Sunday, March 15, 2015

Tocilizumab (Actemra) Starts a Phase-II Trial

Tocilizumab (brand name: Actemra, often shortened to TCZ) blocks the action of IL-6 which is a part of the immune system. It has been approved in the USA since 2010 for use against Rheumatoid Arthritis, which, like type-1 diabetes, is an autoimmune disease.  The hope is that since it works on one autoimmune disease, it will work on another.  Usually the drug is given as an IV drip (which requires a clinic visit), but recently a subcutaneous injection was approved.  Subcutaneous injections are the same type of injection as used for insulin.

Tocilizumab Starts a Phase-II Trial

The trial is straightforward.  It is placebo controlled, double blind.  Of 108 patients in the trial, 2/3s will get the treatment and 1/3 will get the placebo.  The drug is given via IV once a month for a total of seven treatments.  The last data will be collected 2 years after the first treatment.  Researchers will gather data on C-peptide production, A1c numbers, and insulin usage.  This study is being funded by the National Institute of Allergy and Infectious Diseases (NIAID) and done in cooperation with Immune Tolerance Network (ITN), and the Diabetes TrialNet.  They are recruiting honeymoon diabetes (within 100 days of diagnosis), and expect to have ten different sites all over the US.  They hope to have results by August 2018.

The interesting part, at least to me, is how they are handling recruiting children.  They have the standard problem of recruiting honeymoon type-1 diabetics:  The FDA often requires a trial in adults before you can run a trial in children.  Of course, this is a particularly silly requirement for a drug (like Tocilizumab) which has already been approved for use in children.  In order to get around this restriction, the researchers organized their trial in the following way: The first 30 patients will all be adults.  After those adults have been treated for 12 weeks, the accumulated safety data will be reviewed, and (hopefully) the rest of the trial will be open to people of all ages.  But the downside is the delay caused by limiting recruitment to adults for about 30 out of 108 patients.  Finding adults within 100 days of diagnosis is a lot slower than finding children.

This clinical trial is currently recruiting in two locations:
Benaroya Research Institute -- Seattle, Washington, United States, 98101
    Contact: Marli McCulloch Olson    206-342-6943    marli@benaroyaresearch.org
Sanford Research -- Sioux Falls, South Dakota, USA
    Contact: Angela Vanveldhuizen    605-312-1395    angela.vanveldhuizen@sanfordhealth.org
Indiana University, Riley Hospital -- Indianapolis, IN, USA
    Contact: Bonnie Jagielo  317-278-8879  bjagielo@iu.edu

However, they are planning on adding many more sites, including these in California:
University of California San Francisco -- San Francisco, California, USA -- Rebecca Wesch 415-476-5984 weschr@peds.ucsf.edu
Stanford University  -- Stanford, California, USA -- Trudy Esrey 650-498-4450 tesrey@stanford.edu

Many more are listed in the clinical trial record.  The web site is below.

Study Web Page: http://www.extendstudy.org/
One Site's Page: https://www.benaroyaresearch.org/our-research/diabetes-clinical-research/find-study/extend-study
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02293837
Wikipedia: http://en.wikipedia.org/wiki/Tocilizumab
Effect on Type-2 Diabetes: http://ard.bmj.com/content/70/6/1164.extract
(Case study were type-2 diabetics had improved A1c numbers.  Researchers assumed this was due to Tocilizumab's anti-inflammatory properties.)

Tocilizumab's safety profile is pretty good.  This study:
http://arthritis-research.com/content/13/5/r141
looked at serious adverse events and "plain old" adverse events in 8 different clinical trials run for Tocilizumab's rheumatoid arthritis approval. Five of them were phase-III trials.  You can look at the details, but basically serious adverse effects where the same in placebo, low dose and high dose.  For "plain old" adverse effects, high dose was about 10% higher than placebo, and low dose in between the two.

If Tocilizumab does prove effective, there are several other drugs available which work by blocking IL-6, and presumably they would be worth testing as well: Sarilumab, Olokizumab, and Elsilimomab are examples.

Extra Bits and Pieces

I have not found a "cured in mice" type experiment for Tocilizumab, but it has been tested in human tissue samples.  There are some mouse studies from the 1990s showing that IL-6 does effect the development of autoimmune diabetes in NOD mice.

Clinical development for this drug took about 13 years until it became available in the US, and it was first created about 25 years before commercial availability.

In 2011, the FDA approved Tocilizumab for use in children as young as two years old.

If Tocilizumab does prove effective, there are several other drugs available which work by blocking IL-6, and presumably they would be worth testing as well: Sarilumab, Olokizumab, and Elsilimomab are examples.

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.

Sunday, March 8, 2015

Smart Insulin (MK-2640) Starts Clinical Trials

This is a blog posting that I've been waiting four years to write: the start of clinical trials for "Smart Insulin".

First, some general background on "Smart Insulin". The idea here is simple: create a chemical that holds insulin and only releases that insulin when the sugar level in the surrounding region is high. You would not have to measure blood sugar levels or match insulin to food. Instead you would just take this "self-dosing" insulin compound and it would release insulin as needed based on what you ate or did not eat.

"Smart Insulin" was the name of the first strong contender in the field, which was developed by Dr. Zion first at MIT and then at Smart Cells, which was later bought by Merck.  The term is also used generically, to refer to any "self dosing" or "Glucose Responsive Insulin"  (although I'm sure Merck's trademark lawyers would not approve).  No other self dosing insulin is in human trials, but SIA-II, Ins-PBA-F, and Sensulin, are being developed, and those are just the ones that I know about.  Smart Insulin had been tested in mice when it was sold to Merck (in 2010) and so a lot people, myself included, thought it would be in clinical trials quickly.  Obviously, the "quick" part did not happen, but the clinical trial part has started.

Smart Insulin (MK-2640) Starts A Clinical Trial

But the big news is that Smart Insulin has started clinical (human) trials.  In fact, the trial started months ago, in November 2014.   I missed it, mostly because Merck changed the drug's name from "Smart Insulin" to "L-490" to "MK-2640".   The clinical trial was under the name MK-2640, and I missed it.  Luckily Mike Hoskin at DiabetesMine publicized the name change.  You should read his blog for some general background, but notice that MK-2640 (the smart insulin I discuss here) is the second part of the posting:  http://www.healthline.com/diabetesmine/more-brains-smart-insulin

The trial itself has a fairly complex design.  It's two trials combined into one.  Part 1 is a group of 7 different "panels" (dosing regimens) given to healthy people.  Part 2 is a comparison of regular insulin to MK-2640 in people who have had type-1 diabetes for at least a year.  All of this involves 58 people and is expected to be done by July 2015.  Unfortunately, I cannot tell how many people are doing what, so I don't know if each of the 58 people are doing each dosing regimen, or if the 58 people are divided up between the different doses.  Most of the data they are collecting is "pharmacokinetic" meaning they are measuring how much of the drug is available in the body at any given time.  How quickly it "washes out" of the body and so on.  They will also be looking for adverse events and also patient drop outs caused by adverse events.  For a drug like "smart insulin" where variable dosing is critical to its success, focusing on pharmacokinetics makes a lot of sense to me.

The study is recruiting in Chula Vista, California, USA. Call their toll free number: 1-888-577-8839.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02269735
ClinicAnnouncement of Merck buying Smart Cells: http://www.merck.com/licensing/our-partnership/SmartCells-partnership.html

Discussion

My summary is simple: in a few short months, we are going to know a lot more about how "Smart Insulin" works in people, than we know now.

One very good thing about "Smart Insulin", especially when developed by a big pharma company like Merck, is that it can move through the approval process much faster than the other drugs I cover. One of the repeating themes of this blog is that it will take a cure at least 10 years to go through the FDA's approval process, and more years are likely.  That's not rocket science, it is simple math.  The FDA requires three phases, the first phase usually takes a year to recruit the patients and a year to gather the data.  The second and third phases also take a year to recruit the patients, and two years to gather the data, and then there is a year or two for marketing approval, and we are at (2+3+3+2) 10 years.  That assumes that every phase starts the moment the previous phase ends.  In real life there are often months or years of delay between each phase, so in real life these drugs take longer to get approved.

But that is for drugs aimed at curing type-1 diabetes.  For a new insulin, most studies only collect data for three months.  Also, recruiting people is much easier, both because they are adults and because they already are taking insulin, so you're just asking them to take a different insulin.  It's not as scary as something that changes your immune system.   Bottom line is that the phase-I trial is expected to be done in 8 months (recruiting and data collection).  I would expect phase-II and phase-III trials to also be sped up, as compared to cure trials.  The downside is that insulins usually have more than 4 clinical trials before approval, and usually a couple of them are longer than 3 months. But still, I would expect a quicker testing cycle for a new insulin than for a potential cure.

This is a treatment where some people are going to think of it as a cure, and others are going to think of it as a treatment.  That's not an argument I want to spend time on.  I will cover Smart Insulin (at least this first trial) because some people do consider it a cure.  If it is highly effective, then more people might consider it a cure.  Of course, if it doesn't work well or has limitations in how it can be used, then fewer people will consider it a cure.  But I'm happy to cover it for a clinical trial or two.

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.

Sunday, March 1, 2015

Verapamil Starts a Phase-II Trial

Soundtrack is "I'm Bad, I'm Nationwide" by ZZ Top:
http://grooveshark.com/#!/s/I+m+Bad+I+m+Nationwide/3OTEOT

Verapamil Starts a Phase-II Trial

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. TXNIP worked in mice trials (but see discussion below).

Drs. Anath Shalev and Fernando Ovalle at the University of Alabama at Birmingham have started a clinical trial. They are enrolling 52 adult, honeymoon type-1 diabetics; half will be treated, half are a (double blind) placebo control group. Patients will get Verapamil for a year, at the same doses that it is commonly prescribed.  The primary end point is C-peptide levels after a meal. The researchers will also track several other outcomes: insulin usage, A1Cs, TXNIP, beta cell markers, glucose generation, and two measures of BG stability.  They expect to finish in July 2017, which breaks down to about 1 1/2 years to recruit all the patients, and 1 year to run the trial.

This study is funded by JDRF, and is being conducted at The University of Alabama at Birmingham. Contact information is:
Tiffany H Grimes, RN    205-934-4112    tdgrimes@uab.edu
Kentress Davison    205-934-4112    kdavison@uab.edu  

News: http://www.medpagetoday.com/Blogs/DiabetesDiscovery/49622
News: http://www.uab.edu/medicine/diabetes/new-clinical-trial
News: http://www.uab.edu/news/innovation/item/5508
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02372253
Mouse study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314354/
Wikipedia: http://en.wikipedia.org/wiki/Verapamil

Discussion and Opinions

There is a lot to like about this trial.  Using an already approved drug means they don't need to do a phase-I trial; they can start out with a larger group.  It also means if they report good results, off label use becomes a possibility, and could result in much faster availability.

I particularly like the list of outcomes these researchers will measure.  C-peptide (their primary outcome) is the surrogate end point recommended by the FDA for type-1 cures.  But they are also watching insulin usage, A1C numbers, and BG stability, which are of practical importance to people with type-1.  Finally, they are tracking several biochemical changes which should help them understand what is happening "on the inside".

On the downside, they are only recruiting adults.  That's unfortunate, because it will take them much longer to find 52 honeymooning adults, than 52 honeymooning children.  (I know that sentence only makes sense in the world of type-1 diabetes.)  Since the drug is already approved, it's too bad they could not include the people who are most likely to be in the honeymoon phase.  But Verapamil is typically prescribed for high blood pressure or angina, so I suspect there is not much experience giving it to children.

My Opinions About Those Mice....

These researchers have succeeded in preventing type-1 diabetes in mice, by treating during the mouse honeymoon.  But I don't put much stock in mice tests, because there have been so many treatments that have led nowhere in people.  Hundreds of cures in mice and (so far) no cures in people. However, the mice used in these tests were STZ mice, which I'm particularly nervous about. Basically, the researchers took healthy mice and injected them with a toxin (streptozotocin) which killed their beta cells.  These are are referred to as STZ-mice.  They are commonly used as an animal model of type-1 diabetes, however they do not have autoimmune diabetes.  In comparison NOD-mice, also used as an animal model of type-1 diabetes, do have autoimmune diabetes.

In my opinion, STZ-mice are fine for testing new insulins and pumps, and also for doing tests related to long term complications.  However, I don't think they are good models for testing cures, because they lack the ongoing autoimmune beta cell destruction which is the hallmark of real type-1 diabetes.

The danger is that even if Verapamil does cause the body to grow more beta cells, they will be destroyed by the autoimmune attack, and patients will not see any improvement.  This treatment could be combined with something that stops the autoimmune attack, and the combination might be a cure, but testing Verapamil alone is unlikely to give good results.  The researchers understand this; the interview with Dr. Anath Shalev makes that clear.  Her hope is that by carefully measuring BGs (using a CGM) and C-peptides, she will see a small improvement, which will have good health effects (even if it is not a cure).   My blog posting "The Value of a Few Beta Cells" discusses this point:
http://cureresearch4type1diabetes.blogspot.com/2013/10/the-value-of-few-beta-cells.html
Also, a small improvement could provide the justification for a combination trial (Verapamil and an immune modulator/suppressor), and such a combination could be a cure in the future.

But in a certain sense, even discussing the mouse research is a waste of time, once the human trials have started.  Only the human trial results will matter moving forward.

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.