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 the company's experimental gene therapy, UX111, for the treatment of Sanfilippo syndrome type A. The rejection, announced on July 11, 2025, comes weeks ahead of the expected August 18 decision deadline and centers on manufacturing-related issues.

Manufacturing Concerns at the Heart of FDA Rejection

The FDA's complete response letter (CRL) to Ultragenyx requested additional information and improvements regarding manufacturing processes at the company's facility. Importantly, the agency did not raise concerns about the clinical data package or cite issues with clinical inspections. Ultragenyx stated that the FDA's observations are "not directly related to the quality of the product" and believes the issues are "readily addressable."

Ultragenyx plans to work closely with the FDA over the next few months to resolve the manufacturing issues. The company intends to resubmit its application once these concerns are addressed, which would initiate a new six-month review period.

Implications for Rare Disease Treatment and FDA Approach

UX111 is an in vivo gene therapy that uses an adeno-associated viral vector to deliver a functional copy of the SGSH gene to cells, addressing the underlying enzyme deficiency responsible for Sanfilippo syndrome type A. This rare neurodegenerative disease, which manifests in early childhood, affects an estimated 3,000 to 5,000 patients in commercially accessible geographies and currently has no approved treatment.

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 added uncertainty to UX111's regulatory future.

Market Response and Analyst Perspectives

Following the announcement, Ultragenyx's stock price fell about 5% on Friday, July 11, but showed signs of recovery, trading up nearly 1% at the opening of trading on Monday, July 14. Despite the setback, several analysts remain optimistic about the therapy's long-term prospects.

Leerink Partners analyst Joseph Schwartz described the rejection as "a speed bump to approval, rather than a roadblock." Similarly, analysts at Jefferies stated that they "don't see today's update as negative" for Ultragenyx, given that the rejection appears to be focused on manufacturing rather than clinical efficacy or safety concerns.

The FDA's decision on UX111 underscores the complex nature of cell and gene therapy manufacturing. As former FDA Commissioner Scott Gottlieb noted in 2018, the review process for these therapies often focuses more heavily on product issues compared to traditional drug reviews. This rejection adds to a growing list of manufacturing-related concerns in the cell and gene therapy space, with a recent Jefferies analysis finding that manufacturing problems were mentioned in 51% of past complete response letters for since-approved drugs.