaction would usually be considered an "adverse event", but if the patient had trouble breathing, that would be a "serious adverse event".

The First Complexity: How Bad Is Serious?

No matter how many rules the FDA makes, and how many documents it publishes, there will always be room for researchers to interpret a specific events as serious or not.  Therefore, there will always be controversies about it.

For example, in one Chronic Fatigue Study there was controversy because several adverse events required patients to go to a clinic (but not a hospital).  Now hospitalization clearly means serious, but the company producing the drug felt that going to a clinic was not a sign of a serious adverse event. When the FDA reviewed the study, they disagreed, and the the larger number of serious adverse events the FDA counted were part of the reason the drug was not approved.

The Second Complexity: Treatment Related Or Not?

In general, researchers are required to track all adverse events, no matter what their cause. The FDA terminology is "associated with" not "caused by". After all, these are experimental treatments and some of the bad side effects might be unexpected. I've seen a trial for an immune system drug, which listed one serious adverse event: a broken arm. Now, I don't think that broken arm had anything to do with the immune treatment being tested.  But it is still a serious adverse event, and must be reported.
A more complex situation is adverse events associated with the disease being treated.  For example, if you are testing a drug for depression, and someone in the study commits suicide, that is clearly a serious adverse event, but is it treatment related?  How would anyone ever know?

This whole area is usually resolved by comparing adverse event rates between the control group and the treated group.  If there are statistically significantly more adverse events in the treated group as compared to the control group, that is the important result.  Arguing that some of these adverse events are not "treatment related" much less important. More adverse events is bad, no matter if the researchers think they are not related to treatment.  But what about those phase-I trials that don't have control groups?  For those trials, arguing about "treatment related" can be important.

The Third Complexity:  Who Decides?

Someone goes through every event and decides if it is serious or not.  The same is true for "treatment related" if that is reported separately. Obviously, this is a human activity and the results will be imperfect, but the exact procedure used can minimize (or maximize) risk of bias.  The two things to look for are blinding and reviewers.

The review can be done "blind" or not "blind".   The reviewer looks at the event, and maybe some data about the person who had the event, but does not know if the person is in the control group or the treated group (or what dose the person got, if multiple doses were tested).  But if the reviewer knows that the event occurred in the control group or the treated group, the risk of bias is more pronounced.  If the study doesn't have a control group, then this review will never be blind.

The reviewing is usually done by the same researchers running the trial. However, it can be done by a different group of doctors, recruited especially for that purpose.  Having a different group lowers the risk of bias, and this is done for some particularly controversial or emotional trials.

Some Discussion and Opinions

Overall, I think we are lucky in the world of type-1 diabetes research, in that the reporting of adverse events is generally not complex or controversial.  Type-1 diabetics are generally pretty healthy, and also the bad complications of type-1 diabetes are generally well understood.  Therefore, there is consensus as to the types of adverse events that are likely related to treatment, and those that are not.

Especially in larger clinical trials, serious adverse events will happen.  So the important thing to look at is: Were there more serious adverse events in the treated group than in the control group?  Also, if multiple different doses were given to different groups of people, do the higher dosed groups see more serious adverse events, or are they randomly spread throughout all the dosing groups?

Since all adverse events must be reported, it is important to consider the impact of different adverse events as compared to the disease being treated.  For example, rashes or mild fevers are common adverse events (not serious ones). Compared to curing type-1 diabetes, these might be well worth it.  On the other hand, in a drug which merely treats type-1, the very same adverse event might cause you to use a different drug.

Because the long term outcomes of type-1 diabetes is relatively well known, it's easy for patients to "trade off" the adverse events seen in testing a cure, to the long term complications of having type-1 diabetes.

One problem in the whole approval process is the issue of very rare side effects, especially those which happen rarely in healthy, untreated people. Take the following situation, you treat 300 basically healthy, basically young, people with a drug. One of them has a stroke. That's a serious side effect. But it is something that happens -- although very rarely -- in young people who are not taking the drug. With 300 people you may not have the statistical power to know if it is a statistically significant event. Are you going to delay availability and require a larger (and very expensive) study just to eliminate the statistical chance that the drug causes stroke? Or maybe approve the drug, but require a strong (ie. "black box") warning about stroke? Or just decide that it was random bad luck, and approve the drug?
(The situation is much worse with diseases like type-2 diabetes.  Was that stroke caused by type-2 diabetes, or the drug given to treat the type-2 diabetes?)

In a sense, the FDA cannot win in these cases, because no matter which outcome they choose, some people will want the other one.  So if the drug is delayed, some patients (and the company involved) will scream loudly about delaying needed treatments and creating unnecessary hurdles to drug approval.  On the other hand, if the drug is approved, another group of patients (and consumer advocates) will yell about approving dangerous drugs so big pharma can profit.  If the drug is given to 10,000 and one of them has a stroke (by chance? or because of the drug?) then recriminations will be deafening.

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

Wednesday, August 19, 2015

Research In The News (August)

This blog posting contains bits and pieces of news on type-1 diabetes research aimed at a cure.

The Phase-II Trial of Secukinumab Was Terminated

The phase-II clinical trial of Secukinumab was canceled in June 2014. I have not seen any public notification about why it was canceled. Apparently five people were dosed before it stopped, but I have no idea if any results will be published or not.  This trial was being run by Novartis.

You can read my previous blogging on this trial here:

Clinical Trial Record:

Phase-II Trial of BCG By Faustman Starts Recruiting

I made a big announcement when Dr. Faustman announced she was ready to start her phase-II trial. However it took over a year to actually start recruiting patients.  The blog I wrote previously is still accurate (except as described below), so If you want to know what is going on with BCG, I'd start out by reading my previous blog:
and then consider the following updates in the last year:

First the good news: it will include 150 patients, rather than 120 as before.

Second, the bad news: the delay means the study will complete in 2023 rather than 2022 as before (which means publication in 2024 is a reasonable goal).

Third, a change in primary outcome.  The study as I read it now, is going to have A1c measurement as it's primary end point, and C-peptide measurement as a secondary end point.  Previously, I had thought that both would be primary end points, but I might have just misread the clinical trial registration.

However, no matter which is primary and which is secondary, the important end point is the C-peptide numbers, not the A1c numbers.  For cure research, C-peptide is a much better measure of success than A1c.  C-peptide is what the FDA requires for cures, and that is what measures how much insulin your body is creating itself. A1c, on the other hand, is a good measure for type-1 treatments.  So in this case, in 2024, when we are looking at the results, it will be the C-peptide results that matter.

I don't see that there are any other major changes from a year ago: no change to dosing regimen and no change to duration.

Press Release: Trials Record:

Joshua Levy
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.

Sunday, July 19, 2015

Artificial Pancreas Updates From ADA (July 2015)

In my opinion, artificial pancreas (AP) technology was the single most important technology of the American Diabetes Association Scientific Sessions this year.  There were many papers, posters, and presentations on artificial pancreases and related technologies (such as continuous glucose monitoring, stable glucagon, etc.)  Nothing generated more Twitter buzz.

This blog posting attempts to summarize a little of the research presented.  There was way too much for me to cover it all, and so this posting gives light coverage to the most important news.

My overall summary is that we are no longer talking about if there will be an AP.  The question is: when there will be an AP, and how many APs, and how many different types of technology they will use.  I continue to be heartened by:
(a) the progress made by AP research projects over the last few months (and years)
(b) the large number of new companies entering the field
(c) the product roadmap announced by Medtronic as they move their existing partial AP to a full AP.

The AP world is more and more driven by commercial considerations, rather than research considerations, and that is a strong signal that we are close to general availability.  (Close meaning years, but not too many of them.)

This tweet summarizes my thoughts, as well:
“Closing the loop is no longer a mystery; it’s not a puzzle. We just have to do it.”

Second Bi-Hormonal Artificial Pancreas In Development

I recently found out about a second bihormonal AP  (in addition to Dr.  Ed Damiano's).  These researchers are in The Netherlands, and you can read more about it here:

It's a little hard for me to figure out exactly where they are, and I have not found any articles in scientific journals.  However, it appears that earlier this year they ran a two day test on one person, and got quite good results.  The average BG was 125.  Based on that they are hoping to run two clinical trials (called APPEL 4 and APPEL 5) later this year.  They hope those trials will used as the basis for European "CE" approval.

Maybe a Third?

They haven't started recruiting yet, but this looks like a phase-II trial for yet a third bi-hormonal artificial pancreas.  I'll blog more fully if they start recruiting:

Back To Ed Damiano's Bi-Hormonal Artificial Pancreas

Not from ADA, but from another conference, comes this summary of Ed Damino's current status:

But if you want a summary in 140 characters, here it is, from
Damiano says #BionicPancreas showing ave BGs of 135-142, which would equate to 6.5% A1C.
[What's not to like!]

Plus there was this good news tweet:
Ed Damiano says there is room temperature stable glucagon that stays good for up to a year. Needs FDA approval.

Medtronic's 670G

The Medtronic 670G, as announced, will be an "all but meals" style, single hormone artificial pancreas, available in the United States in April 2017.  As far as I know it is the most powerful AP with a clear commercial delivery date.  For comparison, the 640G is already available in Europe, but does not prevent "highs," only "lows".

diaTribe interviewed a patient who has used the 670G as part of a clinical trial:

This is Medtronic's press release summary of results from a 640G study, a 670G study, and some other research they presented at ADA:
The current plan is for the 640G to be available next year, and the 670G the year after.

This news resulted in the following tweets (and many more, of course):

More General AP News

The following, more cautionary tweets report on other aspects of AP research:

During artificial pancreas study, the AP couldn't be used 1 in 3 nights because of tech issues (sensors) or family/health issues.[But I don't know which AP this tweet is about!]

CDE Laurel Messer: Still enough tech issues exist with CGM sensors to impact hoe [sic, should be "how"] closed loop is used in kids and young adults.
Predictive pump technology significantly reduced nighttime lows in kids in almost 1000 night study. [But again: I don't know what AP this refers to!]

The following link goes to a summary of one of the ADA sessions:

Personal testimonial (with graph) of how well an AP works, but I don't know which one!  Anyone recognize the screen?

Bigfoot Explodes Big  (In a Good Way!)

Bigfoot is a one year old company.   They had a very successful ADA and generated a lot of "buzz", which this tweet tries to summarize.
@BigfootBiomed acquires Asante pumps! Goal to enter pivotal trial of full #artificialpancreas system late 2016

A "pivotal" trial is industry-speak for a phase-III clinical trial.  What they are saying is that they hope to start phase-III trials of an AP next year.  That would put them shoulder to shoulder with Medtronic and front running bihormonal research projects.  Even if they are overly optimistic, and they actually start those tests in 2017, they are still not that far away from a commercial AP.

But even more promising (to me) is that Bigfoot feels like a tech start up, not a medical device company. It feels like Silicon Valley rather than Washington D.C.  I can't tell if that's a marketing strategy or the truth, but if you look at the founders, look at the tactics (reuse the failed carcass of another project), and the strategy: it really does look like the way things happen "out here".

When a company like that can successfully create an AP, it means that APs are technology gizmos, and not medical devices, and technology products can improve much more quickly than medical products.  I'm sure the FDA will have something to say about it, but even if Bigfoot is just a 20% step in the direction of Silicon Valley, that's going to "light a fire underneath" some medical device companies.

The following link goes to one diaTribe story, but that story has links to other stories, and you can get the whole saga of how big they've grown, how quickly, and how important that might be:

TypeZero: Yet Another New Company Focused On A Single Hormone AP 

And if that were not enough, TypeZero Technologies is yet another new company trying to create a single hormone AP "from scratch".  DiabetesMine has a summary article:

This is based on AP research done at the University of Virginia which I have reported on before.


There was some debate at ADA about which was better: single hormone artificial pancreases, or bihormonal artificial pancreases.  My first reaction to this debate was this: who cares?  Either one is so much better than what we have now, let the people who like insulin only APs develop those, and let the people who like insulin and glucagon APs develop those, and let the market decide, or maybe let the market decide that there is room for more than one AP technology.  I mean some people have cable while others have satellite, why not the same with APs?  Have we learned nothing from the death of communism?  Let the market decide, as fed by the strongest proponents of each system.

My second reaction to this debate was that it can never be resolved by research. The data we have now is pretty clear: single hormone APs result in average BG numbers about 10 points higher than dual hormone APs  (for example mid 130s vs mid 140s).  However, dual hormone APs are more complex to manufacture, more complex to operate, and involve the tiny risk of long term, very low dose glucagon (and that risk is unknown, and will remain unknown for years).  So some people are going to say dual hormone is 10 points better than single hormone, end of story.  But others will say, mucking about with refilling two reservoirs is just not worth 10 points.  And neither of these opinions is right or wrong, they are just different.  And always will be.

However, even if research cannot answer a question, it can still inform the discussion, and there have been some papers directly comparing the two systems. The following tweet is one summary, but the links to the abstracts below contain more data.

Haidar: Both single and dual hormone artificial pancreases better than pump for BG control at night, dual better for reducing hypos

Joshua Levy
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.

Saturday, July 4, 2015

News from ADA 2015

The American Diabetes Association's annual conference is the largest scientific gathering covering diabetes in the United States.  Even though most of the conference is aimed at type-2 diabetes, the part covering type-1 diabetes is still overwhelming.  About 18,500 people attended this year.

I was not able to go this year (it was in Boston), so I tried an experiment.  I closely followed tweets and news coverage of the convention.  I thought of myself as a wire service and the tweeters/bloggers/reporters at the conference as my freelancers.  I was reading about 1000 tweets a day from the following sources: #2015ADA, #ADA2015, @diaTribeNews, @DiabetesMine, @sarhoward, @AmyDBMine, and @kellyclose.

I'm going to summarize these in two postings.  This posting has four sections: an overview, research in people aimed at a cure, research which has cured mice, and non-cure related research. The next posting will cover artificial pancreas research. There was a lot.

ADA includes a sea of expert opinions, but also the results of many experiments.  So it is especially important to remember these words by Robert H. Mathies  (Often incorrectly attributed to von Braun):

"One experiment is worth a thousand expert opinions"


You can read the abstract to every poster session at the link below, and most of them have a PDF of the poster itself:
Although the posters are easy to search, I cannot set up a link to one once I find it.  So I have put in the poster number (like 1234-P  or 42-LB).  Go to the link above and search for the number to find the abstract and the poster itself, when it's on line.

The following search page can get you to abstracts for many presentations, but I found it very hard to use:!/3699

The link below is a summary of the conference by Insulin Nation.  Some of it is reporter-insider snark, but other points are quite good.  The useful and the useless are mixed together:
P.S. The answer to 41 is "brown fat".

The link below is someone else's summary of the conference.  I completely disagree with the headline, but the section on type-1 research is a good summary.  You'll notice that only one of the possible cures they mention are in human trials now.  (Unless you consider AP or transplantation to be cures.)

Below is a link to Sarah Howard's summary.  She follows possible environmental causes for both types of diabetes, so she focuses on different parts of the conference than I would:

A big theme of the conference seemed to be treating patients rather than numbers, and generally emphasizing holistic care, and looking at more complex (and realistic) measures of health, than single numbers.  For me, this was typified by the following tweet which I saw repeated several times:  "A three-month average cannot tell the full story."  I think the tweet originated with @kellyclose (diaTribe), but I'm not sure.

Research On Potential Cures In Human Trials

I expect to blog on each of these trials in the coming months.

Fastuman Starts a Phase-II Trial Off BCG
Here's the press release:

Obviously, this is big news, and I'll blog about it in the next few months. But in the meantime, you can read my last blog on her BCG research:
The new news is that the trial is actually recruiting patients now.  Any updated details will be in my new blog.

ViaCyte's Phase-I Trial is 1/10th Enrolled
JDRF sent out this update on ViaCyte's Phase-I clinical trial:
There are as many as 4 people in SoCal currently testing @ViaCyte's experimental devices. That's progress.
The trial plans to enroll 40 people, so it sounds like they are 1/10th of the way there (depending on exactly what "as many as" really means).

1102-P: Immune Modulation of Stem Cell Educator Therapy in Caucasian Type 1 Diabetic Subjects
This poster contained information from the Phase-II trial of the Stem Cell Educator currently running in Spain.  I will blog more on this later, but for me, this poster had a "split personality".  On the one hand it was reporting on good changes to the immune system in people who got the treatment.  More good immune cells; less bad ones.  It looks like good news: the Educator is changing the immune system for the better.   On the other hand, there is none of the patient-focused data that would show progress to curing type-1 diabetes.  No data on C-peptide production; no improvements to A1c; no changes reported in insulin use.  (And the phase-I trial did have this kind of data.  So I'm not sure if this poster just focused on the immunology details, and a future paper will include C-peptide data, or if the C-peptide data in this second trial was not worth reporting.)

1099-P and 102-LB: Effect of Cell-Free Mesenchymal Stem Cells Microvesicles (MVs) and Exosomes Therapy on ß-Cell Mass in Type 1 Diabetes Mellitus (T1DM)
As far as I can tell, these two posters were identical, except that the LB poster only listed one author, and included the clinical trial registration number.
Patients were given stem cells (source not described), and compared to a control group.  Results were good:  HbA1c (6.67 ± 0.321 at 12 weeks vs. 8.245 ± 0.72 at baseline), fasting C-peptide levels (1.095 ± 0.215 at 12 weeks vs. 0.245 ± 0.069 at baseline) and C-peptide response following a 75-g oral glucose tolerance test (1.817 ± 0.27 at 12 weeks vs. 0.504 ± 0.065 at baseline).   To me, this looks like it is well worth a follow up.

Transplantation Work
So far with Edmonton protocol of islet Tx, 58% insulin free (need immunosupression), 92% have C-peptide after 7 years.  But those people will need to take immunosuppressives for the rest of their life.

Cured in Mice

Random quote from Richard Asher: "despair is best treated with hope not dope"

Poster 1812-P:
A new peptide (small protein like chemical), called KGYY15 is a honeymoon cure of type-1 diabetes in NOD mice.

Poster 1804-P:
Amylin Induces CD4+CD25+Foxp3+ Regulatory T Cells
Amalyin is a hormone given to type-2 diabetics, but there is some research to show that it would also help type-1 diabetics maintain better BG and A1C numbers.  This poster reports that it also increases the number of a specific type of helpful T cell.  This work is related to human trials, because at least two groups are "growing out" CD4+CD25+ T cells in the hopes that they will be a honeymoon cure to type-1 diabetes. Obviously, if Amylin has the same effect in people as these researchers found in mice, and if the researchers "growing out" these cells in people get a good result, that's good all around.

Using Th17 to prevent type-1 diabetes in mice:

Poster 1818-P: Local Expression of CCL21 in Pancreatic Islets Prevents Autoimmune Diabetes in Mice and Is Associated with Beta Cell Antigen-Expressing Lymphoid Stromal Cells
The poster was not on line, but the abstract was.  CCL21 (another small protein) prevented type-1 diabetes in NOD mice.

Poster 1826-P:
Prevention or Early Cure of Type 1 Diabetes by Intranasal Administration of Gliadin in NOD Mice
The poster was not on line, but the abstract was.

Poster 218-LB:
Nasal Administration of Novel Insulin Degrading Enzyme Inhibitor Ameliorates Autoimmunity in [NOD mice]
The poster was not on line, but the abstract was.

For those keeping track, that is six mouse cures presented at one scientific meeting.  For me, the interesting point will be: how many eventually get into human trials.  One?  None?  Only time will tell.

Non-Cure Research, But Interesting To Me

FDA Bullshit
This tweet really angered me:
Stayce Beck of @US_FDA calls out companies for not including kids in pediatric studies, says it's opposite of what agency wants.
This is completely two-faced, as far as I'm concerned.  Every researcher I interact with wants to have more kids involved in their studies.  Especially for honeymoon research, there are just so many more kids around.  But they can't because the FDA has specific regulations which prevent it!  It's the FDA who is creating and enforcing unreasonable limitations, and to turn around and "blame the victim" is scummy.  And the FDA's policies on kids in research does victimize researchers (as well as children) because it really slows down research and at the same time limits approved options for treating kids.

(I don't think I've ever sworn on this blog before, but this quote -- if true, and if really said by an FDA employee -- really deserves it.   I'm proud to say:  I call bullshit on that!)

Type-1 vs. LADA
There were several posters and papers which reported on differences between people diagnosed with type-1 as kids, and those diagnosed with it as adults.  Some researchers consider these to be the same disease with slightly different natural histories (sort of like chickenpox vs. shingles) while others consider these two to be two different diseases (with different causes or "etiologies"). All of the following posters described differences in early onset type-1 diabetes and late onset type-1 diabetes:
Poster 1801-P: Heterogeneity in Type 1 Diabetics Is Defined by Contrasting C-Peptide Declines, Autoreactive T Cell Burdens, and Metabolomic Differences
Poster 1819-P: IGRP-specific CD4+ T Cell Response Is Distinct between Adult-Onset and Juvenile-Onset Type 1 Diabetes Patients
Poster 212-LB: Anti-paralemmin 2 Antibody as a Novel Antibody for Latent Autoimmune Diabetes in Adults
Poster 1723-P: Determinants and Prognosis of Early- vs. Late-Onset Islet Autoimmunity

Poster 1737-P:
Ecological Study between the Incidence of Type 1 Diabetes and Geochemical Data in Sardinia: Negative Correlation with Zinc and Copper
Sardina has a high rate of type-1 diabetes, and the rate is not the same throughout the island, so these researchers tried to correlate various heavy metals in the environment to the higher type-1 rates in the same areas.  Higher levels of Zinc and Copper were found to protect people from type-1 (ie. higher levels of these metals correlated with lower levels of type-1), and no correlation was found for the rest of the metals they researched.  Here are the metals they checked: As, Be, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sb, Se, Sn, Th, Tl, U, V, Zn.

Unexpected Stability of Type 1 Diabetes Incidence in a U.S. Cohort, 1994-2010
Basically, they found a type-1 rate of about 1 in a 1000 (lower than expected) and found that this number was going up before 2002, but going down after that.  That's not the common wisdom.  Most researchers think the type-1 rate is steadily going up.

For the opposite viewpoint: 1735-P:
The Incidence of Type 1 Diabetes Mellitus in Romanian Children Aged 0-14 Years Increased Constantly
(No poster, but a very nice graph in the abstract.)  This is the opposite finding as the previous poster, but this is the conventional wisdom about what is happening.  The two posters covered different geographical areas.

Dance-501 Inhaled Human Insulin
Research results from another inhaled insulin.  Phase-I trial, 24 people, type-2 diabetics.  Affrezza might have competition someday, and that can only be good, in terms of more choices for type-1s.

Big claim by Dr. Dandona: “Predict w/ this 3x therapy (insulin, GLP-1, SGLT-2) we can get at least 50% of #T1D patients [below] 6% A1c"
If he is right (and that is a big "if"!) this will be a big change in the treatment of type-1 patients. Right now, insulin-only treatment is normal, and A1Cs are rarely this low.  GLP-1 is widely used in type-2, but not widely used in type-1.  In my opinion, the results of the GLP-1 in type-1 studies that we do have, show some improvement, but not a lot. SGLT-2 is even farther away from type-1 use, as there is even less research.  But again, in my opinion, the improvements that have been seen are real (in early testing) but not dramatic.  However, this doctor thinks that by combining these two treatments, we can lower A1c between 1 and 2 points;  that would be great, if it were true, and if type-1s were willing and it was safe to take both drugs for the rest of their lives.

In large Dexcom-funded analysis, CGM users had a 42% lower hospital admission rate and 17% lower ER ad. rate over non-CGM users.

“Preprandial Oral Insulin (ORMD-0801) Reduces Rapid-Acting Insulin Requirements and Fasting Glucose Levels in T1DM Patients”

Some things are more scary than others:
Studies of diabetes blogs don't show discussion of complications but more near term issues like nighttime hypoglycemia

If you got all the way down here, you deserve a laugh:
which came from this tweet:

Joshua Levy
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.

Tuesday, May 26, 2015

Mesenchymal Stromal Cell Results From a Phase-I Trial

Mesenchymal Stromal Cells (MSC) are the stem cells in your bone marrow.  Stems cells can grow into beta cells, and some researchers think they can modulate the immune system (they generate one or more chemicals that cause the immune system to stop attacking beta cells).  So it's possible that stem cells might resolve both cure issues at once.  They might be able to regenerate beta cells and stop the autoimmune attack.  That is what these researchers hope.

Results From a Phase-I Trial

These researchers, at Uppsala University Hospital in Sweden, ran a phase-I trial, randomized and with a control group, but not blinded.  There were 10 people in the treated group, and 10 in the control group.  MSCs were harvested from a patient, treated externally, and then put back in that same patient.  No immunosuppression was used, and I don't think the people were ever hospitalized (the work was done in a clinic).  Data was collected on insulin usage, A1c, fasting C-peptide, and post meal C-peptide, among other measures.

Fasting C-peptide measures how much insulin your body is generating as background. It's measured while fasting, usually first thing in the morning.  This is your natural basal insulin. Post meal C-peptide measures how much insulin your body is generating in response to carbohydrates.  It's measured after eating a meal with a known carbohydrate content. This is a body's natural insulin bolus.

My summary of the results are as follows. In all cases the paper is comparing data measured 10 weeks after the treatment (which the paper considers starting or baseline data) to data measured 1 year after treatment (which the paper considers resulting data):
  1. Fasting C-peptide, A1c, and insulin usage did not significantly change for either group, and there was no significant differences between the groups.
  2. Post meal C-peptide levels for the untreated group dropped about 12%.  Dropping is bad, but it's also normal during the honeymoon phase.  In the treated group, C-peptide numbers rose 5-10%, and that represents improvement.  The difference between the two groups was statistically significant.
  3. There were no safety issues.
Discussion and Opinions

Confirming that the procedure was safe is a good thing, of course, and is the official goal of a phase-I trial.  But this is a procedure that's been done for decades to treat other diseases (especially cancer), so no surprise that it is safe.

I was a little surprised at how consistent the insulin usage, A1c numbers, and fasting C-peptide numbers were.  I assumed that A1c would still be high from diagnosis and would drop, and that insulin usage would rise to the end of the honeymoon, and that fasting C-peptide would drop.  None of that happened during the course of the honeymoon.

The important results are the post meal C-peptides.  For this data, higher numbers are good, because they mean the body is generating more of it's own insulin.  In untreated people those numbers dropped about 15%, which is normal for the first year after diagnosis.  The treated people saw a rise in their C-peptide.  There is no doubt that is good news, but it did not have an impact on the treated people. Specifically, they were still injecting the same amount of insulin, and their A1Cs did not improve.  So it's a small effect.

My memory is that I've seen this level of result several times, for several different drugs, over the last two years or so.  I think I was much more excited about them in the past.  Part of my lack of excitement is that the treatments with these results that I saw a few years ago have not progressed. They don't give better results in more recent studies.  That might be because the research is taking longer than expected, or it might be that getting a small result is much easier than getting a useful (to patients) result.  But in any case: I haven't seen forward progress in other treatments with similar initial results, so I've become less excited about these kinds of results, in general.

So in general, these results go in my "good start, but more is needed" category of results.

This study was published on line Sept-2014 and on paper in Jan-2015:

Clinical trial record:

Joshua Levy
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.