Update On Two AAT Clinical Trials

This is a update on two AAT (Alpha-1 Antitrypsin) clinical trials, with a little more general summary of AAT status at the end.  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.  My previous blogging on AAT is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Grifols' Phase-II AAT Clinical Trial is Unsuccessful

Grifols terminated their Phase-II AAT Clinical Trial in October 2017.  "Terminated" in the sense that they ended it earlier than expected.  Their official comment was "Wk 52 primary endpoint results would be unaffected by follow-up data so trial was discontinued prior to wk 104. No safety data was collected after wk 52."  I have unofficially been told by a participant, that they were told "it was found not to be beneficial enough".

I interpret Grifols termination statement to mean: The primary results (after 52 weeks) were bad enough, so that no matter what the results from 104 weeks, it is not worth it to them to complete the trial.

Discussion
In my opinion, it is morally wrong (and should be illegal), for a company to stop safety monitoring during a trial.  Even if the efficiency results are bad enough such that they don't care about that data any more, they still have a commitment to the patients in the trial to continue the promised safety monitoring.  The patients have already gotten the experimental treatment, so bad side effects or safety issues could still happen.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02093221

Kamada Announces Results From Their Phase-II AAT Clinical Trial

This trial had three groups: a "low dose" group, a "high dose" group, and an untreated (placebo) group.  The primary end point was change in C-peptide generation, and secondary end points included A1c, insulin dose, and safety data.  The results have not yet been published, so I'm working off of a Kamada Press release and email interactions with the team at Kamada.  The basic results are:

• No statistically significant results for the primary or secondary outcomes for the study as a whole (ie. "No significant treatment effect was observed in the overall study population").
• For one subgroup (patients aged 12 to 18), there were "close to" significant results for the primary and some secondary results.  The researchers call this a "positive trend".  The full quote is "Efficacy trend was demonstrated in the pre-determined sub-group of patients between the ages of 12 to 18, treated with the higher dose of 120mg/kg.  The positive trend was observed in this age group for all three key efficacy measures of Type-1 Diabetes".

I consider this trial unsuccessful, because the primary end point was not met.  I would not consider the subgroup data to be successful either, because none of it was statistically significant.  You can read a lot more about my definition of study success here:

https://cureresearch4type1diabetes.blogspot.com/p/recently-on-couple-of-occasions-ive.html

However, the researchers do consider it successful; successful enough to continue the work on a follow on trial aimed more specifically at the 12 to 18 year old group that had the best results here.

Discussion

Differences of Opinion on Success

So, why do I think this study is unsuccessful, while the researchers think that there is a success in there, and another clinical trial will find it?  To understand this, let's look at the three results that they consider most important:

• Better preservation of beta-cell function, as measured by less loss of C-peptide during the honeymoon (p =0.543).  
• Lower average HbA1c and more patients with A1c below 7%  (p=0.052, p=0.048, p=0.073).
• Lower insulin daily dose, for the higher dose treatment group versus placebo (p=0.086).

The standard cut off for statistical significance is p=0.05 or below.  So if you look at the numbers above, one is just in that range, three are close, and one is way out of range.  My view is out of range is out of range, and also the most important number (C-peptide) is not even close to an acceptable p-value.  C-peptide is most important for me, because it's the one that the FDA has previously said is the appropriate measure for curing type-1 diabetes.  A1c and insulin usage can be impacted by eating fewer carbs and having better control during the trial, but the C-peptide that they measured is inherent to how much insulin the body is producing itself.  The fact that they got the worst p-value there makes me profoundly nervous.

The researchers point out that they see good trends in three different measurements: insulin measurements, A1c, and C-peptide, and it is unlikely that you'd get three good trends in the same group of people, just by luck. P-value is designed (more or less) to show the chance that you got a good result by luck, rather than by the effectiveness of the treatment. P-values above 0.05 are considered too likely to be due to luck. However, in this case, the researchers point out, there are three different results, all of which are slightly above the cut-off. Even if one was due to luck, it is unlikely that all three would be due to luck. So the researchers look at all three together and view that as sufficiently unlikely to happen by luck, that it must be due to effectiveness. Most statisticians would look at each measurement separately, and say that each of them looked like it was due to luck, rather than effectiveness.

Since this was a phase-II trial, it was not large to begin with, and focusing on just the 12-18 year olds makes size even smaller, which is a handicap in a study like this.  Another way to view this conflict is as follows: was the clinical trial unsuccessful (poor p values) because the treatment was not effective, or was it unsuccessful (poor p values) because it was small?  Basically, if the trial were larger, would the p values have improved or would the effectiveness have diminished?

However, the path forward is the same in any case.  The researchers must do a follow on trial, which specifically recruits enough people between the ages of 12 and 18, to if the treatment is effective or not.  It is the success of that follow on study which will determine if the research continues or not.

Clinical Trial Record: https://www.clinicaltrials.gov/ct2/show/NCT02005848
Press Release: https://globenewswire.com/news-release/2017/11/01/1172203/0/en/Kamada-Announces-Top-line-Results-of-Phase-2-Trial-of-Alpha-1-Antitrypsin-in-Newly-Diagnosed-Type-1-Diabetes-Patients.html

The Scorecard

However, there is another issue with AAT.  This is not the first data we've seen on this treatment.  Part of the reason I'm nervous about the results from this study, is that I know the results from previous studies, and none of them are particularly good.

Study Number  Phase Size Sponsor   Duration  Completion Date Results
NCT01304537     I    24  Kamada    1 year    November 2012   No strong results
NCT01319331     I    15  Omni Bio  2 years   September 2013  No strong results
NCT01183468    II    16  NIAID     2 years   November 2014   Terminated
NCT01183455    II    66  NIAID     2 years   November 2014   Withdrawn
NCT01661192    II    12  Kamada    3 years   December 2016   Future publication
NCT02005848    II    71  Kamada    1 year    December 2017   This study
NCT02093221    II    76  Grifols   1 year    November 2017   Unsuccessful

Here is my previous blogging on the first two:
http://cureresearch4type1diabetes.blogspot.com/2015/09/aat-completes-phase-i-trial-no-strong.html
http://cureresearch4type1diabetes.blogspot.com/2012/06/possible-cures-for-type-1-in-news-june.html


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.

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:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

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?

Thanks

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:
http://cureresearch4type1diabetes.blogspot.com/2014/09/diapep277-development-canceled-due-to.html

References

Abstract: http://onlinelibrary.wiley.com/doi/10.1111/pedi.12283/abstract
Press Release: http://www.businesswire.com/news/home/20150706005216/en/Kamada-Announces-Publication-Pediatric-Diabetes#.VcY2xPlVhBc
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01304537
Poster: http://www.kamada.com/files/files/Prduct%20Development/Diabetes_print%20Jan13.pdf
Follow On Study Clinical Trial Record https://clinicaltrials.gov/ct2/show/NCT01661192

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 (January)

I feel like I'm about two month behind, but this will get me closer to current news.

Kamada Reports Early Results from A Phase-I Trial

News: http://www.globes.co.il/serveen/globes/docview.asp?did=1000799026&fid=1725
Press Release: http://www.kamada.com/press_item.php?ID=29
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01304537

I struggled quite a while with their press release, but in the end, this is my summary:

Kamada releases results from their phase-I trial, which they describe as "positive". However the data in the press release is too vague for me to come to any conclusion about weather their drug worked. I'm looking forward to a complete, peer reviewed paper.

Kamada manufactures Alpha-1 Antitrypsin (AAT).   You can read more about it here:

http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html

and my previous blogging here:

http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

AAT is an anti-inflammatory chemical which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person doesn't make enough of it on their own.

These are the first results from the first phase-I clinical trial completed.  Unfortunately, there was no control group for this trial, so there is no way to compare people who got AAT with people who did not. The company's press release said that "almost all patients reached glycemic control below 7.5%" and that "the majority of the patients maintained levels of C peptide higher than ... 0.2 pmol/mL".

None of that is bad news, but this trial was for honeymooners (within 6 months of diagnosis).  So none of those results sound particularly stellar to me.  This is where a control group would be particularly helpful, because we could have seen a difference between the two groups, if there was one.  Because people with type-1 diabetes naturally vary a lot during their honeymoon, it is at this time that control groups are most important.  

I've asked the company when the full results will be published, and those might be much more interesting.  At the very least we should be able to see how the C-peptide numbers change over the  study.  That can be compared to the "normal" drop during the honeymoon phase.  My general feeling is that if this data is all the data they publish, then the trial was a failure.  They need to publish more data, especially C-peptide changes to show success.

Discussion

This study is important for a couple of reasons.  First, because of the number of AAT clinical trials. I know of a five AAT clinical trials aimed at type-1 diabetes going on now.  That's a lot; more than any other single drug.  So having mediocre results from the first study completed is not welcome news for any of the others.  Second, because of it's impact on the inflammation theory of type-1 diabetes.  This theory holds that inflammation destroys the beta cells in the pancreas.  The autoimmune reaction triggers inflammation, but does not directly destroy the beta cells.  This theory has never been the majority viewpoint (most researchers think that inflammation is a side effect of the destruction of beta cells, rather than a cause) but it is an active minority opinion.  Since AAT is an anti-inflammation drug, it is one of the first drugs to test this theory.  Since AAT does not appear to have a strong effect, that suggests that the whole inflammation theory might be wrong as well.  That would be unfortunate, since stopping inflammation is a lot easier than stopping the auto-immune attack!  Because there are lots of anti-inflammatories out there, there would have been lots of potential drugs to prevent type-1, if this theory panned out.

It is interesting to me, that even though this study did not have a placebo group (an untreated group), they did have three different levels of treatment.  Some people got 40mg of AAT, some people 60mg, and some people 80mg.  The press release did not include any difference in results between these groups.  That's a little ominous for me.  For a drug that is effective, I would expect one dose to be the most effective; others less so.  On the other hand, if the drug has no effect, then all the groups would be the same, and in this case, no differences were reported.

LCT Updates

Background: LCT is developing an encapsulated pig beta cell cure for type-1 diabetes.
The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunsuppression drugs (as you would for a normal beta cell transplantation).

When last we left LCT, they were finishing a small phase-II trial in New Zealand, and starting a small phase-II trial in Argentina.  Links to press releases for the results and the follow on trial are below:
http://www.lctglobal.com/html/blob.php/121122%20LCT%20-%20Strong%20interim%20results%20in%20Argentinian%20%20DIABECELL%20trial.pdf?attach=0&documentCode=4774&elementId=20084
http://www.lctglobal.com/html/blob.php/121122%20LCT%20starts%20DIABECELL%20Phase%20IIb%20trial%20in%20Argentina.pdf?attach=0&documentCode=4775&elementId=20084

The Argentinian Trial

All the patients got two rounds of implanted islet cells, 12 weeks apart.  Half the patients got a base level, and the other half got twice this level.  The patients who got more islets had better results, which were:

• average insulin dose reduced by 20%
• a reduction of HbA1c from a pre-transplant average of 8.6% to an average of 6.7% at 12 weeks following the second implant
• up to 70% reduction in unaware hypoglycaemic events.

Obviously, this isn't a cure in it's current form (but see below for follow on products).  This study involved a total of 8 people, and so an obvious thing to do is to expand it, and the expansion was also announced.  LCT will implant an additional 20 people, all at the higher dose level.  For me the most interesting information in their press release is this:

“We are using an ‘adaptive trial design’ for our pivotal studies and so the data generated in this 20 patient trial will likely form the foundation data for our registration package,” said Dr Andrea Grant, Chief Executive, LCT. “We remain on track to meet our goal of completing clinical trials of DIABECELL by 2015 and having a product commercially available by 2016.”

I'm not an expert in this area, but I would be surprised if they could register a new medical implant for use in the US based on data from one study of 20 people (and their previous studies which contain about 24 people all together).  Especially with no clinical trials actually done in the US.  I assume that commercial availability will be in one or more of the countries where they have done research: New Zealand, Argentina, etc.

If you want even more information, you can read their CEO presentation, also done in November 2012, here:
http://www.lctglobal.com/html/blob.php/LCT%20AGM%20CEO%20Presentation%20Nov%202012.pdf?attach=0&documentCode=4762&elementId=20084

Which includes a slide "DIABECELL -- The path to patients" which lists four studies:
      A New Zealand phase II study [8 people]
      An Argentinian phase-II study [8 people]
      An Argentinian phase-II/III study [20 people, discussed above]
      A New Zealand and/or German Phase-III study [unknown size, not discussed above]
That forth study would make more sense to me, although I'm still not sure that this would get them approved in the US.  For comparison, the recent anti-CD3 drug approval attempts used two 300 person studies, one of which was done in the US.  And the pivotal DiaPep277 studies on-going right now are the same: two studies of 300 people each.  Maybe implants require less, but that much less?

No News from Russia

I'm also a little mystified because LCT had previously announced that their product had already been approved for sale in Russia:
http://cureresearch4type1diabetes.blogspot.com/2010/12/lct-gets-commercial-approval-in-russia.html
However, since then I can not find any reference to anyone selling it in Russia, or LCT getting any revenues from such sales. (But I don't speak Russian so can't search effectively in that language. If there are any Russian speakers out there, who would like to do some searches, please look for "LCT Biomedical Limited" (the company name) and/or "Natalia Dolgova" (the first company director) and tell me if they are selling anything in Russia.  If you find the web pages, I can Google Translate them.  But so far, I haven't even found them.)

LCT General Update

It is very rare for any executive at a medical company to make predictions about the future.  There are all kinds of rules about what they can and can not say.  So I was quite surprised (and happy!) to see these public posts from "elliott" in a posting on www.islet.org.  Dr. Bob Elliott is a founder of LCT.

Multi-centre Phase 3 studies will comemnce Q1 2013 and be completes by Q1 2015.
Registration based on a successful outcome will take anything up to a year, so we anticipate the LCT product will be marketed by Q1 2016 ie three years from now.
It will not cure diabetes, but is likely to be a valuable way of treating unstable diabetes.
'Fast follower' products will start to be tested clinically in 2014.

'Fast Follower' refers to the next generation of products. We are always seeking ways to improve the product but each improvement as seen in preclinicla studies in animals has to be tested in humans.   I have not give up on the idea of complete insulin independence, and we are making steady progress.

'Unstable' diabetes is the indication we are working on in the trials. But of course all Type 1 diabetics have unstable blood glucose control to a greater or lesser degree, so it really becomes a matter of how bad things are. 

He also said that they have improved the product since the peer-reviewed results were published in 2007, with the implication that they expect better results in the future then they reported in 2007.

Note that his statement that "Registration ... will take anything up to a year" might be true in some countries, but my belief is that in the US, marketing approval (our version of commercial registration) takes 1 to 2 years, especially if measured from the end of a phase-III trial.  I would not be surprised if other countries where LCT operates have faster registration processes.

Finally, I want to say that although LCT describes this 20 person Argentinian trial as "Pivotal" and "Phase-III", I will continue to refer to it as phase-II because of it's size. To be honest, I've seen phase-I trials with more than 20 people enrolled, so I think calling it a phase-II is proper.  Now if LCT gets approval in the US based on a 20 person trial, then I might change my standards. :-)

LCT's web page is http://www.lctglobal.com

Rituxan Safety in Rheumatoid Arthritis

Rituxan (also known as Rituximab or MabThera) is a monoclonal antibody which is being tested as a possible cure, or part of a cure, for type-1 diabetes.  My previous blogging is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab
Monoclonal antibodies are a relatively new technology for developing drugs (only about 20 years old), but already about half of new drug approvals are monoclonal antibodies.  However, some people have expressed worries that, as a class, monoclonal antibodies are unsafe, or their safety profile is unknown or suspect.

This study is a big step towards putting those fears to rest. Since Rituximab is already approved for rheumatoid arthritis, these researchers followed people who used it for that purpose for many years.  The basic result was that people on the drug had a lower disease rate than similar people not on the drug:

The rate of serious infectious events for the 1,145 patients on Rituximab for more than 5 years was 2.76 per 100-person-years, and the rate for the 818 placebo patients in the studies was 3.6 per 100-patient years, they said.

"No new safety signals were observed with increasing duration of exposure including in patients with more than 5 years of follow-up."

"the rates of myocardial infarction [type of heart attack] (0.40 per 100 patient-years) and malignancies were consistent with those observed in epidemiological data from other RA cohorts (0.48 to 0.59 per 100-patient years for MI)."

News: http://www.medpagetoday.com/MeetingCoverage/ACR/35895

Note that many monoclonal antibodies have names that end in mab.  So if you see a drug named Joshuamab or Curecommoncoldmab or anything ending with mab, it is likely to be a monoclonal antibody.

Rituxan as an Injectable Drug

Currently, Rituxan must be given intravenously, rather than being injected under the skin, like insulin.  The difference is important, because intravenous administration usually requires a "medical setting" (like a hospital or clinic, or at least trained medical staff).  While we all know that under skin injections are commonly done everywhere and by anyone, with a little training.

Recently Roche announced publication of two studies showing that they had a formulation of Rituxan which could be injected and was "not inferior" to the intravenous formulation already approved.  Since "not inferior" is the FDA's requirement for approval in situations like this, that's good news.  Even better news is that the basic technology that they used to convert a previously intravenous formulation into an injectable formulation can be applied to other drugs as well.  So with luck, they will be able to make lots of drugs easier to administer.

Press release: http://www.roche.com/med-cor-2012-12-08b.htm

Update from Scott King on Islet Sheet Project

An Islet Sheet is a specific beta cell encapsulation technique, similar to what LCT is trying to do.  Because Islet Sheets have not yet started human trials, I don't follow this research very closely.  However, I know others are very interested in it, and Scott King posted an update on his blog, which you can read here:
http://www.hanumanmedicalfoundation.org/blog/2012/11/26/signal-breakthrough-islet-sheets-thrive-in-pig/

They are hoping for more animal trials in 2013.  King is a very insightful guy and previous blog postings are interesting as well.

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 (April-2012)

Kamada Announces Something On Their Phase-I Trial of AAT

I know the headline is vague, but the news is vague.  This is what they said:

The trial found stabilization and even improvement in diabetes measures of the patients, and a high safety profile in the 20 children and adolescents tested.

Diabetes measures in most of the patients showed stabilization and even slight improvement.

Notice that no actual numbers are provided, and not even what they were measuring!  In my experience, this is a new high-mark in terms of vagueness.   However the safety information is nice.  AAT is already approved for another use, so it has some assumption of safety.  But, that other use is a rare one, so more safety information is important.  Here is a piece of solid news, which was also included, and which I'm happy to hear:

The company expects to publish the final report on the clinical trial in late 2012.

News article: http://www.globes.co.il/serveen/globes/docview.asp?did=1000741416 

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. In addition to this trial, there are 2 or 3 other clinical trials underway testing AAT on type-1 diabetes. And this is part of a more general anti-inflammation technique to try to cure type-1 diabetes. Most researchers believe that inflammation is a result of the body's immune attack on it's own cells. That is, the underlying immune problem causes inflammation and also causes beta cells to die (which causes the symptoms of type-1 diabetes). However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which then causes the symptoms of type-1. The difference is that, in the second model, if you stop the inflammation you can stop the symptoms of type-1 diabetes (the high BG numbers and the low C-peptide numbers). That is a big difference. But this second model is still a minority opinion.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Diamedica Plans to Start a Human Trial of DM-199 


Diamedica has talked about starting a human trial of their DM-199 drug in the past, but I've not blogged about it, because I didn't see any activity.  However, in their most recent press release (URL below) they do say that they have submitted the IND (Investigative New Drug) paperwork.  This is the first step to starting a clinical trial.  So even though I have not seen anything on the FDA's Clinical Trials web site, I'll provide some background here.

This quote is from their web site:

DM-199 Type 1 diabetes - is a novel recombinant protein which has been found to target the three main aspects of Type 1 diabetes by increasing regulatory T cells, reducing insulitis and improving glucose control in [tissue] studies, specifically:

• Halts autoimmune attack - significant dose dependent delay in onset of diabetes in NOD mice leading to a 12x increase in C-peptide (a primary clinical endpoint) to 5-6 nM. [Delays and reduces the onset of type-1 diabetes when given during and before the honeymoon phase.]
• Proliferates beta cells - 1,277% increase in insulin producing beta cells, restoration of blood insulin to near normal levels. [Treated mice generate a lot more insulin of their own, almost as much as non-diabetic mice.]
• Improves glucose control - 291% increase in peak glucose infusion rate ... and a 1.6% improvement in HbA1C (measure of blood glucose levels) in a ZDF rat model. [ZDR rats are an animal model of type-2 diabetes. Photo below.  Obviously, A 1.6 improvement in HbA1C would be a great treatment, even if not a cure, if we can do the same in type-1.]
• Human clinical trial - proof of concept - in a Phase 2a clinical trial with first generation DM-99, glucose levels were lowered by up to 48% after a meal [I have not been able to find a description for this study, or the results, anywhere. I'm not sure if this was done on type-1 or type-2 diabetics.]

Press release: http://www.diamedica.com/news/diamedica-provides-update-dm-199-dm-204-and-appoints-mr-ed-rady-senior-consultant-licensing-par

More info on ZDR rats: http://www.criver.com/en-us/prodserv/bytype/resmodover/resmod/pages/zdfrat.aspx

Background

DM-199 is recombinant protein, a new and improved version of DM-99. DiaMedica has previously done research in animals on DM-99, and they believe that all those good results will also apply to DM-199. It looks to me that all future research will be in DM-199, but they will continue to cite older research on DM-99, to support DM-199 safety and effectiveness.

Here is a newspaper report and a press release based on good results (in animals) with DM-99:
http://diamedica.com/news/diamedica-announces-positive-final-results-type-1-diabetes-study
http://www.marketwatch.com/story/diamedica-announces-positive-final-results-in-type-1-diabetes-study-2010-10-14-114750?reflink=MW_news_stmp

And here is some literature by the company itself:
http://www.diamedica.com/sites/default/files/DiaMedica-may-hold-Holy-Grail-for-diabetes-biotuesday-Feb-6-2011.pdf

This drug is currently in phase-II trials for type-2 diabetes, but has not yet been tested in people for type-1 diabetes. The animals studies are clearly aimed at type-1 diabetes, and they claim both beta cell regeneration and lowering the autoimmune attack.


Victoza (Liraglutide) Starts Another Phase-II (but as a treatment)


Liraglutide is a GLP-1 analog which is sold under the name Victoza and is approved for use in type-2 diabetics in the USA, the EU, and elsewhere. (The most common GLP-1 analog is Byetta.) In addition, there is active research to see if this drug will help type-1 diabetics. My current option is that this research is aimed at providing a better treatment, rather than a cure for type-1. However, this posting gives a summary on the research, since there is quite a bit going on.

Here are the studies ongoing:

NCT01206101 phase-II 50 people March 2012 - Jan 2015 Novo Nordisk

NCT01536665 phase-II 42 people Feb 2012 - Sept. 2012 Novo Nordisk
NCT00993720 phase-II 30 people Oct 2009 - Oct 2010 Hvidovre University Hospital
NCT01299012 phase-I 10 people Oct 2010 - June 2011 University at Buffalo

But what do we know right now?

Here is the results section from the study:

In all fourteen patients, mean fasting and mean weekly glucose concentrations decreased significantly after one week from [an average of] 130 to 110 and from [an average of] 137.5 to 115 respectively. Glycemic excursions also improved significantly at one week. The mean S.D. of glucose concentrations decreased from 56±10 to 26±6 mg/dl (p<0.01) and the CV decreased from 39.6±10 to 22.6±7 (p<0.01). There was a concomitant fall in the basal insulin from 24.5±6 units to 16.5± 6 units (p<0.01) and of bolus insulin from 22.5±4 units to 15.5± 4 units (p<0.01).

From my point of view, the results are underwhelming.  People who already have great control (BGs of 130?  that would be great!) dropped about 20 points.  I'm not sure taking a second drug (a once a week injection) to go down 20 points is worth it.   Now, if the impact is actually 15%, that's a little different, but it's still not a big result (in my opinion).  Now the use of insulin dropped about 30%, and that is a pretty big result.

Abstract:  http://www.eje-online.org/content/early/2011/06/06/EJE-11-0330.abstract

Wikipedia: http://en.wikipedia.org/wiki/Liraglutide
News: http://medicine.buffalo.edu/news_and_events/news.host.html/content/shared/smbs/news/2012/02/dandona-ada-liraglutide-120.detail.html

Public Citizen has officially petitioned the US FDA to remove Victoza from the market.  I would love to write up a full blog on why they think it's dangerous, and why the FDA thinks it's safe, and the trade offs and assumptions involved.  It is a great "teachable moment."  But I doubt I'll have time.  For now, Victoza is on the market.

Discussion of Phases

You might notice that of the four studies going on right now, three are phase-II and one is a phase-I, but that the phase-I study actually started after one of the phase-II studies. Furthermore, Victoza was approved for use in the USA in January 2010, so at least two of the studies could have been phase-IV ("post approval studies").  So why weren't they?  I'm not sure the official answer, but my unofficial answer is simple: researchers have great leeway to call a study phase-I, II, III, or IV as they wish.  Different researchers choose different phase numbers to try to manage expectations.

Discussion of Money

One of the interesting things about this research, was the cost.  The press release from the University of Buffalo says that the ADA is putting in about $600,000 and the study will enroll about 45 people.   For comparison, Dr. Faustman's BCG trial, cost about $10,000,000 and dosed 3 people (according to the published information).   So that means that Dr. Faustman's trial cost over 200 times as much (if compared on a dosed patient by dosed patient basis).  Remember that in both cases, the drug being used was already approved for use for another disease, and in both cases, it has already been used in type-1 clinical trials.

Can Propecia / Finasteride Cause Type-1 Diabetes?

I was recently asked if Propecia / Finasteride could cause or trigger type-1 diabetes.
Propecia is a trade name for Finasteride, and is commonly used for male-pattern baldness.  It changes the way the body processes testosterone (a "male" hormone).

I had not heard of any connection between them, and searched my "usual sources" and did not find any evidence that the drug could cause, or could trigger, type-1 diabetes.  It is sometimes given at the same time that adults are often diagnosed with type-2 diabetes, but that has nothing to do with type-1 diabetes, and there is no evidence of causality or association.  Diabetes is not listed as a possible adverse effect in drug's "package insert".  And I could not find any case reports of a link, nor any research studies showing a link in people.  I didn't check in animals.

I was able to find an FDA briefing document on Finasteride given for a kind of cancer.  This dose was five times larger than the dose for hair loss, and in a very large study (20,000 people total), the levels for "Diabetes Mellitus" for both treated and placebo groups were the same (but no separation between type-1 and type-2, unfortunately).  So again: no connection.

Wikipedia: http://en.wikipedia.org/wiki/Propecia
Side Effects: http://www.drugs.com/sfx/propecia-side-effects.html

Health Blogger Could Be Jailed for Giving Health Advice While Unlicensed
Read all about it here:
http://www.theatlantic.com/technology/archive/2012/04/health-blogger-could-be-jailed-for-giving-health-advice-while-unlicensed/256288/
http://www.carolinajournal.com/exclusives/display_exclusive.html?id=8992

Note that this guy describes himself as a type-1 diabetic and so the reporter for "The Atlantic" does as well, but others refer to him as a type-2.  He was diagnosed in middle age, he was on Actos prior to dx (which suggests that his doctor thought he was type-2) and there is no mention of antibody tests.  On the other hand he had a BG of 700+ when diagnosed. Anyway, the gist of his blog is that carbs are bad and that nutritionists are wrong for suggesting that people eat more of them.  That's a whole can of worms in itself, but the reason I'm posting this is much more because of the "blogger might be charged with a misdemeanor crime" aspect of it, then exactly what the blogger is saying.


Notes on this Blog

I have two pieces of news about this blog:

First, I've got a large non-blog event happening in my life right now, so I'm expecting fewer blog postings in the next six months or so, compared to the number in the past. In the past, I often did 2-3 per month, but I'm expecting 1 or 2 per month, and maybe only 1 every two months for the next 6 months or so.

Second, I'm planning on turning off anonymous commenting on my blog in the next few weeks. If you just read email or by posts on internet forums, then this will not effect you, but if you read my blog directly (URL is at the bottom of this posting), then you will no longer be able to comment anonymously there.

I'm not making this change because I've gotten bad anonymous comments. If you look at my comments you can see anonymous ones that are good and that are bad. The same is true of the named, non-anonymous ones. I'm making this change because I have come to believe that anonymous comments are bad for the internet and bad for society (as the two merge). People who would never be vandals out in the open, might, if they think they are anonymous. So although my blog doesn't see a lot of that, I'm turning it off anyway. It is a statement that I think anonymity on the net is not a good thing. If you are not willing to put your name behind it, you shouldn't do it. Fake names are bad enough, but total anonymity is worse.

Read more at: http://doctor.ndtv.com/faq/ndtv/fid/10081/Can_the_drug_Propecia_lead_to_diabetes.html?cp

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/