Difficult. Impossible. Agonizing. Worse than voting in the national election. All those descriptors were used today by FDA advisory committee members when asked to vote on an investigational rare disease therapy.
The Cardiovascular and Renal Drugs Advisory Committee voted 10-6 supporting Stealth Biotherapeutics’ elamipretide for treating Barth syndrome, an X-linked genetic disorder that weakens the heart and other muscles.
The independent committee is designed to assist the FDA as it considers an application, with a decision for elamipretide expected on or by Jan. 29, 2025. The agency is not bound by the vote, but it typically follows the outcome.
The injection has snagged priority review and, if approved, would be the first therapy for Barth syndrome (BTHS) to hit the market. Elamipretide has also nabbed orphan, fast track and rare pediatric tags for the ultra-rare syndrome, which impacts around one man per million men.
On Oct. 8, the FDA released briefing documents ahead of the vote arguing that Stealth’s data package likely isn’t enough to snare approval, even via an accelerated pathway. The agency considered data from a phase 2 study, an open-label crossover follow-up, and a phase 3 trial evaluating elamipretide’s effect in a distance-walked test, among other things.
The midstage study, known as SPIBA-201, was a placebo-controlled trial that failed to hit the primary goal of improving average distance walked. The measure assessed 12 male participants after 12 weeks of once-daily treatment, revealing a walking distance of 443.1 meters for patients receiving elamipretide compared to 443.9 meters for patients on placebo. The mean increase from baseline in distance walked was 43 meters in the elamipretide arm versus 31 meters for placebo, a difference that was not statistically significant (p-value of 0.5).
The original application for elamipretide—that’s right, this isn’t the first time Stealth has requested approval—was tied to a phase 3 study, called SPIBA-001, that enrolled treated patients from the SPIBA-201 trial and the open-label extension phase, plus previously untreated patients. The trial met its main goal, but the data were compared to the open-label portion of the phase 2/3 crossover study and natural history controls—a strategy the FDA did not like.
Back in 2021, the FDA had multiple discussions with Stealth about elamipretide for treating cardiomyopathy in BTHS. The agency said it had expressed skepticism that the data from SPIBA-201 and SPIBA-001 could establish the effectiveness of elamipretide and recommended that Stealth launch a new phase 3 trial.
Despite this, Stealth submitted a new drug application (NDA) seeking approval of elamipretide in BTHS, prompting the FDA to issue a refusal-to-file letter, stating that the application didn’t contain a single adequate and well-controlled trial that could establish efficacy.
In November 2021, Stealth met with the agency to discuss the refusal-to-file and a possible path forward for the program. While the FDA continued to recommend a new late-stage trial, Stealth informed the agency of its intent to resubmit the NDA without conducting a new trial. The regulator said it could not prevent an applicant from resubmitting and that Stealth should fully address the agency’s prior concerns in the resubmission.
Today, the FDA again took issue with several parts of Stealth’s trials, saying that certain data were difficult to interpret and citing a potential placebo effect in the late-stage trial, though the biotech denies the existence of such effect.
In particular, the FDA believes SPIBA-001’s design could lend itself to two distinct forms of potential bias. The first is selection bias tied to a subsample of subjects in the natural history data as controls. Subjects’ attributes likely to influence the primary endpoint may differ among subjects selected into the subsample or not. Second is a confounding bias that may arise from lack of treatment randomization.
The agency also took issue with the propensity score method applied in the phase 3 trial, arguing that the scoring doesn’t properly address the potential biases introduced by study design.
“The FDA has difficulty attributing the findings from the single-arm open-label extension study SPIBA-201 part two, and the externally controlled study, SPIBA-001, to elamipretide because of significant limitations discussed today,” Ann Punnoose, M.D., clinical reviewer for the FDA’s division of cardiology and nephrology, said during the committee meeting.
“No other trial designs that had been discussed… were ultimately acceptable to FDA, primarily due to powering concerns that are frankly insurmountable in a disease that's rare,” Stealth CEO Reenie McCarthy said during the nine-hour advisory hearing.
“When patient advocacy first approached us in 2014 and asked us to initiate development, we thought we had a good idea of the challenges that would be entailed in developing a drug for a disease that's incredibly rare,” McCarthy said. “I have to say, in retrospect, that I think we severely underestimated the hurdles that we would face, but we really persevered because we were inspired by the potential that we believe we've delivered upon to improve the lives of patients living with this serious, rare disease.”
Trials evaluating elamipretide have been conducted across other conditions, including primary mitochondrial myopathy, age-related macular degeneration and age-related skeletal muscle mitochondrial dysfunction, among others. While some small, early-stage trials revealed beneficial effects, that benefit wasn’t observed in subsequent trials, according to the FDA.
The regulatory agency acknowledged “the devastating impact of BTHS” and “the significant unmet medical need” in the recent Oct. 8 briefing documents. However, the agency still doesn’t believe that available evidence establishes efficacy of elamipretide.
The impact of BTHS is indeed devastating. The cardioskeletal disease often presents in infancy and is characterized by cardiomyopathy, which makes it difficult for the heart to pump blood. Death rates are highest in the first four years of life and most patients don’t typically live past their 40s.
About 130 Americans live with the disease, with 250 affected individuals living worldwide.
“When I started elamipretide at the age of 17, I could have never guessed the strides I would mentally and physically take,” Jacob Wilson, a 24-year-old man with Barth syndrome, said during the advisory committee. “This medicine made me feel like a new person.”
“Within six months on this medication, I gained weight, strength and stamina. I gained 25 pounds. That was a miracle for a guy who has never been able to gain weight. I felt like a completely different person. I was happier and more motivated in life,” Wilson said.
“I could walk blocks without tripping over my inverted feet or gasping for air,” he explained. “These are the things most people overlook, the little things we are blessed to be able to do every day… I understand this isn't a cure all, but the improvements I saw were important to me.”
“The trials that we’d love to have for Barth syndrome are just not feasible given the rarity of the condition,” Brian Feingold, M.D., a pediatric cardiologist in Pittsburgh, said during the open public hearing. Feingold served on Stealth’s advisory board more than three years ago, but no longer has ties to the company.
“The drug has an excellent safety profile, with injection site reactions being the most notable side effect and no life-threatening or potentially life-threatening adverse effects,” said Feingold, who has cared for nine patients with Barth syndrome. “So, to continue to be caught in a catch-22 loop where data on clinically meaningful benefit exists and the adverse effects are relatively trivial in a population that is begging for an opportunity does not make sense to me.”
The FDA did not ask committee members to take drug safety into consideration, but instead deliberate on elamipretide’s efficacy.
The advisory committee had several questions for the agency, with one member asking whether the FDA wanted votes to be cast based on whether the evidence was conclusive or whether the member thought the drug should be approved.
In response, Peter Stein, M.D., the director of the office of new drugs for the FDA’s Center for Drug Evaluation and Research, said the agency doesn’t expect the level of certainty seen in medicines for a common cardiac function. That being said, the FDA wants some amount of certainty, some level of confidence that the drug provides the benefit that it purports to have, according to Stein.
“We certainly will accept some uncertainty that we would not perhaps accept in a different setting, but we also want to be able to conclude that the drug is effective,” Stein said.
"This was worse than our national election," Eric Peterson, M.D., an internal medicine physician who specializes in cardiology, said. Peterson cast his vote in favor of elamipretide. "Obviously their randomized trial was negative... Other empiric evidence that you would want are lacking. That said, I was swayed by the preponderance of the evidence, albeit it all imperfect, that fell on the side of supporting the drug. The evidence from the extension trial, from the historic controls, each having individual flaws, but a pretty big effect. And then the predominance of responses from the community and from the physicians who are treating these patients—given all that, better to be wrong than right here."
"These advisory meetings are never held when the issues are black and white," said G. Caleb Alexander, M.D., an associate professor at the Johns Hopkins University School of Medicine who voted no. "I just, I don't think regulatory flexibility gets you beyond the paucity of affirmative evidence in this setting. There's the absence of key, affirmative mechanistic data."
Several members called for a change to the structuring of approval for rare disease meds, asking for more flexibility in the space.