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BioMarin pauses Voxzogo dosing in subset of Phase 2 patients following slipped capital femoral epiphysis cases across independent trials
BioMarin suspended dosing for certain patients enrolled in two mid-stage Voxzogo studies after multiple cases of slipped capital femoral epiphysis, a hip displacement condition, were identified in independent trial cohorts, according to Endpoints News. The safety signal emerged outside the company's core achondroplasia indication, where Voxzogo holds accelerated FDA approval for pediatric patients with open growth plates. SCFE represents a known orthopedic complication in children with growth disorders, but the clustering across trials prompted the dosing pause while BioMarin and investigators assess causality and patient risk factors. The hold applies to a subset of participants rather than full trial suspension, suggesting the company is taking a targeted approach to risk management. The event raises broader questions about growth-promoting therapies in pediatric populations with underlying skeletal vulnerabilities, particularly as companies expand into adjacent indications such as hypochondroplasia and idiopathic short stature. BioMarin has not disclosed the total number of SCFE events or the specific trials affected, though investors will watch for updates on whether dose adjustments, imaging protocols, or patient selection criteria require modification before dosing resumes.
Ultragenyx reports positive Phase 3 gene therapy data in OTC deficiency with statistically significant ammonia reduction and patient-reported symptom improvement
Ultragenyx reported positive 36-week results from the Phase 3 Enh3ance study of DTX301 (avalotcagene ontaparvovec), an AAV8 gene therapy for ornithine transcarbamylase deficiency, the most common urea cycle disorder, according to the company. Patients treated with DTX301 (n=18) demonstrated a statistically significant 18% reduction in 24-hour plasma ammonia (AUC0-24, p=0.018) compared to placebo (n=19), with ammonia levels maintained in the normal range through Week 36. Notably, eight of nine patients with abnormal ammonia at baseline reached normal levels despite beginning to reduce ammonia scavenger medications by an average of 27% and increasing protein intake by approximately 13%. On the patient global impression scale at Week 24, 71% of treated patients reported being much improved on overall OTC symptoms versus 0% on placebo. DTX301 was well tolerated, with the most common treatment-emergent adverse events being mild to moderate transient hepatic reactions managed with steroids. Hyperammonemic crises requiring hospitalization occurred five times in the placebo group, including one death, compared with one event and no deaths in the DTX301 group. The study continues toward a second primary endpoint evaluating treatment burden reduction through 64 weeks, with data expected in the first half of 2027. DTX301 holds Orphan Drug Designation in the US and EU, and Fast Track Designation in the US.
Pipeline Watch
The FDA is expected to render a decision by March 28 on Rocket Pharmaceuticals' resubmitted BLA for Kresladi (marnetegragene autotemcel), a lentiviral vector-based gene therapy for severe leukocyte adhesion deficiency type I, an ultra-rare genetic immune disorder that is near-uniformly fatal in childhood without allogeneic stem cell transplant, per Rocket Pharmaceuticals. The BLA is supported by Phase 1/2 data demonstrating 100% overall survival at 12 months post-infusion across all enrolled patients. Rocket has received two prior CMC-related Complete Response Letters, making this third review cycle a critical test. If approved, Rocket would be eligible for a Rare Pediatric Disease Priority Review Voucher.
Prime Medicine is pursuing accelerated approval of PM359, a gene editing therapy for chronic granulomatous disease (CGD), after FDA interactions suggested existing two-patient clinical data may be sufficient under the new plausible mechanism pathway, according to BioPharma Dive. CGD is a potentially deadly condition that leaves patients highly susceptible to bacterial and fungal infections, with an estimated 50 eligible US patients. Prime had previously shelved the program during a cash crunch, estimating $20–30 million would be needed to study 12 patients. The plausible mechanism framework represents an early commercial test case for whether FDA's new rare disease regulatory approach can make ultra-rare gene editing programs economically viable.
Nonprofit foundation Solve GNE announced progress toward a Phase I clinical trial for GNE myopathy, a rare progressive muscle disease, with the IND application being finalized in collaboration with Gradalis Inc., per GlobeNewswire. The therapy uses a dual-function plasmid designed to simultaneously deliver the wild-type GNE gene and silence a prevalent pathogenic mutation (GNEM743T) found in the Iranian Jewish community. The foundation has raised over $6.5 million to date, and a newly published preclinical paper describes in vitro and in vivo data supporting the approach. The FDA has reviewed and provided comments on a pre-IND application, with trial initiation anticipated within 12 months.
The NCI-sponsored Phase 2 study of cabozantinib in recurrent or refractory pediatric sarcomas, Wilms tumor, and other rare solid tumors has completed enrollment and entered the active-not-recruiting phase, per ClinicalTrials.gov. The trial explores cabozantinib, a multi-kinase inhibitor targeting VEGFR, MET, and AXL, in hard-to-treat pediatric malignancies including alveolar soft part sarcoma and adrenal cortical carcinoma. Data readouts from this basket study may inform registration strategies for rare pediatric oncology indications.
Competitive Landscape
The Voxzogo dosing pause highlights challenges in balancing growth promotion with orthopedic risk management in children with skeletal dysplasias. Competing programs from Ascendis Pharma and other CNP pathway developers will likely face regulatory questions about SCFE surveillance protocols, imaging requirements, and patient selection criteria as they advance through clinical development.
Ultragenyx now has two gene therapy programs approaching regulatory milestones: DTX401 for glycogen storage disease type Ia (GSDIa) has a PDUFA date of August 23, 2026 following Priority Review, while positive Phase 3 DTX301 data in OTC deficiency set the stage for a potential BLA filing. Both programs use the AAV8 vector platform and target rare metabolic liver diseases with significant unmet need—GSDIa has no approved pharmacologic therapy, while OTC deficiency management relies on nitrogen-scavenging agents that carry substantial treatment burden—positioning Ultragenyx to become a major rare disease gene therapy company if both advance toward approval.
| Program | Indication | Stage | Next Milestone |
|---|---|---|---|
| DTX401 | GSDIa | BLA under review | PDUFA Aug 23, 2026 |
| DTX301 | OTC Deficiency | Phase 3 positive | Treatment burden data 1H 2027 |
The FDA's plausible mechanism framework, released February 23, is moving rapidly from theory to practice. Prime Medicine's plan to seek accelerated approval of PM359 for CGD based on two-patient data is among the earliest test cases. If successful, the pathway could reshape the economics of ultra-rare gene therapy development by enabling approvals without traditional large-scale trials, a critical shift for conditions affecting fewer than 1,000 patients in the US. Industry observers note investor skepticism remains high, with EveryONE Medicines winding down operations the same week the guidance was released.
Forward Looking
- Rocket Pharmaceuticals Kresladi PDUFA decision expected March 28, 2026 for severe LAD-I — approval would represent the first gene therapy for this ultra-rare immune disorder and trigger a Rare Pediatric Disease Priority Review Voucher.
- BioMarin investor update expected on Voxzogo dosing resumption timeline, SCFE event details, and potential protocol modifications for Phase 2 studies in non-achondroplasia skeletal dysplasia indications.
- Ultragenyx DTX401 PDUFA date of August 23, 2026 for GSDIa gene therapy approaches under Priority Review, representing the first potential pharmacologic therapy for glycogen storage disease type Ia.
- Ultragenyx DTX301 treatment burden reduction data from the Enh3ance study in OTC deficiency expected in first half of 2027, with second primary endpoint evaluating reduced ammonia scavenger use and dietary liberalization through 64 weeks.
- Prime Medicine alignment with FDA on PM359 filing strategy for CGD will test whether the plausible mechanism pathway can support gene editing approvals based on two-patient datasets in ultra-rare populations.