The FDA’s recently altered outlook on the evidence required for approval of rare disease drugs could have immediate benefits for companies including Skyhawk Therapeutics, Capricor Therapeutics and Biohaven.
When the FDA cleared uniQure and REGENXBIO to file, or refile, for approval of their respective gene therapies based on current data, the agency put its recent regulatory guidance surrounding external controls into practice—potentially lifting the hopes of other near-term regulatory hopefuls.
Last week, in what Convey Bio founder Benjamin McLeod in a LinkedIn post called possibly “the biggest CGT story of the year so far,” the FDA reversed the decision made under ex-commissioner Marty Makary to require a sham-controlled Phase 3 trial before it would consider uniQure’s AMT-130 for approval. Notably, that requirement was also a reversal of previous guidance given to uniQure by the agency that data from the company’s Phase 1/2 trial could be used as the primary basis for a biologics license application (BLA).
“I think the FDA is making a lot of really smart decisions,” Bill Haney, CEO of Skyhawk Therapeutics, which is also developing a treatment for Huntington’s, told BioSpace.
For Peter Pitts, a former associate commissioner at the FDA and president and co-founder of the Center for Medicine in the Public Interest, the FDA’s new direction can be attributed to the exit of Center for Biologics Evaluation and Research (CBER) Director Vinay Prasad at the end of April.
“I think 2026 is divided into two pieces with a very specific reason, and that reason is the departure of Vinay Prasad,” Pitts told BioSpace. “I think with Dr. Prasad’s departure, FDA has returned to its senses as being a partner in innovation rather than a critic of innovation.”
On Monday, the FDA further leaned into this new position, acknowledging that existing clinical data supporting REGENXBIO’s recently rejected Hunter syndrome therapy could support an accelerated approval application and that no further studies will be required, according to the biotech’s release.
These latest moves also suggest new alignment with recent FDA guidance that cell and gene therapy developers should leverage innovative clinical trial designs, including those involving external controls such as historical or real-world data.
UniQure’s pivotal Phase 1/2 trial—which returned positive three-year data in September 2025—compared the clinical outcomes for 24 patients given AMT-130 to those of propensity score-matched external controls from the Enroll-HD natural history data set. The biotech had been set to apply for FDA approval in the first quarter of this year until the FDA issued its surprise decision that a sham-controlled study would be required.
Meanwhile, RGX-121 was turned away by the FDA in February, with the agency citing “uncertainty” over the eligibility criteria used in its registrational study and the biotech’s use of external controls, which it said “lack the comparability” with trial participants. The FDA recommended the company use “an appropriate untreated control.”
The FDA’s new allowance of externally controlled studies to stand for uniQure’s BLA and REGENXBIO’s resubmission could also lift other late-stage development programs that have used such innovative study designs, as well as the industry more broadly.
“I think it’s going to help every biotech,” Pitts said of the agency’s new approach.
Here, BioSpace takes a closer look at four companies—Skyhawk, Capricor Therapeutics, Biohaven and Stoke Therapeutics—that may be among the first to see their luck turn.
Another feather in Capricor Therapeutics’ deramiocel cap
Capricor Therapeutics’ investigational cell therapy deramiocel aced a pivotal Phase 3 trial in Duchenne muscular dystrophy–associated cardiomyopathy last December, setting the stage for an August decision.
Prior to this triumphant turn, however, Capricor had been through the regulatory wringer with deramiocel. The company’s first application, for accelerated approval of the cell therapy, was backed by data from a Phase 2 study, which featured an open label extension study and natural history comparisons from FDA-funded datasets. The FDA rejected the therapy in July 2025, saying in its complete response letter (CRL) that the data package fell short of the “statutory requirement for substantial evidence of effectiveness.”
The FDA’s July decision surprised Capricor CEO Linda Marbán, who in a statement at the time said the biotech had “followed [the FDA’s] guidance throughout the process.”
The use of an externally controlled study was “one of the major issues” raised in the CRL, Marbán said during a BioSpace webinar earlier this year.
With Capricor now armed with positive results from a placebo-controlled pivotal trial, will the FDA’s revised stance on external controls bolster deramiocel’s chances?
Skyhawk’s Huntington’s drug could take earlier flight
Skyhawk reported positive data earlier this month from a Phase 1/2 trial leveraging an external control comparator. After 12 months, SKY-0515, a small molecule RNA splicing modifier in development for Huntington’s disease, improved scores from baseline on the Composite Unified Huntington’s Disease Rating Scale (cUHDRS) compared to a natural history dataset of symptomatic patients.
Skyhawk already has 144 patients enrolled in its pivotal placebo-controlled Phase 2/3 FALCON-HD study, but Haney said the company has had discussions with the FDA about a potentially accelerated timeline. “They are encouraging us to look for the fastest way we can move responsibly for patients, and we want to do that,” he continued.
“I really admire the FDA for being willing to reopen something that they had closed,” Haney added of the agency’s recent reversals on uniQure, REGENXBIO and more. And if AMT-130 gets the regulatory greenlight, he expressed optimism about Skyhawk’s chances.
“It makes a lot of sense that you would treat various drugs addressing the same patient population according to the same evaluative standards,” Haney said. “So I expect the FDA will do that.”
A second chance for Biohaven’s SCA drug?
The FDA in the past year has also strongly encouraged the use of real-world data.
Biohaven’s troriluzole, in development for spinocerebellar ataxia (SCA), was rejected by the FDA in November 2025. In its new drug application, Biohaven relied on a one-year placebo-controlled study and a three-year real-world evidence study, which met its primary and secondary outcome efficacy endpoints.
In its CRL, the FDA cited “issues that can be inherent to real-world evidence and external control studies including potential bias, design flaws, lack of pre-specification and unmeasured confounding factors,” according to a company press release at the time.
Biohaven has “spent considerable time advocating” for troriluzole in SCA in the past year, CEO Vlad Coric told BioSpace earlier this month. “We stand by the data and believe this is an approvable package, and we are continuing to interact with the FDA, and we will not stop advocating for patients that this should be approved.”
Over the past month, several rare disease drug developers, including Disc Medicine and Replimune, have announced new alignment with the FDA regarding their own recently rejected drugs. Will Biohaven be next?
Stoking an expedited pathway for Dravet ASO?
Like Skyhawk, Capricor and Biohaven, Stoke Therapeutics has its bases covered. The Massachusetts-based biotech is currently conducting a sham-controlled Phase 3 trial for its Biogen-partnered lead candidate zorevunersen in Dravet syndrome, a rare and severe form of epilepsy.
However, Stoke has had discussions with the FDA about potential expedited regulatory pathways based on its Phase 1/2a trial and open-label extension, as well as data from a two-year natural history study, a company spokesperson told BioSpace in April.
In December 2025, Stoke reported long-term data comparing patients treated with zorevunersen across its clinical development program versus natural history controls. Comparisons were adjusted by baseline differences between these two patient groups in an effort to mimic randomization, according to the biotech’s press release at the time. Patients on zorevunersen saw a statistically significant decrease in the frequency of major motor seizures—a hallmark of Dravet—at six months versus external controls.
Stoke expects data from the Phase 3 trial in mid-2027, according to a January company update, with a rolling NDA submission planned to start in the first half of next year.
