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FDA reversals on external control trial designs create regulatory confusion for rare disease gene therapy and cell therapy developers
The FDA has issued conflicting signals on whether external control arms can support accelerated approval for rare disease therapies, creating uncertainty for companies that designed pivotal programs around agency guidance encouraging innovative trial designs, according to BioSpace. UniQure had FDA alignment in 2024 to use natural history external controls as the primary comparator for its AMT-130 Huntington disease gene therapy, but the agency reversed course late last year, requesting a prospective sham surgery-controlled study despite the program demonstrating 75% disease slowing at 3 years. Capricor Therapeutics CEO Linda Marban noted that the use of external controls was one of the major issues raised in the CRL for deramiocel in DMD cardiomyopathy. Jefferies analyst Andrew Tsai told BioSpace the disconnect could have near-term implications for Stoke Therapeutics, Denali Therapeutics, and Praxis Medicines. Former FDA division director Harpreet Singh observed that determining whether an external control is appropriate remains an incredibly complex problem, even as FDA leadership publicly encourages their use. The disconnect between top-level FDA guidance and review division execution has become a defining challenge for rare disease developers in 2026.
Shionogi completes RADICAVA ALS acquisition from Tanabe, adding $700 million in annual sales and establishing rare disease franchise
Shionogi completed the transfer of all global rights for RADICAVA (edaravone) from Tanabe Pharma Corporation, establishing a commercially viable rare disease platform with approximately $700 million in annual global sales, according to the company. RADICAVA ORS is approved by the FDA for the treatment of amyotrophic lateral sclerosis, a progressive neurodegenerative disease affecting approximately 30,000 people in the United States. The drug received Orphan Drug Exclusivity in 2024 based on its major contribution to patient care by providing an oral suspension formulation. Shionogi described the acquisition as establishing its position as a rare disease company ready to introduce new treatments, with the RADICAVA team complementing efforts to build a best-in-class franchise. The transaction is expected to be immediately accretive in fiscal year 2026.
Pipeline Watch
Orca Bio announced the FDA has extended the PDUFA date for Orca-T from April 6 to July 6, 2026 after the company submitted updated chemistry, manufacturing, and controls information classified as a major amendment, per the company. Orca-T holds RMAT and Orphan Drug Designation for GVHD prevention in patients eligible for hematopoietic stem cell transplant. The Phase 3 Precision-T trial showed a 1 year GVHD-free survival rate of 78% versus 38% with conventional allo-HSCT (HR 0.26, p<0.00001).
A clinical trial sponsored by Tippi MacKenzie at UCSF has been registered on ClinicalTrials.gov for prenatal intravenous delivery of an AAV9 vector expressing human beta-galactosidase in fetuses diagnosed with GM1 gangliosidosis Type I and Type II. GM1 gangliosidosis Type I carries a median survival of approximately 2 years, and the US patient population is estimated at fewer than 500 across all types. No approved therapy exists. The trial is in pre-recruitment phase, and no commercial sponsor has been identified.
The FDA resumed review of Capricor deramiocel BLA after receiving positive Phase 3 HOPE-3 data, setting a PDUFA date of August 22, 2026, per the company. HOPE-3 met its primary endpoint on upper limb performance and key secondary endpoint on left ventricular ejection fraction in Duchenne muscular dystrophy cardiomyopathy. If approved, deramiocel would be the first cell therapy for both skeletal and cardiac manifestations of DMD, and Capricor would receive a Rare Pediatric Disease Priority Review Voucher.
Competitive Landscape
The disconnect between FDA leadership encouraging external controls and real-world evidence in rare disease trials and review divisions demanding randomized placebo/sham-controlled designs is reshaping how developers plan pivotal programs. Companies relying on external comparators face resubmission risk, while those investing in controlled designs face ethical challenges in small, severely affected populations.
| Program | Indication | External Control Issue | Status |
|---|---|---|---|
| uniQure AMT-130 | Huntington disease | FDA reversed prior alignment | Sham-controlled study requested |
| Capricor deramiocel | DMD cardiomyopathy | CRL cited insufficient evidence | Resubmitted with HOPE-3 data |
| Stoke Therapeutics | Dravet syndrome | Potential near-term impact | Monitoring |
Shionogi acquisition of RADICAVA positions it as the leading commercial ALS franchise operator with $700 million in annual sales, while the field awaits clarity on whether gene therapy approaches for ALS, including Biogen tofersen (Qalsody) for SOD1-ALS and academic AAV programs, can achieve comparable commercial scale in a disease affecting approximately 30,000 US patients.
Forward Looking
- Capricor deramiocel PDUFA August 22, 2026 for DMD cardiomyopathy — if approved, would be the first cell therapy addressing both cardiac and skeletal manifestations of Duchenne and trigger a Rare Pediatric Disease Priority Review Voucher.
- Orca Bio Orca-T revised PDUFA July 6, 2026 for GVHD prevention in hematologic malignancy transplant recipients; CMC amendment classified as major but no new clinical data requested.
- UniQure Type B meeting with FDA expected Q2 2026 to determine next steps for AMT-130 Huntington disease gene therapy after agency requested prospective sham-controlled study despite 75% disease-slowing signal from Phase I/II external-control data.
- Ultragenyx DTX401 GSDIa gene therapy PDUFA August 23, 2026 under Priority Review — would be first pharmacologic therapy for glycogen storage disease type Ia if approved.