Rare disease organizations gathered in Washington, D.C., this week to push for greater regulatory flexibility for therapies targeting rare conditions. The meetings come after a series of recent rejections by the Food and Drug Administration (FDA), including drugs from Biohaven and Saol Therapeutics.
Sara Klock, a partner at Holland & Knight, addressed the Congressional Mitochondrial Disease House Caucus on Tuesday. “FDA is aware of the pressure rare diseases and ultra rare diseases and the patients face regularly,” she said. Klock referenced draft guidance issued by the FDA on its Plausible Mechanism Pathway as a sign that the agency is willing to show some flexibility in its standards. “I think it gives some hope to industry that the FDA is willing to actually be flexible and not be as stringent on some of the standards that they generally or typically are,” Klock added.
Despite these comments, recent actions by regulators suggest a more rigid approach. Companies such as Capricor Therapeutics, Replimune, and uniQure have also faced setbacks after changes in FDA guidance.
A senate hearing on Thursday included remarks from Jeremy Schmahmann, neurology professor at Harvard Medical School and founding director of Massachusetts General Hospital’s Ataxia Center. According to Fierce Biotech, Schmahmann described discussions with FDA members as “like talking to a brick wall.”
Comments made by FDA Commissioner Marty Makary during an appearance on CNBC’s Squawk Box were cited by H.C. Wainright analysts as further evidence of a strict regulatory stance. The analysts wrote: “[Makary’s] emphatic defense of . . . Prasad—calling him a ‘genius’ facing media push-back—confirms that the rigorous, randomized clinical trial-based evidence bar at CBER remains the operational reality for the FDA.”
At Tuesday’s mitochondrial disease briefing organized with the United Mitochondrial Disease Foundation (UMDF), discussion focused largely on pyruvate dehydrogenase complex deficiency (PDCD) and Saol’s SL1009 drug candidate, which was rejected in September.
The FDA's complete response letter indicated that Saol would need another adequate and well-controlled clinical trial for approval—a requirement CEO Dave Penake has called “not feasible to be done by our company and in this patient population.” Penake said advocates attending the briefing want quick regulatory flexibility: “They want to highlight that this needs to happen quickly.” He expressed hope that congressional oversight could help bring SL1009 to market.
Kristen Clifford, president & CEO of UMDF, stated: “We fully support scientific rigorous standards. At the same time, Congress has provided the FDA with the tools specifically designed for rare and ultra rare diseases, recognizing that traditional trial designs are not feasible in very small populations.”
One tool highlighted was the Rare Disease Evidence Principles (RDEP) framework introduced by FDA in September 2025. The RDEP allows companies developing treatments for ultra-rare diseases—such as PDCD—to seek approval based on single-arm trials rather than traditional randomized studies. Penake described Saol’s program as fitting well within this framework: “In PDCD, there’s a genetic defect that causes an enzyme deficiency. The drug that we use in SL1009...actually restores enzyme activity...too small to maybe study in a reasonably coherent manner...a very targeted mechanism that corrects the disease.”
Saol plans a Type C meeting with FDA at March's end but faces limited supply of SL1009 through summer.
Biohaven encountered similar challenges when its investigational glutamate modulator troriluzole for spinocerebellar ataxia (SCA) was rejected despite meeting primary endpoints under priority review status last November. Biohaven Senior Medical Director Melissa Beiner told BioSpace via email: “The agency has indicated that an additional trial would be required.” The rejection cited concerns about potential bias in one supporting study; earlier statements from regulators emphasized strong treatment effects are needed when using externally controlled trials.
Beiner maintained confidence in their data: “We remain confident in the robustness of our three-year study...and met multiple primary and secondary endpoints.” She noted Biohaven continues dialogue with regulators regarding study adequacy findings.
Both PDCD and SCA are progressive ultra-rare diseases where delays can mean permanent loss for patients. Penake explained: “[PDCD] is a devastating disease...it gets worse every day for these children....Every day takes its toll.” He shared positive outcomes observed over six years tracking patients treated with SL1009—including improvements like walking or speaking.
Patricia Greenstein, assistant professor at Harvard Medical School, commented via email about SCA patients impacted by troriluzole’s rejection: “For a progressive disease with no other approved disease-modifying therapies, ‘delay’ is synonymous with permanent and progressive loss of function....I have had patients on this medication for past 7 years who are still ambulatory without walk aids.”
Beiner said Biohaven aims "to identify a path forward that upholds scientific standards while recognizing" SCA's serious nature.
