Sunday, January 20, 2013

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:
and my previous blogging here:
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/

6 comments:

Łukasz Moliński said...

I wrote to LCT over a year ago to give me some further information about russian approval. Especially when treatment is going to be on the market, what would be the fees, who should I contact to etc. No answer from them so far.

Stalina Dsouza said...

There is no cure. There is treatment, and there is hope. When my daughter was diagnosed at age 9 - I was devastated, and I felt completely alone. I didn't have any diabetes mom friends to vent to. Find a group, get involved. It will help YOU deal with it, which in turn will help your son. The JDRF is a great place to start. I'll give you the steps of our journey so far.

Step 1: Diagnosis: My daughter was in the hospital for 2 days in severe DKA (Diabetic Ketoacidosis)

Step 2: Adjusting shots: Her insulin doses changed 15-20 times in the first 6 months of diagnosis.Yes, it is normal for doses to be changed often with Type 1. Even now, they still change every 3-soI6 months now.

Step 3: Adjusting life: My daughter loved her sports (especially running) and was not ready to give any of them up. Children with Type 1 CAN play any sport they want to. Jay Cutler is an example of a Pro athlete with T1. Check the blood sugar several times before, during, and after exercise and keep those quick (emergency) carbs on hand. My daughter usually drinks some gatorade or powerade while exercising to keep her sugar up. Exercise makes blood sugar go down, sometimes quickly, sometimes slowly. You'll get to know your child's patterns.

Step 4: Learning the signs: Get to know the signs of your sons highs and lows. Teach his school about them as well. The sooner you get his blood sugar stable, the less risk he will have of complications.

Step 5: Learn that it is OK to not be OK: Learning to manage diabetes is HARD. It is OK to ask for help. It is OK to cry on a friends shoulder. It is OK to give a shot at the dinner table if it is where your son wants to have it. It is OK for him to check his blood sugar in the middle of class. It is OK to set up a 504 plan (if you are in the U.S.) at your childs school. The only thing that isn't OK is taking a day off of diabetes, you can't do that, no matter how much you all want a break, you have to press on.

Step 6: Knowing that you've got it, for now: Once you get comfortable, that is when you get complacent. I still research diabetes for my daughter. I could probably go into details as good as our endocrinologist by now, but this post is long enough. Never stop learning what you can. There is always great information available. I still learn new things here and there and it keeps me passionate about keeping my daughter at the best health that I can



For More Details Please Visit : Vertical Pharmacy

Yuval said...

Hi Joshua,

First I would like to say that I am following your posts and they provide very insightful knowledge to me.

Regarding Kamada, just today they published an investor presentation in the Israeli Stock Exchange with some slides regarding the T1DM trial, http://mayafiles.tase.co.il/rpdf/792001-793000/p792142-00.pdf

I assume they will publish some more in the near future since they informed that they are seeking an IPO in the Nasdaq so probably toward the road show, they will give some more data on upcoming trials.

Regards,
Yuval

Leo said...

Hi Joshua .. I want to give you some info in case you still don't know of

http://www.diamyd.com/docs/pressClip.aspx?section=investor&ClipID=738266

I hope you write about it

Łukasz Moliński said...
This comment has been removed by the author.
Łukasz Moliński said...

Testing whether vaccine would be effective if they add some ibuprofen and vitamin D sounds for such a layman like me a little bit hilarious. But maybe they have strong background which lays under this concept. From a different point of view, this is good that some companies started to combine drugs after years of developing non effective drugs towards cure for type 1 diabetes. This is similar to some cancer or lymphomas where no single drug works, but only as a regimen. ABVD in Hodgkins disease treatment for example. And as far I remember Diamyd already failed a trial as a cure for DMT1