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.
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).
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:
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.
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.
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.
“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:
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.
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/
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/
