This week’s Capitol Hill meetings come on the heels of rejections of ultra-rare disease drugs developed by Biohaven and Saol Therapeutics. Physicians and patient groups implored the FDA to expedite these treatments.
Rare disease leaders convened in Washington, D.C., this week to advocate for regulatory flexibility when it comes to therapies targeting rare conditions. The meetings follow a spate of rejections in the space, including for drugs developed by Biohaven and Saol Therapeutics.
“FDA is aware of the pressure rare diseases and ultra rare diseases and the patients face regularly,” Sara Klock, a partner at Holland & Knight, said during a briefing in front of the Congressional Mitochondrial Disease House Caucus on Tuesday.
Klock pointed to draft guidance issued by the FDA on Monday regarding its Plausible Mechanism Pathway as evidence of the agency’s commitment to the space. “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,” she said.
But rejections and communications indicating a more stringent regulator paint a different picture. In addition to Biohaven and Saol, Capricor Therapeutics, Replimune and uniQure have all been thrown for a loop after seeming reversals in guidance from the FDA.
During a senate hearing on Thursday, Jeremy Schmahmann, a neurology professor at Harvard Medical School and founding director of Massachusetts General Hospital’s Ataxia Center, said that talking to members of the FDA was “like talking to a brick wall,” Fierce Biotech reported.
Meanwhile, comments from FDA Commissioner Marty Makary on CNBC’s Squawk Box Thursday morning, particularly pertaining to Vinay Prasad, director of the Center for Biologics Evaluation (CBER), which regulates cell and gene therapy and therefore many rare disease drugs—support the notion of a stricter FDA, H.C. Wainright analysts wrote in a note to investors Thursday afternoon.
“[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,” the analysts said.
Saol and Biohaven: Case Studies
Tuesday’s mitochondrial disease briefing, co-organized by the United Mitochondrial Disease Foundation (UMDF), focused largely on pyruvate dehydrogenase complex deficiency (PDCD) and the September rejection of Saol’s SL1009.
In its complete response letter (CRL), the FDA suggested that Saol would need to do an additional adequate and well-controlled clinical trial to gain approval of SL1009—something that CEO Dave Penake told BioSpace in December is “not feasible to be done by our company and in this patient population.”
PDCD patient advocates planning to attend the briefing will “want to highlight the need for regulatory flexibility in the context of the disease, and they want to highlight that this needs to happen quickly,” Penake said. The CEO said he is hopeful that oversight from Congress can help facilitate SL1009’s path to the market.
“We fully support scientific rigorous standards,” Kristen Clifford, president & CEO of UMDF, said during the meeting. “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 of these tools is the FDA’s Rare Disease Evidence Principles (RDEP) framework. Introduced in September 2025 just a week before SL1009’s rejection, the RDEP allows companies to file for approval with only a single-arm trial and is meant to expedite the approval of therapies for ultra-rare diseases. As a genetic disorder affecting less than 1,000 people in U.S., PDCD matches two of these key criteria, Penake said, calling Saol’s program a “poster child” for the RDEP framework.
“In PDCD, there’s a genetic defect that causes an enzyme deficiency. The drug that we use in SL1009, it’s very targeted, and it actually restores the enzyme activity,” Penake said. The RDEP pathway is “very targeted for populations like this,” he continued—“too small to maybe study in a reasonably coherent manner, a very clear cause of the disease, a very targeted mechanism that corrects the disease.”
Saol has a Type C meeting scheduled with the FDA at the end of March. The company will run out of SL1009 supply by this summer, Penake told BioSpace last week, “so we’re hoping to move this very quickly with the agency.”
Meanwhile, Biohaven has faced similar regulatory challenges with its investigational glutamate modulator for spinocerebellar ataxia (SCA), a group of inherited, progressive neurological disorders. In November, the FDA rejected troriluzole despite the candidate being accepted under priority review and reaching statistical significance on the primary and all secondary endpoints in the registrational study.
Biohaven met with the FDA and “presented several regulatory options based on the existing dataset [for troriluzole],” Biohaven Senior Medical Director Melissa Beiner told BioSpace in an email. Nevertheless, “The agency has indicated that an additional trial would be required.”
In its CRL, the FDA noted issues with Biohaven’s application package, including “potential bias” in the 206-RWE study used to support the application. The regulator in March 2024 said that “a large and robust treatment effect would be needed to overcome the biases of an externally controlled trial in order for it to be used as the primary basis for substantial evidence for effectiveness,” Biohaven recalled in a press release announcing the rejection.
However, Beiner said that Biohaven “remain[s] confident in the robustness of our three-year study, which was conducted under FDA-reviewed protocol and statistical analysis plans and met multiple primary and secondary endpoints.”.
The company has formally requested further review of certain findings related to study adequacy and continues to engage with the Center for Drug Evaluation and Research, Beiner said.
Delay Synonymous With Loss
Both PDCD and SCA are ultra-rare progressive diseases, and “the patient groups don’t really operate on the FDA timeline,” Penake told BioSpace.
“[PDCD] is a devastating disease and it gets worse every day for these children,” he continued. “So they either die and die quickly, or they might survive a little bit longer, but they’re in chronic energy deficit. Every day takes its toll.”
Saol has been tracking some of the patients in its trials for six years, Penake said, with notable successes. “Patients are getting better. We have children who are starting to walk. We have children who are speaking. We have children that are going to school.”
Patricia Greenstein, assistant professor and neurologist at Harvard Medical School, told BioSpace in an email about the real-world impacts of troriluzole’s rejection for patients with SCA, who struggle with coordination, balance and muscle control.
“For a progressive disease with no other approved disease-modifying therapies, ‘delay’ is synonymous with permanent and progressive loss of function,” she said. “The most direct consequence is the loss of the 1.5 to 2.2 years of stability that the 3-year data suggested the drug could provide. I have had patients on this medication for the past 7 years who are still ambulatory without walk aids.”
This irreversable decline is front and center for Biohaven. “Our focus remains on identifying a path forward that upholds scientific standards while recognizing the serious and progressive nature of SCA,” Beiner said.
