Top Stories
FDA lifts Capricor CRL and resumes deramiocel BLA review for DMD cardiomyopathy after HOPE-3 Phase 3 data submission
The FDA lifted the complete response letter previously issued to Capricor Therapeutics and resumed review of its BLA for deramiocel, an allogeneic cardiosphere-derived cell therapy for Duchenne muscular dystrophy cardiomyopathy, per Capricor's announcement. The submission has been classified as a Class 2 resubmission with a PDUFA target action date of August 22, 2026. The reversal follows Capricor's submission of Phase 3 HOPE-3 data, which met both its primary endpoint (performance of the upper limb) and key secondary endpoint (ejection fraction) in the randomized, double-blind, placebo-controlled trial. The FDA has not identified any potential review issues. The July 2025 CRL had cited insufficient evidence of effectiveness and was issued under Prasad's CBER leadership, after the agency canceled a previously planned advisory committee meeting. NeurologyLive reported that Capricor is seeking labeling beyond cardiomyopathy alone, potentially encompassing broader DMD skeletal muscle function. DMD affects approximately 15,000 patients in the US, with cardiomyopathy as the leading cause of death. If approved, deramiocel would be the first therapy specifically addressing DMD cardiomyopathy. Capricor expects to be eligible for a Priority Review Voucher upon approval.
Senator Ron Johnson launches investigation into FDA rare disease rejections, considers calling Makary to testify
Senator Ron Johnson (R-WI) launched a formal investigation into FDA denials of rare disease therapies, requesting complete response letters from the agency and considering calling Commissioner Makary and other senior FDA officials to testify before the Senate Permanent Subcommittee on Investigations, which Johnson chairs. STAT News reported that Johnson called the FDA's approach "outrageous" and described the agency's demand for a sham surgery-controlled trial for UniQure's Huntington gene therapy as "bureaucratic idiocy." The probe follows at least five cell and gene therapy rejections under Prasad's CBER tenure, affecting UniQure, Regenxbio, Capricor, Biohaven, and Replimune. Fierce Biotech noted that the investigation also encompasses the spinocerebellar ataxia rejection (Biohaven) and ataluren access for Duchenne patients. H.C. Wainwright analysts characterized Prasad's departure as removing "the single most consequential individual variable driving regulatory uncertainty" in the rare disease space. An HHS spokesperson defended the FDA's record, stating approval and rejection rates remain consistent with the prior decade.
Ultragenyx DTX301 AAV8 gene therapy hits co-primary endpoint in Phase 3 OTC deficiency trial with 18% ammonia reduction at 36 weeks
Ultragenyx reported positive Phase 3 Enh3ance results for DTX301, an investigational AAV8 gene therapy for ornithine transcarbamylase (OTC) deficiency. At Week 36, DTX301-treated patients (n=18) achieved a statistically significant 18% reduction (p=0.018) in 24-hour plasma ammonia compared to placebo (n=19), maintaining average ammonia levels within the normal range. The trial enrolled 37 patients with this rare urea cycle disorder. A second co-primary endpoint — the percentage of patients achieving response through discontinuation or reduction of baseline disease management — will be assessed at Week 64. Ultragenyx's announcement noted clinically important improvements on patient global impression scales for OTC symptoms and daily living impact. Five placebo patients experienced hyperammonemic crises, with one death; one DTX301 patient had serious acute liver inflammation. Ultragenyx already has DTX401 (GSD type Ia) under FDA priority review with a PDUFA date of August 23, 2026, positioning the company for two potential gene therapy approvals within months.
Pipeline Watch
None of the 13 patients in the Phase 1/2 interim dataset had serious adverse events or adverse events of special interest — including drug-induced liver injury — through 24 months after treatment, per Fierce Biotech. Microdystrophin expression ranged from 39.7% to 97.3% at the pivotal dose. The clean hepatic safety profile differentiates RGX-202 from Sarepta's Elevidys, which has been linked to two fatal liver toxicity events. Regenxbio expects pivotal top-line data in early Q2 2026 and plans a BLA submission under accelerated approval in mid-2026.
BridgeBio presented Phase 3 FORTIFY interim results for oral BBP-418 in limb-girdle muscular dystrophy type 2I/R9 at the MDA conference, showing a 31-second improvement on the 100-meter timed test versus placebo at 12 months, with separation visible at 3 months. CK levels normalized in 38.3% of patients, per StockTitan. BridgeBio plans to file an NDA for traditional approval in H1 2026 targeting a US launch in late 2026 or early 2027. If approved, BBP-418 would be the first therapy for any form of limb-girdle muscular dystrophy.
The FDA approved expanded use of Wellcovorin (leucovorin calcium) for CFD-FOLR1, an ultra-rare neurological condition with fewer than 50 documented cases worldwide, based on a systematic review of published case reports rather than a conventional clinical trial, as BioPharma Dive reported. The approval was narrower than initially anticipated — the agency declined to include a broader autism indication, retreating from September 2025 announcements that had suggested the drug could help children with autism. GSK does not intend to manufacture Wellcovorin; the label update applies to all generic leucovorin versions.
The 2026 Evaluate Orphan Drugs Report forecasts global rare disease drug sales of $409 billion by 2032, up from 15% to over 21% of all prescription pharmaceutical sales, per Fierce Pharma. J&J leads projected 2032 orphan drug sales at ~$31 billion, followed by Vertex with two drugs in the top 10 (Alyftrek at $9.3B, Trikafta at $4.9B). Argenx is forecast to displace Pfizer in orphan rankings, driven by Vyvgart's $11.2 billion projection — the only company with revenue derived entirely from orphan drugs.
Alfasigma will acquire worldwide rights to linerixibat, GSK's IBAT inhibitor for cholestatic pruritus in primary biliary cholangitis, for $300 million upfront plus up to $390 million in regulatory and sales milestones, as AllSci reported. The PDUFA target date of March 24, 2026 means an FDA decision is expected within two weeks. Phase 3 GLISTEN met primary and key secondary endpoints. Linerixibat holds orphan drug designation in the US, EU, and Japan.
Competitive Landscape
Capricor's deramiocel BLA resumption (PDUFA August 22) and Regenxbio's clean hepatic safety profile through 24 months position both programs as alternatives to Sarepta's Elevidys, which has faced fatal liver toxicity events. Deramiocel's allogeneic cell therapy mechanism addresses both cardiac and skeletal muscle, while RGX-202's micro-dystrophin gene therapy shows differentiated safety at the expense of requiring a one-time surgical administration.
| Company | Program | Modality | Status |
|---|---|---|---|
| Sarepta | Elevidys | AAV Micro-dystrophin | Approved (Safety Concerns) |
| Capricor | Deramiocel | Allogeneic Cell Therapy | BLA Under Review (Aug PDUFA) |
| Regenxbio | RGX-202 | AAV Micro-dystrophin | Pivotal Data Q2 2026 |
| BridgeBio | BBP-418 | Oral Small Molecule | Ph3 LGMD2I/R9 (NDA H1 2026) |
The convergence of Prasad's end-of-April exit, Johnson's Senate investigation, and the Capricor CRL reversal suggest the FDA's posture toward rare disease approvals may be softening. For developers relying on external controls, single-arm datasets, or surrogate endpoints, the CBER successor appointment will be the key signal for whether regulatory flexibility returns to pre-Prasad levels.
Evaluate's projection of orphan drugs reaching 21% of global prescription sales by 2032 (up from 15% in 2022) underscores that rare disease remains a structural growth category even as investor attention has shifted toward obesity and AI. The report highlights argenx as a potential gate-crasher into top-10 orphan drug companies, driven entirely by rare disease revenue from Vyvgart, while small molecules now represent 45% of the top 20 orphan drugs in development.
Forward Looking
- Capricor's August 22, 2026 PDUFA date for deramiocel will test whether HOPE-3 Phase 3 data satisfy the evidentiary bar post-Prasad, potentially delivering the first therapy for DMD cardiomyopathy and a priority review voucher.
- Regenxbio pivotal top-line data for RGX-202 in DMD expected early Q2 2026 will determine whether 10%+ microdystrophin expression at Week 12 is achievable in the pivotal population and whether the clean safety profile holds at scale.
- Ultragenyx DTX301 Week 64 co-primary endpoint for OTC deficiency will assess whether ammonia reduction translates to meaningful changes in disease management burden, supporting a potential BLA alongside the DTX401 GSD Ia approval expected August 2026.
- The linerixibat PDUFA date of March 24, 2026 will deliver the first FDA decision under the new GSK-Alfasigma arrangement, testing whether Alfasigma can launch a rare hepatology product on the same timeline that GSK originally planned.