“Our Trials are Totally Different.” The Denise Faustman Interview

There’s no question that Dr. Denise Faustman does things differently.

Dr. Faustman’s research has won her avid fans and raised millions from donors, but it has also provoked significant pushback from major diabetes organizations. Dr. Faustman wears that repudiation like a badge of honor, proof that her work is disruptive and important.

A Maverick Approach

Dr. Faustman takes an unconventional approach. Her work, which is focused on the underlying immune response responsible for type 1 diabetes, has led her to a very old and inexpensive drug, a tuberculosis vaccine used widely in the developing world. It’s a treatment that may have been hiding in plain sight for generations.

Dr. Faustman’s immune intervention trials also concentrate on adults with long-standing type 1 diabetes. By contrast, virtually all of her peers have targetted patients with new-onset diabetes, or even patients that have yet to develop diabetes. This approach is generally considered more likely to succeed, because the targets of the interventions have not yet entirely lost their ability to secrete insulin. But in Dr. Faustman’s telling, it hasn’t accomplished much yet:

“Over the last 30 years, immune intervention trials in type 1 diabetes haven’t had very good outcomes. The important diabetes advances have been different versions of insulin and new forms of blood testing, but the immune intervention trials have been a very sad point. Nothing’s worked very well, no new treatments have been approved.”

“Our trials are totally different. They’re all in people that have had diabetes for decades.”

Dr. Faustman told me that a who’s who of diabetes experts has told that her approach is crazy, a response that has clearly tickled her contrarian side.

“We thought the need is to treat the people that actually have the disease. It sounds like a no-brainer, but keep in mind that nobody else is doing it!”

The decision to study patients with long-established diabetes, which was originally made well over a decade ago, was inspired in part by financial constraints: “we could not afford to do new-onset diabetic trials.” And focusing on an incredibly inexpensive generic drug meant that Dr. Faustman had no way of interesting large pharmaceutical companies and their very large R&D budgets.

“It’s a terrible drug to make money off of.”

BCG

The drug is BCG, the Bacillus Calmette–Guérin vaccine, which was first used a century ago in order to protect patients from tuberculosis. It is considered extremely safe, and is still administered to millions of infants annually, most prominently in the developing world.

BCG first piqued Dr. Faustman’s interest because it was “the only drug in animal models that has worked in established diabetic mice.” Exactly why it worked, though, still requires some unraveling. The results of her Phase I trial – results that were both celebrated and questioned – showed that patients receiving the vaccine experienced impressive improvements in glucose control without restoring insulin production or insulin sensitivity.

Most immune intervention drug trials involve the suppression of immune cells that are harming the body – in the case of type 1 diabetes, the T-cells that attack the pancreatic Beta cells. But the BCG vaccine works the opposite way, not by depleting the immune system, but by putting something else back in.

“BCG adds to the microbiome. It’s actually the tuberculosis organism, inactivated. So you’re putting back in, effectively, tuberculosis. When you revaccinate with this vaccine, the reason it takes a little while is that it gets to your bone marrow and actually resets your stem cells in your bone marrow.”

Why would you want tuberculosis in your bone marrow? Dr. Faustman referred to the hygiene hypothesis, the idea that many autoimmune and allergic diseases are caused at least in part by our excessively sanitary modern world. Myobacterium tuberculosis may have co-evolved with humans for thousands of years, and its absence may therefore trigger immune system dysfunction.

“The absence of this organism has allowed these rogue immune systems to take off and create all these autoimmune diseases. We’re just reestablishing this synergistic relationship to get immune tolerance.”

Because of its many possible effects, BCG has lately become “fashionable” in the research community, Dr. Faustman told me. The old vaccine is being evaluated as a treatment for other serious autoimmune diseases, and it has also been theorized to provide protection against the novel coronavirus that causes COVID-19.

But how does all that help with your blood sugar levels? Dr. Faustman believes that when BCG vaccine “retrains” the immune system, it also causes the immune system itself to begin utilizing large amounts of glucose in the bloodstream.

“What really happens is that their white blood cells now become the regulator of sugar, and have restored sugar transport. So there are underlying defects in type 1 diabetes in the use of the lymphoid system as a sugar regulator, and BCG restores that.”

The Effect

“It’s definitely a game-changer. Our hope, based on the early results, is that it will lower your A1c 10-15%, stably. You can use less insulin, and have better blood sugar control.”

It is, however, a slow process:

“It takes a number of years to have its metabolic and immune effects. We know we need to follow these patients for 3-5 years to get the maximal effect. But it’s got good durability. It’s quite permanent.”

The nine patients that originally received the BCG vaccine for the Phase I trial are still checking in with Dr. Faustman’s lab every six months, and she says that they continue to enjoy dramatic improvements in glucose management.

“Everyone wants to know if we have any [trial participants] off insulin. We have one person off insulin. Normally when he’s on a fairly low dose of insulin his A1c is in the normal range. When he goes off insulin, he no longer goes into DKA, but he goes up to around 7.2%.

“Is it gonna last twenty years? Thirty years? We don’t know yet.”

Sample Size

One of the chief concerns that other experts have raised with Dr. Faustman’s work is the tiny sample used in her Phase I trial: a mere nine patients received the BCG vaccine.

Dr. Faustman is completely unphased by this criticism, arguing that the statistical significance of her results speaks for itself.

“A p-value of .05 is as statistically significant in a sample of 10 as it is in a sample of 200,000. The only difference is, in the sample of 10, everybody responded, and the magnitude of the response was large.

“If you have to design big trials, you have small effects and unresponsive groups. And that’s what you’re seeing in the [rest of the] diabetes community.”

The criticism of her work by major diabetes authorities, particularly ADA and JDRF, doesn’t seem to have phased her, although she admits that it has slowed down the pace of her trials. She quoted one of her most significant boosters, the late Lee Iococca, a rockstar among American executives as the CEO of Chrysler during the 1980s. Iacocca told her, “I love it when they’re shooting the cannons at me. It means I’ve got something good.”

Dr. Faustman continued: “If they didn’t think it was competitive, it wouldn’t matter to them. The fact that they shot their cannons, to issue statements that were not truthful, it shows that it mattered to them a lot, that it was threatening to them.” She believes that the criticism set forth by the ADA and JDRF in a remarkable joint letter was not only misguided but dishonest.

Don’t Do It Yourself

Referring to the BCG vaccine’s long history of safety, Dr. Faustman suggested that there was little downside to her proposed intervention.

I felt an uncomfortable comparison to some of the pandemic era’s health controversies, in particular to the arguments advanced by many in favor of poorly investigated COVID-19 treatments such as hydroxychloroquine and ivermectin. I asked her what she would say to readers that are ready to go get the BCG vaccine themselves, before it’s been evaluated by the FDA. It’s a question she deals with constantly.

About once a month, Dr. Faustman gets a call from a physician, asking confidentially where one might acquire BCG of the correct strain. Sometimes it’s pharmacies attempting to fulfill a prescription, sometimes it’s the patients (or parents) themselves.

“Everyone’s trying to do it in the closet because it’s a safe drug, right? People try to do it all the time. But you should really wait until we get the right strain and the dosing. What we try to say is that if you get vaccinated with the wrong strain of BCG, we’re not sure, when we give you the right strain, that it’s gonna work.”

The BCG vaccine may be easy to come by in countries where it is used frequently, but there’s no telling what strain you’d get and what the effects would be.

For patients that are very eager about BCG, Dr. Faustman recommends registering for one of her clinical trials.

Timeline to Treatment

There’s already a phase II trial underway, which will test the BCG vaccine in adults with long-standing type 1 diabetes. This expands the study size from 9 to over 200; Dr. Faustman expects that good results in a much larger cohort will finally resolve the criticism and controversy that has dogged her for years.

Meanwhile, her lab is beginning its first trial of children with type 1 diabetes.

In an ideal world, she told me, the phase II trial for adults would be followed by phase III, an even larger study which she would then present to the FDA for evaluation. In a best-case scenario, the approved drug could be administered to regular patients in “five to eight years.”

“We’re moving as fast as we can.”

Source: diabetesdaily.com

An Update from the Controversial Dr. Denise Faustman

Remember Dr. Denise Faustman? Dr. Faustman is about as close as the type 1 diabetes world comes to having a celebrity researcher. Her lab, based at Massachusetts General Hospital, has given people with diabetes a lot of hope—and also generated plenty of controversy.

The BCG Vaccine

In 2018, Dr. Faustman’s team released the first results from a Phase I trial of a novel but appealingly simple and non-invasive treatment that could make blood sugar management much easier for patients with type 1 diabetes. The treatment? The bacillus Calmette-Guérin (BCG) vaccine, which has been used to prevent tuberculosis for a century. The BCG vaccine is one the oldest, longest-studied and best-understood vaccines; it is inexpensive and considered very safe. It is administered to as many as 100 million newborns across the globe annually.

The early results were encouraging: patients with type 1 diabetes who received just two doses of the BCG vaccine, spaced four weeks apart, achieved markedly lower A1c levels when compared to a control group. This result was first observed three years after the vaccine administration and continued for the next five years of follow-up. Participants receiving the experimental treatment had an HbA1c of just 6.18%, significantly lower than participants who received a placebo (7.07%). These results understandably created a lot of enthusiasm in the diabetes community.

The Authorities Push Back

The good results, however, also attracted some pushback from important diabetes authorities. The American Diabetes Association and JDRF took the unusual and striking step of co-authoring a joint statement to highlight “limitations” to Dr. Faustman’s research. The study, according to the statement, was minuscule – “nine people at the five-year time point, and three people at the eight-year time point” – and did “not provide enough clinical evidence to support any recommended change in therapy at this time.” While couched in cautious and moderate language, the letter clearly hoped to smother the hype that the BCG study had kindled.

A 2021 profile in Healthline stated that Dr. Faustman has now been “effectively shunned by the research community.” She has had to seek funding outside of the usual sources – something she’s done with aplomb, raising millions from private donors.

How BCG Might Work

Dr. Faustman hasn’t been as much in the news too much lately, but rest assured, she’s still working. And at last month’s ADA Scientific Sessions conference, we received an update to her ongoing work on the BCG vaccine. The team is still learning how and why BCG appears to work the way that it does.

The BCG vaccine is old, but its proposed mechanism in treating type 1 diabetes is new and surprising. BCG does not appear to restore insulin production, nor does it improve insulin sensitivity. So, what could explain the purported improvements in glycemic control?

Many experts have theorized that our immune systems have become less robust because our society is so much cleaner than it used to be. This idea, the so-called ‘hygiene hypothesis,’ also seems like a pretty good explanation for why type 1 diabetes is more common than it used to be. Dr. Faustman believes that the vaccine may help kick parts of the immune system into action, a mechanism that used to happen naturally back when we had a messier society. In particular, BCG helps trigger the proper function of “Tregs,” immune cells that are known to be dysfunctional in people with type 1 diabetes. Over a period of three years, participants in the study saw their Treg function slowly return to normal. This change also causes the immune system itself to burn more blood glucose, a shift that creates big glycemic improvements.

Interestingly, the BCG vaccine seems effective in patients that developed T1D during childhood (< 21 years), but not those that developed the condition as adults.

More Trials Planned

Meanwhile, several other trials of BCG have begun. A Phase II study is happening right now, and will monitor the effects of the treatment in more detail and with more participants; if the good results are confirmed, it could help allay the concerns raised by the research community about Dr. Faustman’s work. In addition, the Faustman lab is targeting a larger pediatric trial, which will test the vaccine in 150 adolescents, some with well-established type 1 diabetes, some newly diagnosed. Perhaps younger patients have an even greater opportunity to benefit.

The appeal of the BCG vaccine is obvious—a simple jab or two that could confer years of significant blood sugar improvements? Who wouldn’t be excited? But it would be best to continue to evaluate Dr. Faustman’s results with caution, given the skepticism of other researchers. Even if she’s right that BCG is a kind of silver bullet that can deliver durable A1c improvements, it will be years before she’ll have the data to make the case.

Source: diabetesdaily.com

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