FDA Rejects Ultragenyx's Gene Therapy for Sanfilippo Syndrome, Citing Manufacturing Concerns

In a significant setback for Ultragenyx Pharmaceutical, the U.S. Food and Drug Administration (FDA) has declined to approve UX111, the company's investigational gene therapy for Sanfilippo syndrome type A. The rejection, communicated through a complete response letter (CRL), centers on manufacturing-related issues rather than concerns about the therapy's clinical data.

Manufacturing Hurdles Delay Potential Breakthrough Treatment

The FDA's decision, announced on July 11, 2025, comes as a blow to patients suffering from Sanfilippo syndrome type A, a rare neurodegenerative disorder with no approved treatments. UX111, an in vivo gene therapy, uses an adeno-associated viral vector to deliver a functional copy of the SGSH gene to address the underlying enzyme deficiency responsible for the condition.

According to Ultragenyx, the FDA has requested additional information and improvements regarding manufacturing processes and observations from production facility inspections. The company believes these issues are "readily addressable" and not directly related to product quality. Ultragenyx plans to work closely with the FDA over the coming months to resolve these concerns and resubmit its application, which would trigger a new six-month review period.

Clinical Data Remains Promising

Despite the setback, Ultragenyx emphasized that the FDA did not raise concerns about the therapy's clinical data package. The company noted that the regulator acknowledged the robustness of the neurodevelopmental outcome data and the supportive evidence provided by biomarker data. The FDA has, however, requested that Ultragenyx include updated clinical data from current trial participants in its resubmission.

The original application was based on data from a small, single-arm trial, with the company seeking accelerated approval using a surrogate biomarker endpoint measuring levels of heparan sulfate in cerebrospinal fluid. Sanfilippo syndrome type A affects an estimated 3,000 to 5,000 patients in commercially accessible geographies, underscoring the potential impact of this therapy if approved.

Industry Implications and Market Response

The rejection of UX111 is more than just a setback for Ultragenyx; it also delays a key test of the new FDA leadership's approach to cell and gene therapies for rare diseases. Recent changes in FDA leadership, including the appointment of Vinay Prasad, M.D., as the new director of the Center for Biologics Evaluation and Research, had already introduced uncertainties about the regulatory landscape for such therapies.

Market reaction to the news was mixed. Ultragenyx's stock initially fell about 5% following the announcement but showed signs of recovery in subsequent trading. Analysts from Jefferies and Leerink Partners described the CRL as a "speed bump" rather than a "roadblock" to approval, maintaining a generally optimistic outlook on the therapy's future.

This development highlights the ongoing challenges in manufacturing complex cell and gene therapies. As noted by former FDA Commissioner Scott Gottlieb, M.D., the review process for these therapies often focuses more heavily on product issues compared to traditional drug reviews. The rejection of UX111 adds to a growing list of manufacturing-related setbacks in the field, with a recent Jefferies analysis finding that manufacturing problems were cited in 51% of past complete response letters for since-approved drugs.