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.

University of Alberta Starts the Mozobil Phase-I Clinical Trial

Note: I'm calling this the Mozobil study, because that is the trade name of one key drug being used, and I don't have a better name for the study.  However, as described below, this study is using five different drugs.  The official title of this study is: Autologous Hematopoietic Stem Cell Mobilization (Plerixafor) and Immunologic Reset in New Onset Type 1 Diabetes Mellitus.  See why I"m going to call it the Mozobil study? :-)

This study is an attempt at "immunological reset" to cure type-1 diabetes.  The basic idea is you give one or more drugs designed to knock down the existing immune system and then one or more drugs designed to build it back up.  Since the existing immune system has the autoimmunity flaw (it attacks beta cells), the hope is the rebuilt immune system will not.

The study will start out by giving people alemtuzumab and the trio of anakinra, etanercept, and liraglutide.  The next day they will get plerixafor, and the trio, and then they will continue to get the trio of drugs for a year.

• The alemtuzumab (sold as Campath/Lemtrada) targets one type of immune cell for destruction (CD52 cells).
• The anakinra (sold as Kineret) and etanercept (sold as Enbrel) modulate the immune system and may lower the autoimmune attack.
• The liraglutide (sold as Victoza) may help the body grow new beta cells.
• The plerixafor (sold as Mozobil) encourages the body to generate new immune cells of the CD34 type.

All of these drugs are already approved in the USA and the EU for treating other diseases.

People with long memories may think this sounds familiar, and it does.  It is similar to the "Burt Brazilian Research" from 10+ years ago.   You can read my blog about it here:
https://cureresearch4type1diabetes.blogspot.com/2008/12/burts-brazilian-research.html
and to read all my blogs about it, use this link:
https://cureresearch4type1diabetes.blogspot.com/search/label/Burt
You can think of this research as being a "kinder, gentler" immune system reset.   Etanercept (used in this study) has a black box warning, but nothing like the safety issues associated with cyclophosphamide (used in the earlier research).

A "black box warning" is a serious warning placed inside a black box in the FDA-mandated drug labeling.  The text will be printed on the drugs "package insert", on the FDA's web pages and on many other web pages and reference books that doctors commonly use to get information on he drugs.  (They are not printed on the label of the pill bottle, however.)  About 9% of prescription drugs have "black box warnings", and the etanercept used in this trial is one of those that has this warning.  More details are here: https://en.wikipedia.org/wiki/Boxed_warning

The Mozobil Study

This study will enroll 60 people, and is not blinded.  Half the patients will be treated immediately, while the other half will not (thus forming a control group for the first year).  After a year, the second group of patients will be treated.  Patients must be over 18 years old, and within 6 months of diagnosis.  They hope to finish the study by Dec 2022.

They are recruiting at the University of Alberta, Edmonton, Alberta, Canada
Web site contact: May 780-407-8755 qcai3@ualberta.ca
Web site contact: Cecilia 780-407-1480 chamming@ualberta.ca
Clinicaltrial.gov contact: Andrew Malcolm, PhD    (780) 407-6952    andrew.malcolm@ualberta.ca 
Clinicaltrial.gov contact: Parastoo Dinyari, BSc    (780) 407-3904    parastoo@islet.ca 

More information: http://www.islet.ca/research/mozobil
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03182426
Alternate: https://www.1trial.com/clinicaltrials/nct03182426/stem-cell-mobilization-plerixafor-and-immunologic-reset-in-type-1-diabetes-t1dm#full_text_view

The web page has a short video.  From about the 1/2 way point to the 3/4 way point the video discusses this research: http://drifcan.com/drifcan-research/

Wikipedia entries for the drugs involved:
https://en.wikipedia.org/wiki/Anakinra
https://en.wikipedia.org/wiki/Alemtuzumab
https://en.wikipedia.org/wiki/Etanercept
https://en.wikipedia.org/wiki/Liraglutide
https://en.wikipedia.org/wiki/Plerixafor
https://en.wikipedia.org/wiki/CD52
https://en.wikipedia.org/wiki/CD34

The primary investigator for this trial is James Shapiro, of Edmonton Protocol fame, who is also working with ViaCyte.

Discussion

Comparisons To Burt
There is no question that the earlier "Burt" research has been the most successful in terms of curing type-1 diabetes.  More than half the people treated in the Burt study did not need to inject insulin for 3 or more years after treatment.  That's big.  Unfortunately, the safety issues in the Burt study were big as well.  One doctor I emailed (doing related research) felt there was an approximately 1% chance of fatality in Burt-like trials, and the treatment required a hospital isolation ward for a period of time, since the patient's immune system was so compromised.

However, this Mozobil trial does not use the highly toxic drugs used by the early Burt research.  Indeed, since all of the drugs used here are already approved for use for other diseases, we know a lot about how safe they are.  Based on the Burt research, we know that an "immune reset" can cure type-1 for a period of years.  Therefore, I can hope that we have the right combination of safety and effectiveness.

Experimental Design
The "treat half immediately and then treat the other half after a year" is a interesting experimental design that I have not seen before.  It has a couple of advantages.  First, everyone who participates will get treated.  (I know that some people don't like going through all the work of a trial, and then being in the control group and not getting the treatment.  That will not happen in this trial.)  But even though everyone will be treated, there will still be a control group for the first year, which will make it easier to see if the treatment is working or not.  Finally, the second group will be treated, but after their honeymoon phase is over.  Even though this second group will not have a control group, we will see how well this treatment works past their honeymoon phase.  Non-honeymoon diabetes is a disease that does not show spontaneous improvement over time, so it should be pretty obvious if the treatment is working, even without a placebo group.

What is a CD number (such as CD34 or CD52?)
CD stands for "cluster of differentiation", which is a unique chemical (often a protein or peptide) on the surface of a cell which is part of the immune system.  Different types of cells can have different CDs on them, and one cell can have more than one.  These CDs control how the cell interacts with other cells and are also markers which identify the cell.  For example, the CD34 marker is found only on stem cells, while the CD52 marker is found only on mature cells, and CD4 marker is found only on a specific immune cell called a "helper T-cell".

Wikipedia has more details:
https://en.wikipedia.org/wiki/Cluster_of_differentiation

Note: the researchers describe this study as a Phase-1 / Phase-2 study, and it is bigger than most Phase-I studies.  However, since I've never seen anything like it before, I'm treating it as a Phase-I study.

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.