Ultragenyx Pharmaceutical Inc. is facing a turbulent period after the U.S. Food and Drug Administration (FDA) rejected its investigational gene therapy, UX111, for Sanfilippo syndrome type A, a rare neurodegenerative disorder affecting children. The rejection comes just days after a failed Phase 3 readout for another antibody therapy, marking a significant setback for the biotech company.
According to a press release issued by Ultragenyx, the FDA’s Complete Response Letter (CRL) cited manufacturing deficiencies rather than clinical data concerns. The agency called for improvements in manufacturing practices and additional information related to facility inspections, despite no objections to the therapy’s quality, clinical trial data, or patient outcomes.
Ultragenyx emphasized that the identified issues are “manageable and process-related”, and not tied to product efficacy or safety. The FDA also requested updated clinical data for patients currently in the trial to be included in the resubmission.
Gene Therapy for Sanfilippo Syndrome Type A
UX111 is an in vivo gene therapy that uses an adeno-associated viral (AAV) vector to deliver a functional copy of the SGSH gene, which encodes the sulfamidase enzyme. This enzyme deficiency causes Sanfilippo syndrome type A, a rare and fatal condition with no approved treatment.
Ultragenyx estimates a commercially addressable patient population of 3,000–5,000 globally. Symptoms typically manifest in early childhood and lead to progressive damage of the central nervous system.
In February 2025, Ultragenyx submitted a Biologics License Application (BLA) for UX111 using surrogate biomarker data—specifically, levels of heparan sulfate in cerebrospinal fluid—from a single-arm study with a limited number of patients. The FDA granted Priority Review, with an original decision deadline set for August 18, 2025.
However, recent shifts in the FDA’s leadership have introduced regulatory uncertainty, potentially affecting the review process for gene therapies.
New FDA Leadership Brings Policy Shifts
Recent months have seen significant leadership changes within the FDA’s Center for Biologics Evaluation and Research (CBER)—the division responsible for reviewing gene therapies. Notably, Dr. Vinay Prasad, a vocal critic of previous accelerated approvals (e.g., Sarepta’s Elevidys for Duchenne muscular dystrophy), now heads CBER. Additionally, Nicole Verdun and Rachel Anatol, senior leaders of the FDA’s Office of Therapeutic Products, were placed on administrative leave.
These changes have prompted concern in the biotech industry regarding the future direction of gene therapy regulation in the U.S.
Despite the rejection, industry analysts remain hopeful. Jefferies maintains a 50-50 probability of eventual UX111 approval, citing that the delay is procedural rather than clinical. The firm emphasized that the CRL does not reflect negatively on the therapy’s efficacy or safety profile.
Leerink Partners echoed this sentiment, describing the rejection as a “speed bump” rather than a roadblock. Both firms pointed to the complex manufacturing requirements for gene therapies as a persistent challenge in the field.
According to Jefferies’ research, 51% of historical FDA CRLs that were later overturned and led to drug approvals cited manufacturing-related deficiencies—a trend that underscores the critical importance of production quality in biologics and gene therapy reviews.
Ultragenyx Gene Therapy Rejected by FDA Amid Manufacturing Concerns, Delaying Sanfilippo Syndrome Treatment
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