Wednesday, February 25, 2009

Following Research into Type-1 Diabetes Cures

Every now and then, I get email from someone asking about all the diabetes research they hear about. Often these are parents of kids who have just been diagnosed with type-1 diabetes. They are being flooded by news that makes it sound like a cure is just around the corner, but they intuitively know that's not true, and are confused about why the news seems so positive, but the results so meager.

At other times, someone will email me a web page that reports some progress on research into a cure for type-1 diabetes, and that person will be all excited. And they will want to know how soon this cure will be ready to use, and why I'm not reporting on it more aggressively. I'll look at the exact same web page (or newspaper article), and think to myself "what's the big deal?"

This posting is my suggestions for what research is worthwhile following, and which is not; which research is likely to lead to a cure sooner rather than later. I'm not claiming that this is the only way to do it, but it works for me:

Even if you limit your reading to treatments aimed at curing type-1 diabetes, there is still a lot out there, and it is still hard to know what you should care about and what you should not. So I suggest that you read my earlier blog entry on "Understanding the Research Funnel" here:
It contains background information on how research progresses.

Rule 1: Ignore animal research.

I suggest that you completely ignore all research which has only been done on animals, and also research which has only been done in petri dishes or animal tissues ("in vitro"), for these reasons:
  1. Human studies (called "clincial studies") must be done after animal studies and before people can use the cure. But human studies take at least 10 years. So anything done in animal studies is more than 10 years away from widespread human use. You will hear about it going through human trials for years before you can use it.
  2. Less than half of the things that are successfully tested on animals are ever tested on humans at all. So even if something is totally successful in animals, there is a less than 50/50 chance it will be tested on people.
  3. I don't know exactly, but it appears that less than 1% of the treatments which are successful in animals are also successful in people. So a successful animal test, you wait over 10 years and have a 99% chance of not working on people.
So, for these reasons, and a few others as well, I don't think it's a good idea to spend much time following animal research. It is just to unlikely to pan out, and too far away from use. Therefore, I generally recommend that people ignore research results in animals. Instead, focus on the research that has already made it to human (or "clinical") trials.

In my mind, every web page, every newspaper article, and every blog entry which discusses research that has been done only on animals, should contain the following warning:

Warning: this research has been done on animals, not people. Even if wildly successful, it has a less than 1% chance of ever being useful for people, and is more than 10 years away from general use. Do not get your hopes up. This is a long way from you being able to use it, and may never work!

Rule 2: Not all Results are Created Equal

I'm completely results oriented. When I read news about research, I focus on the data results. Everyone's got a great idea, and almost everyone's got a sob-story about why you should give them money, and explanations about why they haven't gotten farther than they have. But none of that stuff matters to curing type-1 diabetes. All that matters is 1. results, 2. progress through the different phases of research leading to FDA approval, and 3. money (and money is only important because it helps with 1 and 2).

So with that in mind, this is what I look for in a newspaper article, press release, web page, blog entry or anything else:
  1. Human Results that cure diabetes
    • Lower BG numbers
    • Lower A1C numbers
    • Using less insulin

  2. Results that the FDA Regulates
    • The start or end of a phased human trial
    • Approval to start a new phased human trial, or continue/expand an existing one.

  3. Scientific Results that might lead to a cure
    • Changes in the immune system
    • Changes in sugar metabolism etc.

  4. Operational Progress
    • Funding
    • Development Deals
I focus on these because they directly result in a cure for diabetes (group 1), and will make that cure generally available in the US (group 2). I track group 3 only because they might lead to group 1 and 2 results in the future, and 4 because it funds 1, 2 and 3.

Think about it: "what is a cure"? The answer for me is that you have normal BG numbers, low A1C, and don't have to use insulin. Those are all the group 1 tests. What is "generally available in the US"? That means it has gone through a normal FDA approval process, so passed all three phases of human trials. That's the group 2 tests.

So, the first thing to look for in a news article, press release, web page, or anything else is hard numbers for the group 1 results. Did the treatment result in lower BGs? Lower A1Cs? Less insulin usage? If that data isn't available, then I take my excitement down a step.

The second thing to look for is any change in the phase status of the human trials. Are they starting phase-I trails? Have the finished phase-II trials? Those sorts of milestones are easy to track, and do show important progress. [d1]

The last scientific results that I look for are other findings that the researchers think are important. Usually these are small changes in the immune system that the researchers think are important, but that don't effect A1C or BG numbers. These are -- by far -- the least important, because years before they will generally available, they will have to be refined into group 1 results, and I'll pay more attention to them at that point. [d2]

Fourth, I try to keep track of what I call "operational progress" which is separate from scientific progress, which is described above. Operational progress refers to progress which is not based on science, but which (I hope) is motivated by scientific progress. This can cover many different things, but mostly it involves money. If a company gets $10 million dollars, that means another company has reviewed it's research and thinks it is likely to work (and be profitable). If a company signs a marketing agreement, again that is good news, because it means someone else has reviewed the work, and thinks it is promising. [d3]

Rule 3: Accept no excuses!

If someone isn't making progress or the they don't have good results in terms of BG, A1C or insulin usage, they they will certainly have excuses as to why they don't have these things. My advice is to ignore these excuses, and just note the fact that they don't have results.

I don't have time to talk about all the hundreds of excuses different people have come up with when they haven't done the studies and don't have the results. But let me give you two examples. You will often hear people say "I've got a cure for type-1, but the big pharma companies make too much money off it and no one will fund me!" Not true. There are lots of small pharma companies that don't make a dime off of type-1 treatment, who would love to make a mint by curing type-1. Add to that the NIDDK and other US government agencies who would love the publicity of curing type-1. Not just the US government, but the UK, and many other governments would love to fund such a thing. Then add in the non-profits; not just JDRF, but ADA, DRI, JLN, and many more. There are many sources of funding besides "big pharma".

A related argument is the "my cure is generic so no one will make money so no one will fund me" Wrong again. First of all, there are many drug companies that only produce generics and would love to produce more of them. Second, government agencies and non-profits don't care if some company is going to make money or not. In fact, they would probably prefer funding research into a generic drug [d4]. And so on....

Rule 0: Only follow research that is peer-reviewed and published in an indexed journal.

We are very lucky in the world of type-1 diabetes, that we don't need to worry (too much) about outright frauds and quacks. So we don't need to worry (too much) about someone claiming to cure type-1 diabetes, who actually isn't. However, if you want to apply these rules to other diseases, you might not be so lucky. Some diseases have a real problem with frauds and quacks [d5] and a quick and easy way to filter these out is to insist on peer reviewed research published in indexed journals. There are scores of peer reviewed, indexed journals so if the research can not be published in any of them, it is a fair bet that there are problems with it. And as you apply this rule, remember Rule 3: Accept No Excuses! Every quack who can't get his stuff published in a peer reviewed, indexed journal will have lots of excuses about why not. Ignore them all.

Some extra discussion

[d1] I also keep track of predictions, hopes, and plans about these phases. So I look for statements like "this phase-II trial will finish in 2011", or "we plan (or hope) to start phase-III tests in 2009". I don't track these because I consider them progress by themselves (after all, anyone can hope to start something next year). I track them so I can look back and see if the researchers have a history of accuracy in their future predictions.

[d2] Beware especially of researchers who talk about group 3 results because they don't have any group 1 results! Or researchers who have been trumpeting the same group 3 results for years without translating them into group 1 results.

[d3] Although be careful of all of these. Some companies publicize every C-level hire, as though it showed their research was working. Or treat being bought as a sign of success (which is sometimes true, but not always).

[d4] A perfect example of this is Teva, which recently put $10 million into Andromedia which owns DiaPep227. Teva is a large scale producer of generic drugs (maybe the world's largest).

[d5] In general diseases which naturally change are the most subject to quackery and fraud. Type-2 diabetes and Autism are both examples. Both get better and worse over the years for a large number of poorly understood reasons. So this means the quack (or fraud) can sell something and if the patient naturally happens to improve, the quack gets to take credit for it! Type-1 doesn't work that way, because (except during the honeymoon phase) the patient will rapidly get very ill if standard treatment is replaced by quackery. And if quackery is added to regular treatment, most people can keep track of their own insulin use, and realize that it is not helping.

Joshua Levy

Monday, February 16, 2009

Preparing for a Phase-I trial: Curing Type-1 with Lettuce

I admit that the first time I read about this, I thought "But it's not April 1st!". And the second time, I thought it was a new way to produce insulin for treating diabetes, rather than a possible cure for type-1 diabetes. But I was wrong both times: this research is real and is aimed at a cure.

Basically, Dr Daniell (a researcher at the University of Central Florida) is teaching the body's immune system to stop attacking insulin producing cells. Here is a quote from a news article describing how it works:
In Dr. Daniell's method, the lettuce plant cells help the insulin reach the intestine. Once the plant cells get there, bacteria slowly break down the cell walls and gradually release insulin into the bloodstream. This creates an immune response in the body and teaches it to release its own insulin. "It is the same insulin that is injected, but here what we are doing is instead of injecting it in the blood system, we are presenting it to the immune cells and then asking the immune cells to see that this is your own protein," Dr. Daniell said. "What we have done is to teach the body how to cure this disorder. This is a totally new concept, a new platform to use this oral delivery system to fix this immune disorder."
Because Dr. Daniell expects to start testing on people in the next year, I will add this research to the "Preparing for Phase-I Trials" part of my web page. However, here is a blog entry which I did not write, but which pretty much summarizes my opinion of this research right now:

Pay particular attention to the part where Amy points out that giving insulin to mice prevents them from getting type-1 diabetes, but that this same trick doesn't work for people. I'm sure that's why Dr. Daniell is having so much trouble raising the $20 million that he needs.

Here are some news articles covering the research:,0,3036816.story

I will get excited about this research when it works for the first time on people. This is the kind of thing where mice research doesn't prove much.

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:

My quick review is that this data is more of the same, so my previous comments on LCT still apply: (most recent comments) (all comments) (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:
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:

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.