The Exsulin company is hoping to start Phase-I human trials in June 2009 (so right soon now). They are testing a new formulation of INGAP called Exsulin, a drug designed to regrow beta cells in the pancreas.
Their Phase-I clinical trial is small, short, and open to people who have had type-1 diabetes for more than 2 years, so we should have some results soon. It is a three group design. One group gets nothing, one gets a full dose, the other gets a half dose. They are checking for all the right stuff: C-peptide, fasting glucagon, fasting glucose, total daily insulin dose, and HbA1c. They are using two sites Montreal and Rochester.
This is described on their web site:
http://www.exsulin.com/underway.html
INGAP (now renamed Exsulin) has a 12 year history of research. NOD mice trials worked well, but human trials didn't show much success (sound familiar?) The phase-I study is described here: http://www.clinicaltrials.gov/ct2/show/NCT00034255. The phase-II study is described here: http://www.clinicaltrials.gov/ct2/show/NCT00071409. It was funded by Proctor and Gamble but the results were not good enough to move forward.
The original developers of INGAP got back rights to it after P&G didn't like the phase-II results. Their analysis of the results convinced them that INGAP was helping grow new beta cells, but that those new cells were being killed off too quickly to help the patient. (Maybe because of the body's immune system, or maybe because of inflammation, or maybe for some other reason.) So it is natural for them to pair Exsulin with another drug to treat the other problem, and see if both together can cure type-1 diabetes. But the research they are starting now is just Exsulin, not paired with anything.
Joshua Levy
Showing posts with label Non-honeymoon. Show all posts
Showing posts with label Non-honeymoon. Show all posts
Friday, May 29, 2009
Wednesday, May 27, 2009
DiaKine starts Phase-I clinical trials on Lisofylline (LSF)
DiaKine is about to start it's first clinical trial in a research program aimed at curing type-1 diabetes. Their treatment is Lisofylline (LSF), an anti-inflammatory drug that (in NOD mice) has prevented type-1 diabetes and (when given with exendin-4) cured existing type-1 diabetes.
Previously (in May 2008) DiaKine has formed a joint project with Kinexum Metabolics, to run a human trial (phase-II) using both of their drugs together (LSF and INGAP). The combination had already given good results in NOD mice. That trial was supposed to start in "late 2008". Kinexum Metabolics has since changed it's name to Exsulin (not INsulin, but EXsulin. Get it?) I can't find any record of the LSF+INGAP trial starting, but each company is testing it's own stuff seperately, so maybe after that, they'll test them together. I know a lot of people are interested in an anti-inflammatory and a beta-cell growing combination therapy, and obviously these two companies are interested in that, also. In any case, this trial is LSF only, not the combo they talked about earlier.
The current trial involves 8 people, and is supposed to start in May 2009 and be done by December 2009.
This research is being done in New Jersey.
You can read a news article here:
http://www.earthtimes.org/articles/show/diakine-therapeutics-diabetes-immune-modulator-drug-set-for-human-clinical-trial,821004.shtml
The US FDA's clinical trial record is here:
http://clinicaltrials.gov/ct2/show/NCT00896077
And the official press release is here (and is better than most):
http://www.diakine.com/assets/news20090512.pdf
The press release talking about LSF+INGAP together is here:
http://www.diakine.com/assets/news20080506.pdf
I want to thank the Wainscoat family for bringing this to my attention.
Joshua Levy
Previously (in May 2008) DiaKine has formed a joint project with Kinexum Metabolics, to run a human trial (phase-II) using both of their drugs together (LSF and INGAP). The combination had already given good results in NOD mice. That trial was supposed to start in "late 2008". Kinexum Metabolics has since changed it's name to Exsulin (not INsulin, but EXsulin. Get it?) I can't find any record of the LSF+INGAP trial starting, but each company is testing it's own stuff seperately, so maybe after that, they'll test them together. I know a lot of people are interested in an anti-inflammatory and a beta-cell growing combination therapy, and obviously these two companies are interested in that, also. In any case, this trial is LSF only, not the combo they talked about earlier.
The current trial involves 8 people, and is supposed to start in May 2009 and be done by December 2009.
This research is being done in New Jersey.
You can read a news article here:
http://www.earthtimes.org/articles/show/diakine-therapeutics-diabetes-immune-modulator-drug-set-for-human-clinical-trial,821004.shtml
The US FDA's clinical trial record is here:
http://clinicaltrials.gov/ct2/show/NCT00896077
And the official press release is here (and is better than most):
http://www.diakine.com/assets/news20090512.pdf
The press release talking about LSF+INGAP together is here:
http://www.diakine.com/assets/news20080506.pdf
I want to thank the Wainscoat family for bringing this to my attention.
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:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
Below is my discussion of the three recent news items:
Living Cell Technologies Gains Additional Benefit From DIABECELL
http://www.lctglobal.com/downloads/cms_latest_news/2009-04-05-Clinical%20Update%20Apr09.pdf
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:
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
http://www.lctglobal.com/downloads/cms_media_resources/2009-04-08-Xeno%20Apr09.pdf
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:
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
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
Below is my discussion of the three recent news items:
Living Cell Technologies Gains Additional Benefit From DIABECELL
http://www.lctglobal.com/downloads/cms_latest_news/2009-04-05-Clinical%20Update%20Apr09.pdf
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
http://www.lctglobal.com/downloads/cms_media_resources/2009-04-08-Xeno%20Apr09.pdf
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
Wednesday, February 11, 2009
Follow up to Phase-I: LCT Releases Longer Follow Up Data
LCT has released some more data on their Phase-I clinical trial. This includes longer term data on the first five people in the study, and some news on two later people. LCT encapsulates insulin generating cells from pigs in a special coating so that the body's immune system does not attack them, but nutrients can flow in and wastes and insulin can flow out. You can read their press release here:
http://www.lctglobal.com/downloads/cms_media_resources/2009-02-10-LCT%20Announcement%20Feb%2009%20ClinUpdate%20Final_110209.pdf
My quick review is that this data is more of the same, so my previous comments on LCT still apply:
http://cureresearch4type1diabetes.blogspot.com/2008/12/lcts-research.html (most recent comments)
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT (all comments)
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies (general status, prior to this announcement)
The quick summary is this:
It can work on anyone (honeymoon and non-honeymoon patients).
The low doses used so far have worked for some people, but not for everyone, but higher doses are expected to work better for more people.
Some people have been temporarily cured (no BG checks or using insulin) for days or weeks as part of this phase-I trial.
The big unknown is how long the implants will work, or how often the new implants will need to be added.
Plus all the normal phase-I risks: only a small number of people have had this treatment and only at low doses, etc.
What I'd really like to see from these guys is a graph showing insulin usage over a 1-3 year period. Or, even more specifically: for people who had a big drop in insulin usage after getting the implants, how much of that drop stayed with them for 1, 2 or 3 years?
Overall, I think this is a strong research program, although this update doesn't have much meat on it.
Joshua Levy
http://www.lctglobal.com/downloads/cms_media_resources/2009-02-10-LCT%20Announcement%20Feb%2009%20ClinUpdate%20Final_110209.pdf
My quick review is that this data is more of the same, so my previous comments on LCT still apply:
http://cureresearch4type1diabetes.blogspot.com/2008/12/lcts-research.html (most recent comments)
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT (all comments)
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiabecellbyLivingCellTechnologies (general status, prior to this announcement)
The quick summary is this:
It can work on anyone (honeymoon and non-honeymoon patients).
The low doses used so far have worked for some people, but not for everyone, but higher doses are expected to work better for more people.
Some people have been temporarily cured (no BG checks or using insulin) for days or weeks as part of this phase-I trial.
The big unknown is how long the implants will work, or how often the new implants will need to be added.
Plus all the normal phase-I risks: only a small number of people have had this treatment and only at low doses, etc.
What I'd really like to see from these guys is a graph showing insulin usage over a 1-3 year period. Or, even more specifically: for people who had a big drop in insulin usage after getting the implants, how much of that drop stayed with them for 1, 2 or 3 years?
Overall, I think this is a strong research program, although this update doesn't have much meat on it.
Joshua Levy
Thursday, February 5, 2009
Diamyd Starts Phase-II Trial Aimed at Established Type-1 Diabetics
Diamyd has announced NIDDK is starting a clinical trial to study a combination of their GAD65 immunesupressive together with two drugs designed to stimulate the body's own beta cell growth and insulin generation.
You can read the press release here:
http://www.diamyd.com/docs/PressClip.aspx?PageID=4&ClipID=486
the headline is:
Diamyd's product is an immunesupressive that specifically targets GAD, which is one of the markers for type-1 diabetes. This treatment is currently in two large phase-III trials for honeymoon (recent onset) type-1 diabetics, one in the US and one in the EU. Data from phase-I and phase-II trials, also on honeymooners, show that treated patients use less insulin than untreated patients. Some quite a bit less, and some did not need to use insulin at all for short periods of time. So this is all good news for honeymoon diabetics.
This phase-II human trial takes the same basic treatment and combines it with drugs already approved for type-2 diabetics in an attempt to cure (or improve) non-honeymoon diabetics.
The Study that is Starting Now
They want to enroll 164 people, starting Feburary 2009.
There is no information on how long it will last, or when results will be available.
It is Randomized, Double-Blind, and Placebo Controlled.
One interesting wrinkle is that it is only open to honeymoon diabetics, even thought the treatment is clearly focused on non-honeymooners. I think this is because GAD65 has only been tested on honeymoon diabetics, and is not yet approved for the mass market, so limiting these tests to honeymooners only will speed things along (no extra safety testing for a new population). Anyway the press release makes clear that they are trying to regenerate the body's own ability to make new beta cells (and thus more insulin), and that it is designed for non-honeymooners.
Here is how Diamyd describes it:
This new Phase II study will be the first to combine regenerative agents and Diamyd®. The regenerative agents to be evaluated are lansoprazole and sitagliptin, which are both marketed drugs in the US. The study, to be led by Professor David Harlan at NIDDK, aims to enroll 82 adult patients. "We are excited to start this study to investigate if combining Diamyd® with potentially regenerative stimuli can meaningfully improve treatment of established type 1 diabetes", says Professor Harlan, chief of the Diabetes Branch at NIDDK and professor of medicine at the Uniformed Services University of the Health Sciences.
Notes: NIDDK is part of NIH: the National Institues of Health, part of the federal [USA] government. Also, I think the 82 people listed above is the number who will get the treatment. Another 82 will get placebos, for a total of 164.
You can read more about it at the US Government's Clinical Trials site: http://www.clinicaltrials.gov/ct2/show/NCT00837759
Why is this Important?
In my mind, this clinical trial is very important for two reasons:
First is the tactical reason: Because Diamyd's drug is already undergoing phase-III trials, it could be approved for general use (with a prescription) in 3 or 4 years. The other drugs used in this trial have been generally available for several years. So in just 3 or 4 years we will have results of this phase-II trial and general availability of all the drugs needed. So if this trial is successful, you could actually get the treatment as an "off label" use, if your doctor was willing to write the prescriptions.
Second is the strategic reason: There are several drugs in phase-III and phase-II clinical trials which are targeted at honeymoon type-1 diabetics and which work by stopping the immune attack and "saving" some insulin production. This trial is the first attempt that I know of to take a honeymoon only cure, and make it work on non-honeymooners. But if it works, the same idea could be applied to ToleRx's treatment, Andromedia's treatment, MacroGenic's treatment, Rituximab, Thymoglobulin, Abatacept, etc. That gives us all a lot more chances for a cure using treatments which are already well into the approval process.
Also, one of the controversies in type-1 cure research today is this: does the body naturally regenerate beta cells (and thus insulin production) or not? If the body does, then every honeymoon only cure will become a cure for everyone, if you just wait for the body to regrow it's own beta cells. However if the body does not, then those cures will only work for honeymooners. However, if this clinical trial is successful in finding a path that works with non-honeymooners, then the whole question of regeneration of beta cells is not important: if they naturally regenerate: great. If not, this experiment (if successful) shows how they can be regrown anyway. Type-1 can be cured in either case.
This is big news. This is good news.
You can read the press release here:
http://www.diamyd.com/docs/PressClip.aspx?PageID=4&ClipID=486
the headline is:
DIAMYD® COMBINATION TRIAL AIMED AT REGENERATING INSULIN-PRODUCING CAPACITY IN ESTABLISHED TYPE 1 DIABETES GETS APPROVAL FROM FDA
BackgroundDiamyd's product is an immunesupressive that specifically targets GAD, which is one of the markers for type-1 diabetes. This treatment is currently in two large phase-III trials for honeymoon (recent onset) type-1 diabetics, one in the US and one in the EU. Data from phase-I and phase-II trials, also on honeymooners, show that treated patients use less insulin than untreated patients. Some quite a bit less, and some did not need to use insulin at all for short periods of time. So this is all good news for honeymoon diabetics.
This phase-II human trial takes the same basic treatment and combines it with drugs already approved for type-2 diabetics in an attempt to cure (or improve) non-honeymoon diabetics.
The Study that is Starting Now
They want to enroll 164 people, starting Feburary 2009.
There is no information on how long it will last, or when results will be available.
It is Randomized, Double-Blind, and Placebo Controlled.
One interesting wrinkle is that it is only open to honeymoon diabetics, even thought the treatment is clearly focused on non-honeymooners. I think this is because GAD65 has only been tested on honeymoon diabetics, and is not yet approved for the mass market, so limiting these tests to honeymooners only will speed things along (no extra safety testing for a new population). Anyway the press release makes clear that they are trying to regenerate the body's own ability to make new beta cells (and thus more insulin), and that it is designed for non-honeymooners.
Here is how Diamyd describes it:
This new Phase II study will be the first to combine regenerative agents and Diamyd®. The regenerative agents to be evaluated are lansoprazole and sitagliptin, which are both marketed drugs in the US. The study, to be led by Professor David Harlan at NIDDK, aims to enroll 82 adult patients. "We are excited to start this study to investigate if combining Diamyd® with potentially regenerative stimuli can meaningfully improve treatment of established type 1 diabetes", says Professor Harlan, chief of the Diabetes Branch at NIDDK and professor of medicine at the Uniformed Services University of the Health Sciences.
Notes: NIDDK is part of NIH: the National Institues of Health, part of the federal [USA] government. Also, I think the 82 people listed above is the number who will get the treatment. Another 82 will get placebos, for a total of 164.
You can read more about it at the US Government's Clinical Trials site: http://www.clinicaltrials.gov/ct2/show/NCT00837759
Why is this Important?
In my mind, this clinical trial is very important for two reasons:
First is the tactical reason: Because Diamyd's drug is already undergoing phase-III trials, it could be approved for general use (with a prescription) in 3 or 4 years. The other drugs used in this trial have been generally available for several years. So in just 3 or 4 years we will have results of this phase-II trial and general availability of all the drugs needed. So if this trial is successful, you could actually get the treatment as an "off label" use, if your doctor was willing to write the prescriptions.
Second is the strategic reason: There are several drugs in phase-III and phase-II clinical trials which are targeted at honeymoon type-1 diabetics and which work by stopping the immune attack and "saving" some insulin production. This trial is the first attempt that I know of to take a honeymoon only cure, and make it work on non-honeymooners. But if it works, the same idea could be applied to ToleRx's treatment, Andromedia's treatment, MacroGenic's treatment, Rituximab, Thymoglobulin, Abatacept, etc. That gives us all a lot more chances for a cure using treatments which are already well into the approval process.
Also, one of the controversies in type-1 cure research today is this: does the body naturally regenerate beta cells (and thus insulin production) or not? If the body does, then every honeymoon only cure will become a cure for everyone, if you just wait for the body to regrow it's own beta cells. However if the body does not, then those cures will only work for honeymooners. However, if this clinical trial is successful in finding a path that works with non-honeymooners, then the whole question of regeneration of beta cells is not important: if they naturally regenerate: great. If not, this experiment (if successful) shows how they can be regrown anyway. Type-1 can be cured in either case.
This is big news. This is good news.
Monday, December 15, 2008
LCT's Research
Someone asked me (in personal email) to give a summary of LCT's research [r1] in much the same way I summarized Faustman's research. Unfortunately, I just don't have the time to do that detailed a job. That Faustman post took me hours of research to put together. However, here is a summary of LCT's research, but with fewer details and fewer references. I'm sorry that I can't put more time into it.
The Pre-History of LCT's Research
In the 1970s and 1980s, it was commonly thought that type-1 diabetic's beta cells had been destroyed, and if they could just be replaced, their diabetes would be cured! This led to several attempts a cures, especially whole pancreas transplants, beta cell transplants, and drug treatments designed to get beta cells to regrow (such as human growth hormone). Of course, none of these worked very well, because the body's immunology attack on itself simply killed off the new beta cells. (Although if you gave immune suppressing drugs, you could get it to work a little bit, and you needed those drugs to prevent organ rejection of the new tissue, anyway.) This whole area of transplants is still being pursued, but it is no where near as successful as it was hoped to be decades ago.
When it became clear that the body's immunology attack kept going, some researchers tried the following approach: they encapsulated beta cells inside a wrapper and then implanted the bundle it in a person. The wrapper would need to be a very high-tech material that would allow nutrients and oxygen to flow in, and wastes to flow out, and insulin to flow out, and the chemicals which triggered insulin production to flow in. But if they succeeded, it would be like having a natural pancreas inside you, but protected from the immune system.
It's a great solution if you can do it, but very hard to do. In the last 20 years or so, there have been at least half a dozen companies that have tired this. Many have gone through several bankruptcies, name changes, and purchases by other companies. So far, none have been successful. In general, these companies try solutions from a "Chinese menu" one from column A and one from column B. Column A is the material inside the wrapper. The source of insulin. Column A has things like "human beta cells from cadavers", "human beta cells from live doners", "pig cells", "cloned embryonic stem cells", "cloned adult stem cells", etc. Column B is the wrapper material. Almost every company in this area has developed their own wrapper, and they all claim their wrapper is the best (and most of them try to incorporate good ideas from other's work, as much as they can).
One of these companies is LCT [r2]. From column A they selected pig beta cells, but from a special population of pigs that had lived for decades without contact with any other mammals on an island in the middle of nowhere. From column B they developed their own wrapper technology.
LCT's Research in the late 1990s
By the mid 1990s, LCT was ready to start human trials. These trials were underway in about 1998 when disaster struck. The disaster had nothing to do with their experiment. It had to do with the British food supply. Really! Mad cow disease hit, and it was caused by a previously unknown class of organisms called prions, which can be passed from animals to humans. Since LCT's work was basically transplanting pig tissue to humans, there was some concern about this, especially since at the time, there was no testing for prions either in the pigs or in the tissues being transplanted.
New Zealand reacted to all this by stopping the LCT phase-I clinical trial immediately. So LCT's most important task became to get their clinical trials started again.
LCT's Research in the 2000s
LCT then did several studies to show the safety of their technique. They showed that their pigs did not have a prion disease, that they were not likely to get a prion disease, that the technique was not likely to transfer it to people. that no one had ever gotten a prion disease from pigs, etc. Also, they improved their encapsulation technique. But all this was to no avail. New Zealand would not authorize any clinical trials. [d1]
This caused a lot of delay, and eventually LCT decided to run a phase-I trial in Russia (see below).
Meanwhile, almost all of the other companies working with encapsulated beta cells went out of business, or abandoned that line of research. In particular, pig cells turned out to be a better line of research than human cells (and that include all types of stem cells). Some companies that had been trying to use human beta cells (of various types) tried to switch to pig cells, when it became obvious that pig cells were working better, but this just emphasized the fact that LCT was way ahead of them, since they had always been using pig cells.
LCT's Current Clinical Trials
LCT ran their phase-I clinical trial in Russia. They hired an American company to oversee it and make sure that it was up to US FDA standards, but the trial was run in Russia.
They were going to just implant about 4 people in Russia (and about 4 more in New Zealand), but when they could not get approval in NZ, they did 2 extra people in Russia. One with a higher dose of islet cells. The results of this phase-I test in Russia were pretty good [r3]:
1 (out of 6) patients went 5 months without needing to inject insulin, but then needed to restart
4 patients required much less insulin before the treatment than after (some 40% less, some 20% etc.)
1 patient was not successful, requiring more insulin after the transplant, than before it
At about the same time, LCT released results of testing one of the people involved in their mid-1990s clinical trial [r4]. Basically, what they found from that exercise, is that the implanted cells were still there and still working (at least a little). But there was no way to know if this person's implants (now 10+ years old) were generating enough insulin to have any real effect on his BG, A1C, or insulin requirements. Even so, this was good news.
The most recent news from LCT is two fold: they have finally gotten permission to run a clinical trial in New Zealand [r6], and are working tords getting approval for a clinical trial in Denver (USA) [r5]. The New Zealand clinical trial they are about to start they are calling a phase-II trial. This makes sense, since it is after the Russian phase-I trial, but it doesn't make sense from a headcount point of view. They are only enrolling 8 people, so that is phase-I sized. I don't know if they will up the dose from their earlier trial; I certainly hope so.
I don't have a reference in front of me, but I thought that the Denver trial was going to be a standard phase-II trial: 50-100 people, etc. However, since they are calling their NZ trial a phase-II, maybe they will call this one a phase-III or add more people to it? I don't know.
The Future of LCT's Research
LCT has some really good results, but they are based on less than 8 people, and only about 6 months of treatment. So the future of their research needs to show better results, for longer periods of time, on more people.
Show better results: This is what I worry about the least. Most of the people in their phase-I trial were given the absolute minimum dose of new islets, and yet they had large drops in their insulin needs. One person used no insulin for a period of time! Since actual transplants can use 2x, 4x, or many more times the number of islets, I think it is very reasonable to assume that higher doses will result in less insulin needed. In many cases, no insulin needed.
For longer periods of time: For me, this is the biggest worry. How long will these new islets last? Or, how often will they need to be replaced? There are two potential problems here. The first is that islet cells may have natural lifespans, which cause them to stop working after a certain number of years. There has been some research suggesting this (sorry: no references for this), but the exact lifespan is not known. Secondly, and more importantly, the encapsulation or transplantation of the cells may cause them to start to die off. This could kill of the transplanted islets much more quickly. For example, if the wrapper is not "good enough" islet cells may start to run out of oxygen, and very slowly die off over weeks or months. This has been a very real problem with other company's encapsulating technologies.
On more people: Because so few people have been given these islet transplants, there is always the possibility that there is some major problem that we just don't know about, because not enough people have gotten the transplant. I don't think that is very likely, but as more people are treated, we'll develop more certainty that it is safe.
My Opinion of this Research
My personal option of this research is mixed. I think that it is very likely to work, eventually. But I'm not sure how long it will take for them to tweak out all the problems. Also, it requires surgery. And I suspect that the early people to get it may need follow up surgeries every 5 or 10 years. On the other hand, I think that there are lots of people who, if you tell them "we can cure diabetes for 10 years for $50k and a three day hospital stay", many will do it. And that is a very reasonable goal for this technology within the next 5 to 10 years. And in 10 or more years, it may be cheaper or last longer, or both.
If you want to follow LCT, I recommend their web site: http://www.lctglobal.com/, which is very glossy.
There is another source, which I recommend only with serious reservations, and that is http://www.islet.org/forum/wwwboard.htm. This forum is run by an LCT cheerleader. He aggressively censors people who say bad things about LCT, or ask awkward questions. (And yes: I've been banned from the group several times.) I also believe that the forum owner makes many posts under many different names, to create a sort of false consensus on how wonderful LCT is doing. I have definitely seen the list owner post under multiple different names, I'm just not sure how many of the names on the board are real, and how many are fake. My best guess is about half are fake, but I'm really not sure.
More Discussion
[d1] Obviously there is a huge political saga here, which I will not get into.
Some References
[r1] My tracking of LCT is available here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#LivingCellTechnologiesDiabecell
[r2] LCT home web page is here: http://www.lct.com.au/
[r3] http://www.scoop.co.nz/stories/SC0803/S00061.htm
This is a news article with selected data from the first 6 months of the Russian phase-I trial.
[r4] Results of some tests on a guy who had this done 10 year previously: http://www.diabetesincontrol.com/results.php?storyarticle=4688
[r5] http://www.cwdfoundation.org/Grants2008/LCTBDC.html
[r6] Press reports on the New Zealand approval:
http://www.fiercebiotech.com/press-releases/living-cell-technologies-receives-health-ministers-approval-start-leading-edge-live-c
The Pre-History of LCT's Research
In the 1970s and 1980s, it was commonly thought that type-1 diabetic's beta cells had been destroyed, and if they could just be replaced, their diabetes would be cured! This led to several attempts a cures, especially whole pancreas transplants, beta cell transplants, and drug treatments designed to get beta cells to regrow (such as human growth hormone). Of course, none of these worked very well, because the body's immunology attack on itself simply killed off the new beta cells. (Although if you gave immune suppressing drugs, you could get it to work a little bit, and you needed those drugs to prevent organ rejection of the new tissue, anyway.) This whole area of transplants is still being pursued, but it is no where near as successful as it was hoped to be decades ago.
When it became clear that the body's immunology attack kept going, some researchers tried the following approach: they encapsulated beta cells inside a wrapper and then implanted the bundle it in a person. The wrapper would need to be a very high-tech material that would allow nutrients and oxygen to flow in, and wastes to flow out, and insulin to flow out, and the chemicals which triggered insulin production to flow in. But if they succeeded, it would be like having a natural pancreas inside you, but protected from the immune system.
It's a great solution if you can do it, but very hard to do. In the last 20 years or so, there have been at least half a dozen companies that have tired this. Many have gone through several bankruptcies, name changes, and purchases by other companies. So far, none have been successful. In general, these companies try solutions from a "Chinese menu" one from column A and one from column B. Column A is the material inside the wrapper. The source of insulin. Column A has things like "human beta cells from cadavers", "human beta cells from live doners", "pig cells", "cloned embryonic stem cells", "cloned adult stem cells", etc. Column B is the wrapper material. Almost every company in this area has developed their own wrapper, and they all claim their wrapper is the best (and most of them try to incorporate good ideas from other's work, as much as they can).
One of these companies is LCT [r2]. From column A they selected pig beta cells, but from a special population of pigs that had lived for decades without contact with any other mammals on an island in the middle of nowhere. From column B they developed their own wrapper technology.
LCT's Research in the late 1990s
By the mid 1990s, LCT was ready to start human trials. These trials were underway in about 1998 when disaster struck. The disaster had nothing to do with their experiment. It had to do with the British food supply. Really! Mad cow disease hit, and it was caused by a previously unknown class of organisms called prions, which can be passed from animals to humans. Since LCT's work was basically transplanting pig tissue to humans, there was some concern about this, especially since at the time, there was no testing for prions either in the pigs or in the tissues being transplanted.
New Zealand reacted to all this by stopping the LCT phase-I clinical trial immediately. So LCT's most important task became to get their clinical trials started again.
LCT's Research in the 2000s
LCT then did several studies to show the safety of their technique. They showed that their pigs did not have a prion disease, that they were not likely to get a prion disease, that the technique was not likely to transfer it to people. that no one had ever gotten a prion disease from pigs, etc. Also, they improved their encapsulation technique. But all this was to no avail. New Zealand would not authorize any clinical trials. [d1]
This caused a lot of delay, and eventually LCT decided to run a phase-I trial in Russia (see below).
Meanwhile, almost all of the other companies working with encapsulated beta cells went out of business, or abandoned that line of research. In particular, pig cells turned out to be a better line of research than human cells (and that include all types of stem cells). Some companies that had been trying to use human beta cells (of various types) tried to switch to pig cells, when it became obvious that pig cells were working better, but this just emphasized the fact that LCT was way ahead of them, since they had always been using pig cells.
LCT's Current Clinical Trials
LCT ran their phase-I clinical trial in Russia. They hired an American company to oversee it and make sure that it was up to US FDA standards, but the trial was run in Russia.
They were going to just implant about 4 people in Russia (and about 4 more in New Zealand), but when they could not get approval in NZ, they did 2 extra people in Russia. One with a higher dose of islet cells. The results of this phase-I test in Russia were pretty good [r3]:
1 (out of 6) patients went 5 months without needing to inject insulin, but then needed to restart
4 patients required much less insulin before the treatment than after (some 40% less, some 20% etc.)
1 patient was not successful, requiring more insulin after the transplant, than before it
At about the same time, LCT released results of testing one of the people involved in their mid-1990s clinical trial [r4]. Basically, what they found from that exercise, is that the implanted cells were still there and still working (at least a little). But there was no way to know if this person's implants (now 10+ years old) were generating enough insulin to have any real effect on his BG, A1C, or insulin requirements. Even so, this was good news.
The most recent news from LCT is two fold: they have finally gotten permission to run a clinical trial in New Zealand [r6], and are working tords getting approval for a clinical trial in Denver (USA) [r5]. The New Zealand clinical trial they are about to start they are calling a phase-II trial. This makes sense, since it is after the Russian phase-I trial, but it doesn't make sense from a headcount point of view. They are only enrolling 8 people, so that is phase-I sized. I don't know if they will up the dose from their earlier trial; I certainly hope so.
I don't have a reference in front of me, but I thought that the Denver trial was going to be a standard phase-II trial: 50-100 people, etc. However, since they are calling their NZ trial a phase-II, maybe they will call this one a phase-III or add more people to it? I don't know.
The Future of LCT's Research
LCT has some really good results, but they are based on less than 8 people, and only about 6 months of treatment. So the future of their research needs to show better results, for longer periods of time, on more people.
Show better results: This is what I worry about the least. Most of the people in their phase-I trial were given the absolute minimum dose of new islets, and yet they had large drops in their insulin needs. One person used no insulin for a period of time! Since actual transplants can use 2x, 4x, or many more times the number of islets, I think it is very reasonable to assume that higher doses will result in less insulin needed. In many cases, no insulin needed.
For longer periods of time: For me, this is the biggest worry. How long will these new islets last? Or, how often will they need to be replaced? There are two potential problems here. The first is that islet cells may have natural lifespans, which cause them to stop working after a certain number of years. There has been some research suggesting this (sorry: no references for this), but the exact lifespan is not known. Secondly, and more importantly, the encapsulation or transplantation of the cells may cause them to start to die off. This could kill of the transplanted islets much more quickly. For example, if the wrapper is not "good enough" islet cells may start to run out of oxygen, and very slowly die off over weeks or months. This has been a very real problem with other company's encapsulating technologies.
On more people: Because so few people have been given these islet transplants, there is always the possibility that there is some major problem that we just don't know about, because not enough people have gotten the transplant. I don't think that is very likely, but as more people are treated, we'll develop more certainty that it is safe.
My Opinion of this Research
My personal option of this research is mixed. I think that it is very likely to work, eventually. But I'm not sure how long it will take for them to tweak out all the problems. Also, it requires surgery. And I suspect that the early people to get it may need follow up surgeries every 5 or 10 years. On the other hand, I think that there are lots of people who, if you tell them "we can cure diabetes for 10 years for $50k and a three day hospital stay", many will do it. And that is a very reasonable goal for this technology within the next 5 to 10 years. And in 10 or more years, it may be cheaper or last longer, or both.
If you want to follow LCT, I recommend their web site: http://www.lctglobal.com/, which is very glossy.
There is another source, which I recommend only with serious reservations, and that is http://www.islet.org/forum/wwwboard.htm. This forum is run by an LCT cheerleader. He aggressively censors people who say bad things about LCT, or ask awkward questions. (And yes: I've been banned from the group several times.) I also believe that the forum owner makes many posts under many different names, to create a sort of false consensus on how wonderful LCT is doing. I have definitely seen the list owner post under multiple different names, I'm just not sure how many of the names on the board are real, and how many are fake. My best guess is about half are fake, but I'm really not sure.
More Discussion
[d1] Obviously there is a huge political saga here, which I will not get into.
Some References
[r1] My tracking of LCT is available here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#LivingCellTechnologiesDiabecell
[r2] LCT home web page is here: http://www.lct.com.au/
[r3] http://www.scoop.co.nz/stories/SC0803/S00061.htm
This is a news article with selected data from the first 6 months of the Russian phase-I trial.
[r4] Results of some tests on a guy who had this done 10 year previously: http://www.diabetesincontrol.com/results.php?storyarticle=4688
[r5] http://www.cwdfoundation.org/Grants2008/LCTBDC.html
[r6] Press reports on the New Zealand approval:
http://www.fiercebiotech.com/press-releases/living-cell-technologies-receives-health-ministers-approval-start-leading-edge-live-c
Tuesday, June 10, 2008
More Data on Bayhill's Phase I trial
I just poked around the Bayhill's web site a little. They are in the middle of a Phase-I trial aimed at curing type-1 diabetes. I noticed two pieces of very good news, and added both to my status page on cure research.
First, they have some data from the clinical trial that is on going right now, and that data looks very promising. This is the exact quote from their web page:
Check out the status of this, and all the other type-1 cure research that I track by clicking on the "Status of Research Discussed" to the right.
First, they have some data from the clinical trial that is on going right now, and that data looks very promising. This is the exact quote from their web page:
In the BHT-3021 phase I/II trial, nine patients have been randomized to the 1 mg dose cohort to date. BHT-3021 has demonstrated safety and tolerability, with no increase in adverse events among the first nine patients relative to placebo. Preliminary data also indicated that after the initiation of dosing with 1 mg of BHT-3021, there was a rapid reduction of approximately 50% in titers of anti-insulin antibodies that was sustained throughout the dosing period. In contrast, the anti-insulin antibody titers were unchanged with placebo dosing. Autoimmune T cell data from these initial patients are pending at this time.Second, this trial is open to people who have had type-1 diabetes for any length of time. It is not "honeymoon" only, as so many are.
Check out the status of this, and all the other type-1 cure research that I track by clicking on the "Status of Research Discussed" to the right.
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