Monday, April 27, 2009

Etanercept (ENBREL) Completes a phase-I Trial in New Onset Type 1 Diabetes

This is a "new to me" phase-I study of
Etanercept (ENBREL) , which just published it's results last week: and you can read the abstract of the results here:

This is "give a drug quickly after diagnosis of type-1 diabetes to preserve some beta cell function" type treatment. The drug,
Etanercept (ENBREL), is a product of Amgen, who sponsored the research, and is US FDA approved for several self-immunity related conditions including Rheumatoid Arthritis and Psoriasis. You can read more about it here:
Note that although the name is similar, this not Efalizumab which I reported on recently.

The results were solidly good, after 24 weeks:
  • HbA1c was lower in the etanercept (5.91 +/- 0.5%) compared to placebo group (6.98 +/- 1.2%)
  • The percent change in c-peptide AUC showed a 39% increase in the etanercept group and a 20% decrease in the placebo group
  • Insulin dose decreased 18% in the etanercept group compared to 23% increase in the placebo group
So the result in plain English is that the treated patients had, on average, A1C measures 1 lower than the non-treated group. They were generating about 60% more of their own insulin (as measured by c-peptide), and used about 40% less insulin. Overall, very nice results for a phase-I trial.

And before you ask: I don't know if they are planning a phase-II study, and I don't know if this will work on non-honeymooners. I did find two interesting papers that reported that people who had type-2 diabetes and who were treated with Etanercept for rheumatoid arthritis had large drops in their BG numbers. How that maps to people with established type-1 diabetes, I'm not sure. Lastly, although this drug is approved by the US FDA different people may well have different opinions about it's safety. It does carry a black-box warning due to higher rates of infection. (Black-box warnings are the strongest warnings that the US FDA requires on prescription medicines to warn people of potential dangers.)

TNF: Friend or Foe?

This research brings up an interesting conflict in research to cure type-1 diabetes: is TNF a friend or a foe? TNF (tumor necrosis factor) also called TNF-alpha is a protein that kills tumors. It also kills other cells in the body. Several treatments currently in clinical trials for various self-immune diseases are based on interfering with the TNF receptor, and Etanercept is one of these. On the other hand, Faustman holds the opposite theory. Her treatment is based on increasing levels of TNF. The drugs she used on NOD mice (CFA), and in people (BCG) are both expected to raise the level of TNF. Now these two beliefs are not exactly opposite, because Etanercept blocks a TNF receptor, while BCG (and CFA) stimulate the production of TNF itself. However, it is unclear how both Etanercept and BCG can both have a good impact on type-1 diabetes since they effect TNF in opposite ways. If one helps cure type-1 diabetes, the other should make it worse, and visa-versa (at least at first impression). So it is possible to interpret the success of Etanercept as bad news for Faustman. Of course it is also possible that the two work in completely different ways, and TNF is a "red herring" in terms of curing type-1 diabetes.

Here is a link to some discussion of Faustman and TNF:

Joshua Levy

Monday, April 20, 2009

The short life of Efalizumab (BRiTE) Phase-II Clinical Trial

In early April, I found out about a new phase-II clinical trial, called BRiTE, that tested Efalizumab as a possible honeymoon cure for type-1 diabetes. Efalizumab (tradename "RAPTIVA") is a product of Genentech and is already approved for use on psoriasis and rheumatoid arthritis, which are autoimmune diseases in some ways similar to type-1 diabetes. I was in the process of writing up the summary when the news turned bad.

Later in April, Genentech and the US FDA announced that Genentech was voluntarily withdrawing Efalizumab from the market. I assume that this will mark the end of the type-1 clinical trial as well. Genentech has received 3 reports of progressive multifocal leukoencephalopathy (PML) in people treated with RAPTIVA. This disease is caused by a virus and is almost always fatal (survivors are often brain damaged), and is very rare.

This is a cautionary story for our testing process for new treatments. As the US FDA has said:
Raptiva was approved for the treatment of moderate to severe plaque psoriasis in 2003. There were no cases of PML seen in the clinical trials that supported the approval of Raptiva. At the time of approval, a total of 2,764 patients had been treated with Raptiva. Of those 2,764 patients, 2400 had been treated for three months, 904 for six months, and 218 for one year or more.

Since the approval of Raptiva (efalizumab) in October 2003, the FDA has received reports of three confirmed cases and one possible case of progressive multifocal leukoencephalopathy (PML) in patients who were 47 to 73 years of age who were using Raptiva for the treatment of moderate to severe plaque psoriasis. Two of the patients with confirmed PML and one patient with possible PML died. All four patients were treated with Raptiva continuously for more than three years. None of the patients were receiving other treatments that suppress the immune system while taking Raptiva.
Notice that there is no discussion of clinical testing lasting longer than 2 years, and that the people who got PML had all been taking the drug for over 3 years. The testing that RAPTIVA got is pretty much the same testing that the various type-1 cures currently under development are getting.

And you may want to think back to the bravebuddies discussion of a few months ago ("Ask the FDA to better serve diabetes patients" and "COMMENT ON FDA PETITION", when people were complaining about extra testing that the FDA wanted to require to make sure drugs approved for diabetes did not cause heart problems. Those drugs were getting approved with less than 1 year of testing, and people were howling that the FDA wanted two years or maybe more!)

This is also something to remember if an immunity drug based cure becomes available. If one does we will all be asking ourselves the same question: should my child be first in line to get this cure? It's now been FDA approved, should I get it for my kid right now, or wait. And if I wait, how long? These are not going to be easy questions to answer.

My understanding is that Efalizumab lowers the autoimmunity by targeting a specific type of T-cells, called CD11a. Several other treatments for type-1 diabetes which are currently in clinical trials work by targeting specific types of T-cells, although I don't know of any other drug that targets CD11a cells specifically. ToleRx and MacroGenics both target CD3 cells, while Pescovitz's research targets CD20 cells, and Faustman is targeting certain CD8 cells.

Here is the Clinical Trial record for the type-1 test:
And a press release of the withdrawal:

Joshua Levy

Sunday, April 19, 2009

Atorvastatin (Lipitor) in New Onset Type 1 Diabetes Mellitus

This is a "new to me" study, that actually started in July 2007 and is expected to end July 2010. It is phase-II and included 54 people, who are within 6 weeks of dx for type-1 (so honeymooners only). 2/3 of the people will get Atorvastatin (Lipitor) and will be compared against the 1/3 who don't get the drug.

The US clinical trial record is here:

Now, for those of you who did a double take, when you saw that Lipitor was involved: Yes, this is the same statin drug which is used to lower cholesterol, and is the best selling drug in pharmaceutical history. There was no phase-I study for this treatment, because they knew the drug was safe, they went straight to phase-II.

Apparently, Atorvastatin (Lipitor) results in lower insulin requirements when give to "rodent models". I assume they are talking about NOD mice. I'm not sure why this drug might work, but it does lower inflamation, so maybe that's it.

I know of one study which gave Atorvastatin (Lipitor) to people with established type-1 diabetes in the hopes it would limit artery damage. It was not successful. However, I don't see that those guys reported A1C, BG, or insulin usage numbers turning the trial:
Of course, the studies are focused on different time frames, honeymoon vs. non-honeymoon so they may well come to different results.

Joshua Levy

Friday, April 17, 2009

Recent LCT Press Releases

LCT has recently had three news items on their progress. They have completed a phase-I clinical trial. Their basic technology is to take pig beta cells and encapsulate them in a wrapper which protects them from the body's own immune attack, but that the same time lets the cells generate insulin in response to BG levels. Background information on LCT is here:

Below is my discussion of the three recent news items:

Living Cell Technologies Gains Additional Benefit From DIABECELL

LCT recently finished a phase-I clinical trial of seven people. A few patients had short periods when they did not need to inject any insulin, others required less insulin, and some people were not helped at all. The very best result was that one person was insulin independent for two months. So they took that person, and gave her another implant. This time her insulin requirement dropped 50%. They waited a few more months and gave her a third transplant. After this third transplant, she is again insulin independent. They don't say how long after the third transplant it has been. The first transplant was 5 ku/kg, the second was also 5 ku/kg, and the third was 8 ku/kg. Two key quotes from the paper are:
reports insulin independence in a patient with insulin dependent type 1 diabetes
At this early stage of clinical trials, results show that insulin independence is potentially achievable at least in some patients and that repeat implants are safe.
My Thoughts on this Paper

It is important to remember that this press release discusses only a single person, so I'm very cautious about reading too much into it. Especially since this one person had the best results of all the people in the phase-I trial. She was the person who was insulin free for the longest period after the first transplant. So by publishing only her follow on results, they are really "cherry picking" their results. ("Cherry picking" refers to only including the people who had the best results, and ignoring the people who had other results. It can be a huge source of bias in scientific research.)

Keeping all that in mind, I think these results imply that the current LCT implant product is effective for less than 6 months, when given in the 5ku/kg dose. Here is my reasoning: for this patient, a dose of 8 ku/kg leads to insulin independence the one time it was used. But a dose of 5 ku/kg sometimes does and sometimes does not. But the second 5 ku/kg dose did not lead to insulin independence, which suggests that there was less than 2ku/kg cells still working from the first implantation. (Because if there was more than that, there would have been 8ku/kg total effective when he second operation was done: 3 left over from the first operation, and 5 new ones.) So that implies that the LCT implants don't last very long right now. That's not the end of the world, of course. LCT has years to improve these before they are approved for general use, but it does suggest that they have a long way to go, if people want a cure that only requires an operation every few years. Of course for those who will accept a cure that requires an operation every few months, that is much closer.

Put another way: This patient got a dose and went for 2 months without needing insulin, but then needed it again. Her second dose did not provide any insulin independence. If there were still some working cells from the first implantation, then they would have combined with the new cells to give insulin independence again. But that did not happen.

A note on the Politics of this Information

The most important thing about this press release, is that there is no new news here. The patient in question was "insulin independent" for two months, at the start of the phase-I trial (months ago), and is now "insulin independent" again (with no duration reported).

So why a press release now? My answer: Politics.

LCT has been working for almost a decade to get approval for human testing in New Zealand. Initially, they were questions about the safety of xenotransplantation (especially with respect to a particular pig disease called PERV). LCT did a lot of safety based research, and put those questions to rest years ago, but still New Zealand refused to allow clinical trials. Finally, LCT moved ahead with clinical trials in Russia, which were successful. New Zealand was finally shamed into approving the clinical trails "conditionally" on LCT getting some scientific safety approvals. That wasn't a problem, because LCT has had solid scientific safety studies done for years. They got the approvals, and the New Zealand political minister still has not approved their testing. Hence the press release.

The only good news is that LCT is (or was, see below) also working toward starting a phase-II trial in the US mid this year, and that should happen independently of New Zealand.

Living Cell Technologies Welcomes Report On Safety of Pig Cell Transplants

Here LCT publicizes research done by others. One of the fears of LCT's treatment is that a pig retrovirus might infect people via the transplant. This is especially true of very hard to detect retrovirus, such as PERV, which is similar to retroviruses which are known to cause incurable diseases in sheep, cows, and humans, and to jump from species to species.

LCT had previously done studies to show that the pigs in their flock did not have PERV, and that PERV could be detected prior to transplantation, and that PERV in the beta cells was unlikely to be transferred to people who got transplants, even if in the pigs. So they had already show a solid three barrier safety infrastructure.

Here they report on research were several types of non-human primates were injected with PERV and other viruses and non-virus pathogens found in pigs, after the primates had been injected with drugs specifically to weaken their immune system. None of the primates got sick. That is pretty much the ultimate safety testing. It shows that even if all the safety systems break down, and PERV go straight into a person, and the person has a very weak immune system, then they still will not get sick.

This is good news, and should put to rest any lingering worries about PERV safety in LCT"s treatment.

From the "Note from the CEO" column in the March 2009 LCT Newsletter:
LCT has been in discussions with advisors in Russia to outline a commercialisation route and business plan. To focus on this commercialisation plan, Dr Robert Caspari stepped down as CEO as activities in the United States are of lower priority. Dr Caspari remains a valued member of our board of directors.
Also, there is no mention in this newsletter of the previously proposed, larger scale, clinical trials to start at the Barbara Davis center in Denver, USA.

Some people have interpreted this to mean that the larger phase-II trial they had been talking about running in the US has been put on hold in favor of more work in Russia. Obviously that would be disappointing to people in the US who were hoping to take part in the trial.

Also, if they can not resolve their differences with the New Zealand minister, and can't get started in the US, that leaves only their Russian testing. I'm also worried about the impact of "all Russian" clinical trial data on future US FDA approval. Officially, I think the FDA treats well done clinical trial data the same, no matter where it was done. But I'm a little worried that unofficially, having nothing but Russian data may delay things.

I hope that this entire interpretation is wrong (ie. they are getting rid of their American CEO, but that will not impact their American clinical trials). That would be the best news. They wanted to start that trial mid-2009, so we should know soon if there is a delay.

Joshua Levy

Saturday, April 4, 2009

Two New Trials to Test Kineret / Anakinra

I recently found out about two clinical trials into the drug Kineret also known as Anakinra (an Anti-Interleukin-1 treatment). A phase-I study which started in March 2008, and a phase-II study which started in January 2009. Last year there was some interest in the idea that inflammation was a causative factor in type-1 diabetes. These are the first human trials that I know of which are based on attacking inflammation to try to cure type-1 diabetes (in honeymooners only, however). This drug is already approved by the US FDA for the treatment of rheumatoid arthritis. It has also already be used in clinical trials focusing on type-2 diabetes and some autoimmune diseases (in addition to RA).

The phase-I study is 15 kids (aged 6 to 18) who are within one week of diagnosis. The trial is scheduled to end in July 2009. It is being done by Soumya Adhikari at Children's Medical Center Dallas, Texas, United States, and is funded by their own foundation. You can read the US Clinical Trail Record here: I can find no other information on this trial on the web.

The phase-II study is being done by the Steno Diabetes Center in Denmark is testing using Kineret on newly diagnosed type-1 diabetics. The study is called "AIDA". It is multi-site, all in Europe. You can read more about it here: The study is funded by JDRF, Steno, and Oresund.

This is their description of the drug:
Kineret® is already being used in the treatment of patients suffering from arthritis and studies are now suggesting that it may also be useful for patients with Type 1 diabetes. The active substance in Kineret is interleukin-1 receptor antagonist, a blocker of an immune-signal molecule named interleukin-1. During inflammation this blocker is produced by your body to limit tissue damage caused by inflammation, and kineret is an exact copy of this naturally occurring molecule.
The study will use 160 patients, starting in January 2009 and ending (they hope) in September 2011. Half will get the drug, half placebo. After 80 patients have been followed for 6 months, they will do analysis on the available data, and decide if it is worth continuing the trial, and if it is safe to do so. I don't know if this interim analysis will be published or not. (I hope so!)

Patients will inject themselves once a day, for two years, so this is a pretty big commitment on their part. Since patients must be 18 or over, and with in 12 weeks of diagnosis, I suspect it will take them quite a while to enroll 80 people, even as they have 23 sites participating. Although the fact that it is using an already approved drug should make it easier to recruit.

The US Clinical Trial Record for this is NCT00711503, which you can see here:

There is more information on the Steno center here:

If you are newly diagnosed (less than 12 weeks), and in Europe, here is a list of trial sites:

A Little Discussion

Everyone knows that type-1 diabetics have a lot of inflammation in their pancreas and especially around their beta cells. 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 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 numbers). And that is a big difference. But this second model is still a minority opinion.

The treatment being tested should lower inflammation, so if the second model is correct, it will lessen the symptoms of type-1 diabetes, maybe remove the symptoms entirely: the body will naturally produce more insulin. In any case, one of the great things about this research, is that we should have some solid data soon. The phase-I trial should complete mid this year, the early data from the phase-II later this year, and the final data from the phase-II by year after next.

Joshua Levy