Mass. General Launches Trial Of Old TB Vaccine For Type 1 Diabetes

Type 1 diabetes, the autoimmune form that usually strikes young people, is big and getting bigger: As many as 3 million Americans may have it, and their numbers are growing quickly and mysteriously.

So any promise of potential progress is a big deal, and it was splashy news back in 2012 when Dr. Denise Faustman, director of the Immunobiology Laboratory at the Massachusetts General Hospital, reported positive results for a test of a tuberculosis vaccine called BCG — Bacillus Calmette-Guerin — in a tiny trial of three longtime diabetes patients. Of particular appeal: BCG has been around for nearly a century, has been shown to be safe and, long since generic, is also cheap.

Now, Faustman has just announced the launch of a far bigger human clinical trial, aiming for 150 patients from ages 18 to 65. Though BCG is known as a vaccine, the trial will use it not to prevent diabetes but to try to reverse the disease — at least partially — in patients who already have it.

Dr. Faustman's research, funded mainly by the Iacocca Foundation, has been considered somewhat controversial, so the results of the new trial — which is expected to last five years and is a "Phase II" trial to assess how effective the treatment is — could lay that debate to rest.

Our conversation, lightly edited:

So how do you see the headline here? And should it begin 'This is not a cure'? What's your main message to the public?

I think the main point of what we’re doing is: These are the first trials trying to intervene immunologically in people with long-standing autoimmunity and trying to reverse the disease, but doing it with a cheap, inexpensive, hundred-year-old drug.

But how would you calibrate the promise, or hope, of how well this might work for people?

It’s interesting because these trials, although we were kind of the first in the world to start in Phase I, they’ve caught on, on a global basis — using repeat BCG in diverse autoimmune diseases, such as multiple sclerosis, such as Sjögren’s disease. So, although we were kind of lonely to begin with, suggesting this hundred-year-old drug might have major therapeutic impacts, we’re not so lonely anymore. In fact, in Europe, there are Phase III trials going on in multiple sclerosis.

So, we're seeing clinical effects in patient populations where people thought it wasn’t possible to reverse or partially reverse a disease. So we’re pretty hopeful that this inexpensive way might make a significant dent on the clinical course of a disease and do it at incredible cost savings to the public.

So, does that go as far as possible 'cure'?

Well, how do people define cure? If I said we’d be elated to prove in a Phase II that we improved glucose control, people would say, 'That’s impossible. It’s never been done before, especially on a long-term basis.' But that’s what we’re striving for, actually; really tough endpoints in Phase II, based on the promise — the global promise — of this drug now in large population studies.

So you're saying it could significantly impact the disease?

We immunologists always like seeing bad T-cells die and good T-cells proliferate, and the pancreas making a little bit more insulin measured by C-peptide — but patients could care less about that, right? Patients are interested in what’s called hemoglobin A1c: What’s my average blood sugar control? And in these Phase II trials, we’re going to use that as a tough end point, because of what we see is happening with these vaccinations.

When you say a tough endpoint, what level of improvement would satisfy you?

Every patient knows this, and certainly every physician knows this: If you lowered your hemoglobin A1c by 50 percent, there is global data that you would cut complications by over 50 percent. So lowering your hemoglobin A1c has a huge impact on the clinical course of the disease.

To back up a little, we tend to think of vaccines as preventive, but you're talking about treating a disease that already exists. Why call it a vaccine?

Well, we could call it a drug, but when you’re dealing with something a hundred years old, that’s probably dressing it up too much. And I always think of a drug as something you give every single day, or you have to take every single day. Vaccines can be preventative; they also can be used for treatment. The big clinical example in treatment is cancer vaccines, which are in the news all the time. I think of a vaccine as something you give not too frequently, and that it’s injectable, and it might have a long duration of action beyond the administration time.

And it acts on the immune system?

Absolutely. We worked 20 years at discovering that Type 1 diabetics, as well as people with other autoimmune diseases like multiple sclerosis and Sjögren’s disease, have a deficiency of a hormone — it’s kind of a hormone, it’s called TNF, in scientific terms it’s called a cytokine.

And so we said, 'OK, how do we give back TNF? Do we go out and manufacture TNF?' You can’t buy it in Mexico. It’s not manufactured. And then we realized there was an old-fashioned vaccine that was developed for tuberculosis prevention over a hundred years ago. When people, normal people, let alone people with autoimmune disease, get that vaccine, they make TNF, they make more of this missing hormone. So we said, let’s do it the cheap way, the safe way, and use a vaccine to induce a hormone in you that would be very beneficial.

To make a very long story very short, how did you figure that out?

Yes, it was a 20-year story — most science doesn’t fall from the sky. But once we realized we needed to boost TNF, then it’s kind of a more set project, looking at drugs that might boost TNF. So you could create a new drug; you could give TNF itself; or, if you’re in an academic setting, the other way to look at it is what’s out there that you can use that was safe already. So that’s how we ended up on the BCG vaccine.

So did you do massive drug screening?

Generic drug screening — absolutely. And then when we got done, we said, 'Oh my gosh, everybody’s known this for years. Why don’t we just go for the cheap, safe one, so that we don’t get bogged down in long manufacturing, and we don’t get bogged down in having to do lots of primate studies because we know this vaccine is impeccably safe?'

I love it when there's something already on the shelf...

I know, though not everybody loves that, I should mention.

So you've just begin enrolling patients in this new bigger clinical trial?

Yes, We’d love to have people contact us. It's 18 years old to 65 years old, at diabetestrial@partners.org. They have to come in and then we have to check to see what stage of Type 1 diabetes they are. They can’t tell; they won’t know.

In terms of clinical trials, I usually think of Phase I as being just about safety and Phase II as starting to look for whether the drug works. But is that what's happening here?

Well, in Phase I we did two things. It’s a hundred-year-old drug, but it’s being used in multi-dosing and used in a patient population, so we still did a Phase I. But in Phase I we also established what we call biomarkers, which means blood tests that tell us that the drug is working. And those were blood tests that allowed us to say, 'Do we see this drug killing bad T-cells? Do we see this drug inducing good T-cells or good white blood cells?' So we developed those biomarkers, so now as we go into Phase II we’ll look for efficacy, a clinical effect.

Any more caveats for the public?

I think the diabetes community has been upset for a long time because they realized most intervention trials are in people who just got diabetes yesterday, or the day before, or three weeks ago. And then when they log into diabetes trial websites, they realize that most of the trials are not being designed for them. And certainly the people with Type 1 diabetes are the major people with the disease.

And so this is kind of nice that because these are nonprofit, philanthropically supported trials, we’re actually taking the big step of trying to intervene in people who most need a therapy that would result in a better clinical outcome. So that’s step number one.

And then step number two is, unlike a lot of intervention trials, where the drugs being tested are pretty toxic, might make you pause a little bit, we have a hundred years of safety and 4 billion doses to know that this drug is pretty safe; it’s probably safer than any drug that you get from your pharmacist. More people have seen it over a hundred years than any drug sold by CVS.

So then the question is: Can we get it to work well enough to have a clinical impact? And so we’re pushing those barriers in Phase II to go for really tough clinical outcomes, so we move forward in this trial.

And if it's successful, no one's going to make a lot of money off of it, right?

Yeah. That’s a problem, right? And also what will it do? If it prevents complications, then what markets will it impinge on?

Type 1 diabetes alone is a $17-billion-a-year treatment industry. So, if we can develop something that helps to normalize hemoglobin A1c's that’s a vaccine and infrequently administered, it’s a good day.

What we all know is, it’s kind of like insulin. Insulin was discovered in 1920, with pig insulin. And it was, I don’t know, $10 for a week. Well if you really can figure out mechanism and can intervene, then we know what will happen: The pharmaceutical industry will go, 'Wow, that’s amazing. Now we’re going to make the next, more high-class biologic.' But it’s our goal to see if we can get over that barrier and then we hope everybody pounces on it and tries to make the next 10 better drugs on the pathway.

Your work has been out to the general public since that study in 2012, have you heard about people just trying to go out and get the vaccine?

Well, off-label use of drugs does happen, and it’s probably happening more in Europe, although Europe — where there’s a bigger emphasis on developing cost-saving drugs that change complication rates — has more trials going.

In the U.S., you literally can’t get BCG right now. There was an article in the Wall Street Journal just this week on how the two major companies that were manufacturing it had major manufacturing violations in the last four years, and you can’t get it. It’s used also at high dose for bladder cancer.

But still, are people going to fly to Mexico? Are people going to fly to Brazil? That’s a possibility, but what we keep telling everybody is that we’re actually, for clinical trials, moving pretty fast. It’s not like trials that have to move slowly because of concerns of safety. Our goal here at Mass. General Hospital is to get it through licensure as fast as possible so it’s available to all.

And it’s not a privileged therapy. I used to work in the field of islet transplants. And that’s kind of a privileged therapy; some people are going to get it, and some people aren’t. That’s not the case here. If we’re successful, it will be available for all very rapidly.

How soon could that be?

We’ll see. It’s always based on the FDA scrutinizing the data. What’s the impact of the effect of the drug? If the impact is little, then you go to a Phase III trial, so that slows things down. But, if the impact is great, there are ways to move the drug forward to the public at faster rates.

So this trial is five years...

I hate guaranteeing or promising, but five years is not unrealistic.

And trials are all about testing it, right? We’re excited about it because it’s safe, and we’re trying to develop something for patient populations that didn’t have alternatives, but the data will be the data. These are double-blinded, placebo-controlled trials with full FDA oversight, so we’ll get an answer and it will be a real answer.

So it will be 150 patients enrolled, but half placebo?

Actually, two to one. We always try to bias it so more people get the drug than don’t get the drug. What we also do is, if you’re in the placebo group — because you’ve spent a lot of time with us — at the end of the trial, if the drug shows promise and you now want the drug, we’ll make it available to you, so that you don’t feel you got randomized and got gypped. We think that’s the most fair way to do trials.

Last question: How would you sketch out what happens in your body in relation to BCG?

We all know the incidence of autoimmunity globally is going up. We didn’t have so many peanut allergies in schools 20 years ago. Something is different. The most basic way to think about it is that humans evolved, even Neanderthals evolved, with a huge synergy with mycobacteria — that’s BCG. And so what’s happened in the last 20 years is that your water’s now purified and you’re not drinking mycobacteria. It’s literally in the dirt in your backyard — you’re no longer plowing a field getting exposed to mycobacteria. You’re no longer milking cows getting exposed to mycobacteria. And furthermore every strawberry and blueberry you eat has no dirt on it.

So you’ve taken away this organism that’s very synergistic with your immune system. When you have mycobacteria in you, you make more TNF, that hormone that you need. So as you clean up your environment – you know, the people that have a spray can of Purell, sterilizing every high chair for their toddlers – you are now taking away one of the good bugs that help mold your immune system. So if you think of it in really lay terms, we’re putting back in something that you interacted with from the dirt for the last million years. And so it’s a benign bug and we think it has major impact on immune responses.