RARE Daily

A Plea to the FDA to Give an Ultra-Rare Disease Drug a Fair Hearing

October 12, 2023

In 2021, the U.S. Food and Drug Administration notified Stealth Biotherapeutics that it would not consider its application seeking approval for elamipretide as a treatment for the ultra-rare mitochondrial disease Barth syndrome. The agency wants the company to produce evidence of the drug’s efficacy in a larger population of Barth syndrome patients then it studied, but the company believes it has exhausted the population in the United States of patients who fit the clinical trial criteria. Patients have lobbied the agency to give the drug a hearing, but there is growing concern that if the FDA fails to act, elamipretide will become unavailable to patients, who say the drug has given them the ability to lead a normal life. In an effort to move the FDA, Shelley Bowen, co-founder and director of family services for the Barth Syndrome Foundation, launched a Change.org petition calling on the agency to give a full and fair hearing to the drug. We spoke to Bowen about Barth syndrome, the fight over approval for the first drug to treat the condition, and why it points to a systemic problem with the lack of consistent use of the flexibility Congress granted the FDA to get treatments to patients with ultra-rare diseases.



Daniel Levine: Shelley, thanks for joining us.

Shelley Bowen: Thank you for inviting me to be here. I appreciate it. I’m a fan of the podcast.

Daniel Levine: Thanks. We’re going to talk about Barth syndrome, the problems of getting the FDA to recognize the value of an experimental therapy for an ultra-rare population without therapeutic choices, and how advocates are pushing the agency to review a drug they’re refusing to consider at this time. Perhaps we can begin with Barth syndrome. For listeners not familiar with the condition, what is it?

Shelley Bowen: Barth syndrome is an ultra-rare condition that primarily affects boys. The gene responsible for Barth syndrome is located on the X chromosome. We do know of girls who are affected, but rarely is that the case. The incidence was investigated a few years back and published in Pediatrics and estimated to be one in a million males. Currently we know of 134 in the United States and 283 worldwide. So, it’s ultra, ultra-rare. It is frequently fatal. Our statistics that we look at, basically from people that we’ve been in touch with over the years, and we started the organization in 2000, we started tracking everybody that we were in contact with. But 20 percent of those that we know die by the time they’re two, 45 percent by the time they’re 16, and 75 percent die by the age of 30. I have lost two boys from Barth syndrome. One died when he was four and my other son Michael, died when he was 23. And the leading causes of death, Danny, are cardiac related, so arrhythmia, heart failure. Cardiomyopathy is a cardinal characteristic of the condition, or sepsis. These kids can have neutrophil counts of zero. They have neutropenia, I should have said that they have neutropenias, another cardinal characteristic, but with a neutrophil count of zero, it leaves one at risk of becoming overcome by a fungal or bacterial infection and cardiomyopathy.

Daniel Levine: You mentioned that you lost two sons to this condition. How were they diagnosed and what were you told at the time?

Shelley Bowen: Well, this was back in the pre-gene days, right? So my boys were very, very, they were very small. They had cardiomyopathy. We weren’t sure what was going on. This is back in the eighties. Dr. Barth had originally described the disorder in 1983 in a publication. We were told by a geneticist that we think that this is genetic. I remember reading an article years ago, and this is back in the days where in a paper and going to the medical library, and he sent me a copy of the article that had been published and for the first time I felt like—this was in 1990, and I felt like if somebody can characterize the condition, somebody can do something about it, even though it was described as being fatal. Unfortunately, two hours after I read that publication, my son Evan died and I went home not knowing what the future would be for my son Michael. I traveled to Amsterdam to visit with Dr. Barth in 1996 and I had been told that everybody with Barth syndrome was gone, had died. But Dr. Barth encouraged me to find other families, and this is before internet, and somehow when I finally did search, and searched and searched on the internet, finally found somebody in 1998 and built a website and for the first time we rallied together and my son was not the only one living with the condition. So, we decided early on that we were going to do something about this because we were tired of having people die and it being so rare that nothing was being done about it, because to us it was our children meant everything in the world. So, we decided then that we were going to do something about it and we are committed to do something about it still today.

Daniel Levine: What happens as this condition progresses?

Shelley Bowen: Well, the cardiac function, what we have learned in the natural history is that the cardiac function does decline over time. So it is progressive, it is being appreciated now as being a progressive condition. What I see, to put it in lay terms is that what I see, my father had Parkinson’s, and the fatigue that I see in these kids and young men really mirrors what I saw with Parkinson’s with my father. It’s not that you have to take a nap or you have to sleep in order to recover. It’s that you literally, your body is heavy, it gets heavier and it takes more force and more energy to move and ambulate and just to exist. And if you push yourself beyond your limit, you can get sick and you’ll spend a lot of time trying to recover. So the recovery time is really difficult for these kids. They typically become deconditioned because if you know that you’re going to get sick, if you push yourself too far, you don’t do it. So, fatigue is the most debilitating aspect of this condition and this is something that we learned through listening sessions that we have conducted with our group as well as our PFDD meeting, which we hosted in 2018.

Daniel Levine: And what’s the prognosis for someone with a condition today, and are there treatment options at all?

Shelley Bowen: Well, as I mentioned the fatality statistics earlier, it’s not good—75 percent fatality by the time you’re 30 is horrible. And looking at potentially having debilitating fatigue and having to use a walker or some kind of an ambulatory device in order to get around by the time you’re 40, that’s not ideal. So the prognosis isn’t great. So no, and there are currently no treatments available for Barth syndrome, which is what makes us so upset about where we are right now with a drug that has been proven to be safe. And from the people that we know who have taken it, they believe that it is effective and these are people who are living with a condition.

Daniel Levine: In January 2023, we featured Reenie McCarthy, CEO of Stealth BioTherapeutics, and I encourage listeners to go into the archive and listen to that episode, but Stealth is developing an experimental therapy elamipretide. It’s had a twisted path. The agency has passed it around with various divisions and provided it with inconsistent direction. It’s refused to review its application seeking approval. Without giving a blow by blow history, can you explain where the company and patients who need this drug find themselves today?

Shelley Bowen: Well, I can’t speak to what the company is doing. And I agree, I would encourage anybody to listen to your January podcast with Reenie. I do know that the company has truly been allies with us in trying to get this across the threshold with the FDA. We have engaged with them, as well as with the FDA because we know that people are waiting for this to try [it]. They want options. And this is a drug that people who have taken it have said has made a huge difference in their lives. So our community is committed to try. They are willing to take the risk that something doesn’t work. We’ve done videos, we have submitted, we have had meetings with the FDA saying just that yes, we are willing to try, particularly if something is found to be safe, which in this case it has been, and we just can’t come up with more patients. It’s rare, Danny, it’s one in a million and maybe there’s 150 people in the United States. There are no more people to recruit. And this is our frustration is that we feel that even though the FDA has said that the patient’s voice matters, we’ve spent a hundred thousand dollars on our externally led patient-focused drug development meeting, and we don’t see any transparency that the patient’s voice has come into—been weighed in at all in this process. And we have had multiple listening sessions and been in contact frequently with the FDA and we don’t see where that’s been heard.

Daniel Levine: The agency, I’d argue, has shown a willingness to be flexible when it comes to ultra-rare diseases. But this is a drug that’s wound up in the division of cardiology and nephrology at FDA. Is it true this is a division that has never approved a drug for a rare pediatric heart condition and only approved four rare disease drugs?

Shelley Bowen: It is our understanding that that is the case. That’s where our frustration lies with the inconsistencies across the various divisions of the FDA. And yes, there are certainly examples wherein precedents where the FDA or some divisions have exercise flexibility or they’ve been given the authority to look at ultra-drug indication somewhat differently than they would with larger indications, and we just don’t feel that this is happening with this indication and it’s to do another study. It is just baffling. It’s just absolutely baffling, and it’s safe. This drug is safe.

Daniel Levine: And to reiterate something you mentioned before, my sense is it’s not an unwillingness to do a larger study, but there’s just no more patients to study. Is that correct?

Shelley Bowen: They aren’t there. I mean just to say, go out and find more patients, which is what we have been told to do, is incredulous, incredulous. We don’t want anybody to be diagnosed with Barth syndrome. If there are others who are out there, we would love to know about them, but one in a million, if you do the math, they’re not out there. We don’t have the numbers. And we recruited 10 percent of our population, 10 percent of the people we know participated, and that’s even before you even consider inclusion and exclusion criteria. That’s a lot.

Daniel Levine: Is it understood what the drug does?

Shelley Bowen: I think that I would really lean on our key opinion leaders and our principal investigator who was involved in the study to answer that, or perhaps Reenie.

Daniel Levine: You launched a change.org petition in September to ask the FDA to review the drug and give it a fair hearing. What’s been the response?

Shelley Bowen: Well, we just launched it and since then we have over 18,000 signatures on the petition, which in comparison, we launched an earlier petition where we received 4,200 signatures. Currently we have 18,000 on this petition asking the FDA to just look at all of the data. We’re not saying we demand that you approve this, but we believe that the data will stand up on its own. And we believe that looking at all the data, including the open label extension data, will prove that this drug has made a difference, that the improvement that has been reported for the cardiac function has never been seen before. And this is something that it can’t be denied. Just look at all of the data, look at all of the data.

Daniel Levine: What’s the plan to move this forward? How do you get the FDA to change its mind?

Shelley Bowen: Well, we’re reaching out to them and we are appealing to the sense of reason and asking them to look at all of the data, recognizing that this is an ultra-rare condition and please look beyond the numbers, recognize that it’s safe, recognized what it’s doing. Also, there is one particular case that we have highlighted in our petition about a baby who was taking the drug. And I can tell you I’ve been doing this for a long time, since 2000. So, I have never known of anyone to go on a VAD—on a ventricular assist device—or a Berlin Heart, in this case, and improved to the extent that they have done so well that they can have it ex-planted and go home with their native heart. Generally, somebody dies when they’re on a VAD or they have to have a transplant, but this child has gone home with this native heart, with a normal cardiac function, and this is a baby. A baby can’t have a placebo effect or a bias. He doesn’t will himself to get better. And this story is outlined in our letter to the FDA.

Daniel Levine: If the agency holds to its position, what will happen to elamipretide? Do you expect Stealth to continue to pursue it? I mean, as committed as they may be to the Barth syndrome community, they have obligations to shareholders. They have other products in development. What happens to this drug?

Shelley Bowen: Well, unfortunately if the agency does not approve it, or even if they refuse to file the application within the timeframe that is allotted, it is very unlikely that anybody who is currently taking the drug, including this baby that I just told you about that has had this remarkable recovery, will no longer have access to it. We have people who are working now full-time and doing well and thriving who have lived with Barth syndrome their entire life. I’ve heard it said when somebody asks you what is it like to have named the condition, in this case Barth syndrome, what is it like? Somebody can’t say this is what it’s like because they’ve never known what it’s like to be healthy and not have Barth syndrome. In this case, people who are taking this drug now know what it’s like not to have Barth syndrome and feel like they can do things. They can stay up with their families. They can do things that we as healthy people may take for granted. And to be told that you are going to have that taken away from you and you’ve got to go back to living a life that is compromised is just, I can’t help but get choked up when I think about it because you think about how could you do that? How can you do that? But the company isn’t going to be able to continue to offer it if the FDA doesn’t look at the data and doesn’t approve the drug.

Daniel Levine: Beyond the patients who need this drug, what’s at stake? What are the consequences for drug developers pursuing treatments for ultra-rare diseases and patients waiting for these treatments?

Shelley Bowen: Well, it’s our concern that we’re already seeing a number of companies that are pulling out of their ultra-rare drug pipelines. As you know, this is a tight-knit community. And so, if a drug company pulls out of an ultra-rare pipeline or rare disease pipeline, it affects all of us. It affects people we know and we realize that other conditions, there are other conditions where people are suffering. When you consider the cumulative number of Americans that are affected by rare and ultra-rare conditions, that’s a big impact. And I think there’s already a chilling effect on what we’re looking at in drug development for ultra-rare conditions. So, this is a fight that’s bigger than just elamipretide. This is the fight that is about, there needs to be to be better processes in place at the agency to review indications for ultra-rare conditions and give people the opportunity to have therapies where they can improve their life. There are precedents where it has happened in other drug indications for ultra-rare conditions. It just shouldn’t be luck of the draw as to what division you get assigned to.

Daniel Levine: Shelley Bowen, co-founder and director of Family Services and Advocacy for the Barth Syndrome Foundation. Shelley, thanks so much for your time today.

Shelley Bowen: Thank you, Danny.

This transcript has been edited for clarity and readability.

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