The case of Stealth BioTherapeutics and its rare disease drug could become a regulatory bellwether for other biotechnology companies seeking to understand how flexibly new leaders at the Food and Drug Administration will evaluate medicines for uncommon conditions.

At the center of the ongoing back-and-forth is elamipretide, which Stealth is trying to get cleared for Barth syndrome, an ultra-rare and often fatal pediatric mitochondrial disease with no approved treatment.

“We often talk about Barth syndrome as being a litmus test for FDA because it highlights that for ultra-rare diseases, standard regulatory approaches don’t work,” said Lindsay Marjoram, director of research for the Barth Syndrome Foundation.

Now, that litmus test is playing out in real time as Stealth rides an FDA roller coaster in its quest to get elamipretide across the finish line.

After rejecting elamipretide’s approval in May, the FDA accepted the company’s newly resubmitted application last week. The FDA’s willingness to reconsider the drug was “huge” for Stealth, the company’s CEO, Reenie McCarthy, said.

“It gives us a timeline,” she said. “It’s manageable for us to survive this delay.”

How the FDA ultimately decides could impact how other ulra-rare disease drug developers seek approvals in the future.

What’s at stake for Stealth

The FDA’s rejection of elamipretide came as a shock that “blindsided” the company because an FDA advisory panel had supported the drug, McCarthy said. It also raised doubts about how long the company could keep its doors open.

The rejection followed an approval process riddled with delays, including decisions about whether the FDA would assign the drug standard review or priority review, and a missed decision date in April.

“We would have been expecting from our original submission [in January 2024] to have been approved potentially in 2024 under priority review,” McCarthy said.

But last year came and went without an approval and the FDA’s ever-lengthening review period put a heavy financial strain on Stealth.

“It [pushed] out the financial commitments from our investors,” McCarthy said. “We were making decisions [to defer] progress on other programs. We stopped other clinical trials that were supposed to initiate. We ended up with a reduction in force of 30%.”

In the meantime, patients have also been relying on access to elamipretide through the company’s expanded access program.

Although McCarthy said just under 30 patients are receiving elamipretide, that's a “fairly large number,” considering the U.S. patient population numbers about 150.

“It’s traumatic for them to know they might lose access,” Marjoram said. “People are counting their vials. They’re trying to map out … how long will my baby or how long will I, personally, be able to stay on the drug.”

Barth syndrome causes muscle weakness, heart failure, infections and debilitating fatigue, and has a high infant fatality rate, with 85% of early deaths occurring by age 5. While Marjoram said that about 20% tp 25% of patients receive a heart transplant, that only fixes one of the “downstream symptoms” and isn’t curative. Elamipretide is “actually getting to the mitochondria” to improve patients’ quality of life, she said.

“Our folks have more energy, they are able to walk further, [and] they’re able to climb stairs more functionally or more stairs than they could before,” Marjoram said. There have even been newborn babies listed for heart transplants who have become delisted because “they do so well on elamipretide that their heart function stabilizes and they don’t need a heart transplant anymore.”

The impact of endpoints

The FDA not only accepted Stealth’s new drug application more quickly than expected, but told the company that it can expect a quicker decision, too. A decision date is set for Sept. 26, rather than a typical six-month review.

“The FDA is recognizing the urgency of the unmet need and reacting accordingly on a resubmission that, quite frankly, just doesn’t have that much new data,” McCarthy said. “So the review time should be light and the FDA is acknowledging that and committing to act early, which is huge.”

Stealth is aiming for an accelerated approval of elamipretide on the basis of improvements in knee extensor muscle strength, an intermediate clinical endpoint. The resubmission also included a protocol for a post-marketing trial to confirm clinical benefit. Notably, there were no safety concerns with the drug.

While Stealth now sees a light at the end of the tunnel, the protracted journey highlights the inherent problem with trying to fit ultra-rare disease approvals into the typical FDA framework, since the tiny patient population doesn’t allow for the larger, placebo-controlled clinical trials the agency likes best. One of Stealth’s elamipretide trials included just 12 patients. Marjoram said that’s actually an “astonishing participation rate,” given the small patient population combined with inclusion and exclusion criteria.

For other drug developers, the question of the FDA’s willingness to approve elamipretide on the basis of an intermediate clinical endpoint could impact their own strategy for seeking an approval.

“There are bigger ideological questions about what’s the right pathway for ultra-rare?” McCarthy said. “This finally crossing the finish line will bring some hope to ultra-rare disease innovation.”