An Ultra-Rare Disease Drug Developer Tries to Navigate Regulatory Uncertainty

When Stealth Biotherapeutics sought approval for its experimental therapy to treat the ultra-rare and life-threatening condition Barth syndrome, the U.S. Food and Drug Administration said it wouldn’t review its application because it did not consider it having an adequate and well-controlled study that provided evidence of effectiveness. The notice was part of a history of interactions between Stealth and the FDA that that the company said was characterized by inconsistent guidance as it moved from division to division within the agency. We spoke to Reenie McCarthy, CEO of Stealth, about the challenges the company has faced in seeking FDA approval for its Barth syndrome therapy, the lack of consistency it found within the agency, and why this could have a chilling effect on the development of ultra-rare disease therapies if left unaddressed.

Daniel Levine: Reenie, thanks for joining us.

Reenie McCarthy: Thanks. It’s great to be here. Danny.

Daniel Levine: We’re going to talk about Barth syndrome, Stealth’s efforts to develop a therapy to treat it, and the regulatory challenges of developing a therapy for an ultra-rare condition. Let’s start with Barth syndrome. This is known as a mitochondrial disorder. For listeners not familiar with it, what is it?

Reenie McCarthy: That’s a great question to start off with. Barth Syndrome is an ultra- rare genetic disease. It’s maternally inherited. It essentially is a nuclear genetic defect that affects a mitochondrial phospholipid called cardiolipin. So, the way it manifests is severe cardiomyopathy, essentially heart failure, severe exercise intolerance, growth delays, and neutropenia, which is being prone to infection and very limiting from a lifespan perspective.

Daniel Levine: Is this a condition that progresses over time?

Reenie McCarthy: It does progress over time, but it has periods of greater intensity. So, for example, babies, infants, 85 percent of these children die by the age of five and that’s likely due to immediate metabolic stress in infancy. If they survive early childhood, the next highest risk period is puberty. And again, this is a mitochondrial disease, so think about the metabolic stress of growth, which poses a lot of stress on these children, often putting them back into heart failure. And then as they get older, certainly the skeletal muscle weakness and the fatigue are progressive over time. And most of these patients, if they survive early childhood, won’t make it past their third or fourth decade of life.

Daniel Levine: What treatment options exist today and what’s the prognosis for someone with the condition?

Reenie McCarthy: So, there are no approved therapies for Barth syndrome. It is an ultra-disease that affects less than 150 people in the United States. Part of contributing to why it’s so rare is the fact that it is so very lethal in early childhood, even when there are miscarriages due to this disease, for example, as well. So, the prognosis is poor and again, in all cases, this is a life limiting disease. No patients are known to have lived in normal lifespan.

Daniel Levine: How is it generally diagnosed and is part of its small population the fact that we may be missing patients who are out there?

Reenie McCarthy: Possibly. Diagnosis once it’s suspected can be done with essentially just a blood spot. It is a genetic mutation, so genetic testing can pick it up, but it obviously has to be suspected because it’s not on newborn screening panels. Unfortunately, what has happened more times than I like to think about in the small Barth community is that one child will have expired of the disease and then a sibling is born and it’s then expected. So, sometimes it’s really only suspected if it’s known to be a family trait.

Daniel Levine: Stealth is working on a number of different conditions that involve mitochondrial dysfunction. It’s lead experimental therapy is elamipretide, which is in development for a number of conditions, but Barth syndrome’s the lead indication. What is the therapy and how does it work?

Reenie McCarthy: Yeah. So, elamipretide targets the mitochondria, which you’ll remember from your biology classes, is the powerhouse of the cell. Mitochondria are involved in a number of rare genetic diseases, but they’re literally involved in many disease pathologies. Even common diseases like heart failure involve mitochondrial dysfunction. Our compound is targeting a phospholipid called cardiolipin, which is essential for normal mitochondrial structure and function. So again, thinking of this as the powerhouse of the cell, if the structure’s not right, you’re not going to be making enough energy and you’re actually going to be producing too much of a toxic byproduct called oxidative stress. So, our drug essentially stabilizes this key building block of the mitochondria called cardiolipin to normalize mitochondrial function.

Daniel Levine: What’s known about elamipretide from studies that have been done to date?

Reenie McCarthy: Yeah, it’s an interesting development pathway. There’ve been over 150 peer-reviewed publications looking at elamipretide in many different animal and cell models. Again, in diseases as common as heart failure or as rare as some of these genetic mitochondrial diseases in clinical trials, certainly in Barth syndrome, we believe we’ve seen compelling signals, but it’s a very small patient population. We’ve done studies in a larger rare mitochondrial disease called mitochondrial myopathy, where we see that patients with nuclear genetic mutations seem to respond to therapy with improved exercise tolerance. And we’ve seen signs of improvement in vision and dry age related macular degeneration.

Daniel Levine: In October 2021, Stealth received a refusal to file letter from the FDA. This is a notification the agency makes when a company is seeking approval for a novel therapy and it notifies the company it will not review its application. The concern was that clinical studies the company did involve too few patients for the agency to make a determination on the efficacy of the drug. What were the discussions with the FDA leading up to the filing and how extensive were the discussions? What, did the FDA say it would consider as adequate evidence?

Reenie McCarthy: So, our FDA journey, Danny, has unfortunately been quite an odyssey. We started in the division of neurology products in 2019, which is where our IND had been submitted years earlier. They, at the end of a phase 2 meeting, actually transferred our IND over to the division of gastroenterology, which is somewhat unprecedented to have a switch that late in development. Then the division of gastroenterology reorganized into the division of rare disease in medical genetics with an associated leadership change. And eventually in 2020 or 2019, we asked to have a consult with the division of cardiology. So, within the space of two years, we were essentially looking and talking to four different review divisions at the FDA. The guidance was not consistent cross review divisions. Certainly, we’ve had been encouraged to do certain trial designs that then other leaders or other personnel and other review divisions didn’t like. At one point we were told that we should submit the NDA by the division of cardiology because it would essentially be unethical to conduct another clinical trial in such a rare disease, it’s almost impossible to generate the level of rigorous evidence with so few patients that the agency would typically want to see. But then two weeks before our scheduled NDA submission date, we were contacted by the agency and told “no, we think you need to do another pre-approval placebo controlled trial. So, there’s a lot of back and forth in kind of mixed messaging, different guidance about different trial designs. I do think that as we sit here today, we continue to treat these patients over time. This was open label at this point, and some of the signals in objective endpoints like cardiac endpoints, are reaching levels of significance that the agency is essentially articulating a path forward on an accelerated approval basis. But it’s definitely been a long journey.

Daniel Levine: It strikes me that that’s a fairly unusual path to be tossed from one division to another. What was the justification for doing that?

Reenie McCarthy: So, the division of neurology products told us that they thought that the division of inborn errors of metabolism and gastroenterology would be a better division for this program. Certainly, we have had recent approvals in that division with Brineura. We were, again, similarly looking at an ultra-rare patient population exploring the use of things like natural history controls for them. So, that was the rationale we were given for the first switch, which took us completely by surprise. And it does cost time and delays, as you can imagine, when you’re switching to different review divisions. Then there was an internal reorganization of that division into rare disease and medical genetics and some leadership changes that occurred. For us, we requested the consult to cardiology because we were seeing this emerging cardiac signal, which we thought would be better interpreted by heart failure specialists. But you’re right, it’s very, very unusual.

Daniel Levine: We’ve seen therapies for ultra-rare diseases approved. You mentioned Brineura. That’s one examples. Zokinvy is another for Progeria that comes to mind. These studies involve around 25 patients. If I remember correctly, why was the company unable to do a larger study?

Reenie McCarthy: So, we did a placebo controlled crossover trial, which enrolled 16 patients with Barth syndrome. That study was recruiting over a year. At the end of the day, the principal investigator who is at one of only two global worldwide clinics for Barth syndrome, her perspective is that we enrolled the only 16 patients who would’ve met study inclusion criteria. So, there just aren’t very many of these patients. It’s very challenging to recruit patients. And at the time there was another clinical trial of another old drug repurposed that was being run in Europe. And so, the ex-US patient population was also fully utilized. So, I think that was part of our challenge.

Daniel Levine: In the absence of conducting larger studies, were there discussions about using things like natural history comparators or synthetic patients?

Reenie McCarthy: Yeah, we did do a phase 3 natural history control trial where we took the data from our open-label extension patients and we prognostically matched in, as robust a fashion following FDA guidance as you can imagine, to historic controls. And that trial met its primary and most secondary endpoints showing a greater than a hundred meter improvement on six minute walk test, which was essentially, a more than 25 percent improvement for these boys from their baseline, improvements in strength and  in balance, as well as improvements in cardiac function. The FDA’s dislike of that design in our setting, which marks a departure really from the precedent set in Brineura, was that most of our endpoints were effort dependent endpoints, right? If you try harder, for example, maybe you can walk further. And so, the FDA felt that you can’t ever control for placebo effect with natural history controls. And that was the reason that they didn’t actually even cite that study, which did meet its endpoints, in the refusal to file notification.

Daniel Levine: Did the FDA offer you any path forward other than doing a larger study?

Reenie McCarthy: At various points in time and repeatedly we were encouraged to take the patients remaining on open-label extension off drug in a randomized withdrawal trial. When we agreed to do that study, before even submitting the NDA, [it was] during one of the times when FDA said, submit that, no, don’t submit, we agreed to run that protocol. And again, we were at that point in a different review division and the FDA said that that study design would not be informative, and so we shouldn’t conduct that trial. So no, at the end of the day, the FDA did not give us a different path forward. So, we got the refusal to file notification, and we met with the FDA again about really trying to come up with a new placebo controlled pre-approval trial design. But even then, the powering expectations we were discussing with the agency led us to conclude that we really wouldn’t be able to recruit or complete that trial in any reasonable time period. And we have to pay for these trials. So, there has to be some investment thesis behind this, which was getting increasingly challenging. That’s really where, when we closed out the open label extension, saw a much more significant improvement with longer therapy and heart function, and went back to the agency to talk about accelerated approval, which is where we are now.

Daniel Levine: Given this is a condition with fewer than 150 patients in the United States and Stealth is looking at other indications for elamipretide, why start with Barth syndrome? Why not pursue one of the larger indications first?

Reenie McCarthy: Yeah, it’s a great question. I think this was a situation where we were approached by patient advocacy in 2014 and again, by the only multidisciplinary center, which is John Hopkins in the U.S. that treats this disease. And they both independently asked us to do a trial in Barth syndrome. The genetic defect in Barth syndrome directly affects cardiolipin, which is the target of our drug. And our perspective at the time was we can do a small clinical trial, this is a single center trial, and if it doesn’t work, we have a number of other indications that we’re also pursuing where you’re doing a more traditional path of phase 1, phase 2, phase 3 clinical trials. We kind of got stuck in this situation where we didn’t see statistically significant results in the original placebo controlled treatment period. It was too short with three months, but we were hearing about life-changing impact of the drug with longer term therapy and open-label extension. For example, the investigator has sort of graded five of the eight patients who continued into the open-label extension, over the long term is no longer having any signs or symptoms of disease. They’re able to do things like go to school or work after school jobs or even full-time jobs, which is somewhat unheard of in this disease. And so given that, it was very hard to walk away from the patient population, which is what brought us into this regulatory journey.

Daniel Levine: We’re in this emerging age of precision medicine, the conditions you’re pursuing for elamipretide all involve mitochondrial dysfunction. Is there any way to combine patients with different diseases and define the common mitochondrial dysfunction to demonstrate improvement that way?

Reenie McCarthy: It’s a great question and we’ve tried that. So, if you think about a disease like heart failure or diabetes, the reason we need such huge clinical trials is there’s always variability within patient populations. The same is true even in ultra-rare diseases like Barth syndrome. So, you’re even more concerned about a homogenous patient population when you have so few that you’re treating because the way stats work, you don’t have much room for variability. I think it is hard to introduce too much heterogeneity into these trials in the setting of mitochondriopathy, which is skeletal muscle weakness, exercise intolerance, and fatigue due to either mitochondrial or nuclear DNA mutations affecting the mitochondria. We saw that heterogeneity in the phase 3 trial where one subgroup of patients with mitochondrial DNA mutations really had a very large placebo effect. And it nullified the drug effect in that phase 3 effort that we made. So, we did try that by putting different patient populations together. I think our lessons learned coming out of that trial because we did see a response in a subgroup of patients with nuclear genetic defects and we’ve been able to take those learnings and design a new phase 3 trial, which is enriched for responders. So, you can learn from it, but those are painful lessons to learn in the clinic.

Daniel Levine: What’s the path forward in Barth syndrome for Stealth?

Reenie McCarthy: We’ve seen with patients who remained in the open-label extension until the time we closed it out after four years, a more than 40 percent improvement in heart function for patients with Barth syndrome. We know from the natural history of this disease that that heart function and particularly stroke volume and diastolic volume both decline over time. And so, they have a very small amount of blood that they’re actually pumping out to profuse their organ systems. And that likely contributes to the progressive skeletal muscle weakness, exercise intolerance, and fatigue for these patients, which does worsen as they grow older. So, for us to see a 40 percent improvement over time that is significant. And the FDA has suggested that that may open the path to an accelerated approval. There is work to do though, even for accelerated approval. The FDA wants to make sure that you’ve properly defined your effect size. That will require us to re-benchmark this potentially to natural history controls. And they also want to understand how to design a phase 4 clinical trial so that we know how many patients to enroll. So, we’re doing some work right now to essentially conduct those modeling exercises in conjunction with ongoing discussions with the division of cardiology. I would say that, again, we’ve had a tough FDA experience and a lot of inconsistent feedback from different review divisions, but I think the division of cardiology is trying to find a path, and they have met extensively with patient advocacy as well to better educate their teams about this rare condition.

Daniel Levine: How unique is the problem Stealth faces with the FDA?

Reenie McCarthy: I don’t think it’s unique. I think that this is a significant challenge in ultra-rare drug development. You do have divisions in the FDA that are more willing to use the accelerated approval pathway, the division of oncology, for example. But you have different divisions with different perspectives on that, and even different individuals within different divisions who have a lot more concerns about the FDA’s track record, as it were, in enforcing post-marketing commitments, and so, there is this reluctance to rely on that pathway. I do think you have inconsistent answers with different people in different divisions in the FDA, and I think that this is very chilling for ultra-rare drug development. You know, we’re in this situation where there’s so many uncertainties. This is the first therapy that’s ever been tried for Barth syndrome. There’s no regulatory pathway defined, there’s no biomarkers defined. There’s no previous clinical trials that have been done. And so, you’re kind of tilting at a lot of different windmills and to add regulatory uncertainty into the mix, it’s potentially chilling, again for the development of ultra-rare diseases.

Daniel Levine: Well, as a CEO making decisions about what drugs to advance in a pipeline, how does this possibly change the thinking about pursuing an ultra-rare indication?

Reenie McCarthy: I would think twice about it for sure. I mean, we undertook what was a fairly discreet development effort in this disease, and we ended up with results that were too compelling for us to walk away from with good conscience. We do have rare pediatric designation for this product for this indication. So investing some additional time and effort on regulatory activities and even natural history type studies was justifiable. What isn’t justifiable, what I don’t think we can raise financing for, is another pre-approval clinical trial. And certainly, I would think twice before, moving into a similar situation again.

Daniel Levine:  What’s the solution? How can the FDA do its job to ensure the safety and efficacy of therapies while making a viable pathway for ultra-rare disease drugs?

Reenie McCarthy: So, from a safety perspective, we’ve heard from the FDA that if the FDA could take risk versus benefit into consideration the way Europe does, quite frankly, with some of their approval pathways, that there wouldn’t be an issue here. Because the safety profile of elamipretide has been fairly well characterized. We have mild to moderate injection site reactions. It’s a once daily injection. And so there really isn’t a safety concern here. I think it’s the efficacy side of the equation. And you have this situation where there’s a concern about type 1 versus type 2 error with the FDA, really looking for strong efficacy signals that, again, we’ve heard from senior FDA officials that it is as unethical to require placebo controlled trials meeting traditional P values in ultra-rare diseases as it would be in the cases of situations like anthrax, where you use the animal rule to potentially approve drugs. So, I think there’s a recognition within the agency that the efficacy standards are really, really challenging to meet in these situations. I just think that there’s a little bit of consternation about how, to your point, they can navigate that and still comply with their statutory standards. Certainly, some of the new proposals for accelerated approvals are both giving the FDA a little bit more teeth in terms of their enforcement power, which should address some of the concerns the agency has about using that pathway. But there’s also a proposal to have a centralized oversight within the FDA so that there’s broad awareness of drugs that go through that accelerated approval pathway to ensure better consistency. I think that consistency is key, like better consistency across different divisions and different reviewers within the FDA would certainly as a CEO allow you to calibrate your risks much better.

Daniel Levine: Reenie McCarthy, president and CEO of Stealth Biotherapeutics. Reenie, thanks so much for your time today.

Reenie McCarthy: Thanks, Danny. It was great talking to you.

This transcript has been edited for clarity and readability.