Burt's Brazilian Research

I've gotten a couple of questions about Burt's research, which is being done in Brazil. Below is my update on this research, together with some thoughts on it.

What is he trying to do, and what is the current status of the Research?

The basic plan is a two pronged attack [r1]: First, drugs are given to shut down (or almost shut down) the immune system. Second, the patient is given drugs to stimulate adult stem cells, which are then removed from his or her blood, treated, and reinjected into the patient. [d1]

In some ways, this research is similar to Trucco's [r7] and also Gitelman's [r6].
Gitelman is using ATG in his research, and that is one of the drugs used in Burt's research as well.

What is the good news?

The good news, is that it works. Burt's results -- in term of curing people for months and even years at a time -- are amazing. Much better than any other research that I know of. More than half of the people treated stopped requiring insulin for the entire time they were followed: a period of months, in some cases years! The rest of the people (except one) required much less insulin after the treatment than before it. That's huge, and no other treatment has come close.

To be specific, one year after treatment, of the 15 patients treated, only two were using injected insulin at the end of the first year after treatment, and 11 of the patients had never (or almost never) had to use injected insulin after the treatment [r8]. The [r1] reference also contains A1C data for these patients, which is also very good.

In a later follow up [r5] the results were also good. Out of 21 patients (and excluding one who had DKA), 13 patients were permanently free of insulin for as long as the study followed them. Some of these people were followed for more than 3 years!. 6 more patients were insulin free for some months after treatment. Just eye-balling that data, it looks to me like those 6 were insulin free for about 66% of the months after treatment. Only 2 patients from the 21 treated were never insulin free.

What is the bad news?

The bad news, is that it might be dangerous; even deadly. This treatment is quite complex. High doses of immunosuppressive drugs are given, and then different drugs are given to create stem cells, and then those are treated with other drugs. Finally, another bunch of drugs are given to lessen the severity of various side effects of the primary drugs. So there is a lot going on. In particular, the immunosuppressive drugs have serious short term and long term side effects. Some of the patients in the clinical trials were hit by some bad short term side effects of these drugs (although nothing permanent). There are also long term dangers of these drugs. In some cases, drugs in this class raise your chance of getting rare cancers even years after they were used.

Now, all of the drugs given as part of this study are approved for human use (for other treatments), but they are also well known to have dangerous side effects. In many cases, these drugs are approved to treat deadly cancers where the general tolerance for side effects, and even the chance of death is much higher than for a child with type-1 diabetes. My biggest single problem in getting excited about this research, that I don't know exactly how dangerous these drugs are, in the doses given here.

An interesting digression on "honeymoon" only clinical trials.

This study is a classic "honeymoon only" clinical trial. Only people who had been diagnosed for less than six weeks were admitted into the study. On the other hand, if a person's body can regenerate new insulin producing beta cells (as many researchers now believe), then this cure could work on established diabetics, too. Burt and his team believe that giving the immunospressive drugs early (when the body still has some working beta-cells) is important. However, if the body naturally regenerates these cells, it may turn out not to matter so much.

Some discussion of stem cell research issues.

This work uses stem cells, and it is being done in Brazil, even though it is based on research done in the US. This has led some people to jump to the conclusion that it uses embryonic stem cells, and was forced out of the US by right wing Christian objections to embryonic stem cells. However, I do not think this is what happened to this particular research. Not only are these guys using adult stem cells, they're using the patient's own stem cells. So only the most wacko religious loony is going to object to that.

On the other hand, there are other ethical issues involved in this research, which you can read about [r2,r3]. Basically, they involve using children in the initial clinical trial. There is no doubt that this trial followed all the proper legal and ethical rules for Brazil; but doing phase-I research on children when the drugs given are known to have serious side effects does raise ethical issues.

If I had more time....

If I had more time, I would certainly spend some of it researching the safety profiles of the various drugs used in this research. After all, if the drugs are safe, then this research is showing the highest cure rate of anything out there. Conversely, if the drugs are dangerous, then they will need to do a lot of research to find safer alternatives or lower doses, before I will personally be interested in this treatment.

Another project, if I had more time, would be to create a simple table comparing the most recent results of different clinical trials. For each trial include data points like: % drop in insulin use (average and standard deviation), % drop in A1C, % chance that a patient will go a month without using insulin, % chance that a patient will go a year without using insulin, etc.

If I had a spare 10 million (US$) lying around....

If I had a spare 10 million to spend, I would try duplicating this research on non-honeymoon diabetics, and I'd do it in the US. After all, since these would be people who had type-1 for years, so it could be done on adults, and so it could be done in the US.

A few random thoughts.

One interesting complexity in this research, is that it failed on the first person it was tried on. That person had DKA. After that, people who had DKA were excluded from the study, and everyone had much better results. Almost all diabetics, at some point, get DKA for some period of time. So if this is to become a widespread treatment for type-1, then the role of DKA will need to be better understood.

This sort of treatment might already be a competitor of islet cell transplant therapies. After all, those people must be on immunosuppressives for their whole lives (although at low dose). It might turn out that Burt's short term, high does treatment is overall safer than the long term, low dose that they get now.

Extra Notes and References

[d1] this is the exact quote, which I have a hard time translating into English. If anyone knows more specifically what it means, here it is, from [r1]:

Hematopoietic stem cells were mobilized with cyclophosphamide (2.0 g/m²) and granulocyte colony-stimulating factor (10 µg/kg per day) and then collected from peripheral blood by leukapheresis and cryopreserved. The cells were injected intravenously after conditioning with cyclophosphamide (200 mg/kg) and rabbit antithymocyte globulin (4.5 mg/kg).

[r1] Abstract of the JAMA article published in 2007
http://jama.ama-assn.org/cgi/content/full/297/14/1568
http://jama.ama-assn.org/cgi/content/abstract/297/14/1568

[r2] http://jama.ama-assn.org/cgi/content/extract/298/3/285

[r3] http://jama.ama-assn.org/cgi/content/extract/298/3/285-a

[r4] Some results and discussion:
http://66.102.1.104/scholar?hl=en&lr=&q=cache:0B8eccFzyUUJ:www.scielo.br/scielo.php%3Fpid%3DS1516-84842008000600014%26script%3Dsci_abstract%26tlng%3Den+burt+diabetes+brazil

[r5] A different report:
http://www.scielo.br/pdf/rbhh/v30s2/14.pdf

[r6] Gitelmans work is described here, on my web page:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG

[r7] Trucco's work is described here, on my web page:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#Children%E2%80%99sHospitalofPittsburghTrucco

[r8] See the graphs here:
http://jama.ama-assn.org/cgi/content/full/297/14/1568/JPC70002F1

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

New to Me: Phase-I Clinical Trial of Polyclonal Anti-T-Cell (ATG)

This clinical trial treats honeymoon diabetes (during first 6 weeks) with ATG. The hope is for some beta cell preservation. This is a prelude to Gitelman's phase-II ATG trial, described here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG, except that this trial is still ongoing. However, they have published interrum results (on their first 17 patients) here: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1783538

My eyeballing of the interrum results looks like the ATG group used about 60% as much insulin as the untreated group after about 12 months, and this seemed pretty stable. It did not look to me like the effect was "wearing off". This was good enough to motivate a follow-on, phase-II clinical trial, which is currently underway. I'm also very interested in what happens to these 17 patients after 2 years, 3 years etc. If the lower insulin requirement gradually goes away, that's too bad. If it stays stable, then that is very promising. If it gets even better slowly over time, that suggests that the body is growing new beta cells, and would be good news both for ATG treatments and for many others.

US Government Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT00190502

Estimated Enrollment:	28
Study Start Date:	November 2000
Estimated Study Completion Date:	December 2007

This work was sponsored by the Ministry of Health, Czech Republic, and is being done in Prague.

New Phase-I Clinical Trial: IL-2 and sirolimus

This trial is open to people diagnosed between 3 months and 4 years ago, so it's not a classic "honeymoon only" study, but it is limited. Patients will be given two drugs over a three month period. The hope is to preserve some beta cells. This is a classic phase-I trial, looking only at safety in a small number of patients.

US Government Clinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT00525889 (NCT00525889)
Immune Tolerance Network Trial Record: http://www.immunetolerance.org/studies/a-phase-i-trial-il-2-and-sirolimus-recent-onset-type-1-diabetes-mellitus (ITN018AI)
Info for patients: http://www.benaroyaresearch.org/files/webfm/diabetes/web_il2_rapa_intervention.doc
General info on Sirolimus: http://en.wikipedia.org/wiki/Rapamycin
General info on IL-2: http://en.wikipedia.org/wiki/Interleukin_2

Estimated Enrollment:	10
Study Start Date:	August 2007
Estimated Study Completion Date:	January 2012
Estimated Primary Completion Date:	January 2010 (Final data collection date for primary outcome measure)

This study is being done in Seattle Washington, and is sponsored by NIAID.

Joshua