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

Ultragenyx Pharmaceutical Inc. has faced a significant setback as the U.S. Food and Drug Administration (FDA) declined to approve its investigational gene therapy, UX111, for the treatment of Sanfilippo syndrome type A. The rejection, focusing on manufacturing-related issues, comes as a blow to the California-based biotech company and raises questions about the regulatory landscape for cell and gene therapies under new FDA leadership.

Manufacturing Concerns Take Center Stage

In a complete response letter issued to Ultragenyx, the FDA requested additional information and improvements related to manufacturing processes and production facility inspections. The company emphasized that these observations are "readily addressable" and not directly related to the quality of the product itself. Ultragenyx plans to address these issues in the coming months and anticipates a six-month review period following resubmission of the application.

The FDA's focus on manufacturing aligns with a broader trend in the cell and gene therapy space. As former FDA Commissioner Scott Gottlieb noted in 2018, the review process for these complex therapies often inverts the traditional drug review model, with up to 80% of the focus on product issues rather than clinical data.

Clinical Data Remains Robust

Despite the manufacturing setbacks, Ultragenyx received positive feedback on its clinical data package. The FDA acknowledged the robustness of the neurodevelopmental outcome data and the supportive evidence provided by biomarker data. This recognition suggests that the therapy's efficacy and safety profile remain promising, potentially smoothing the path for future approval once manufacturing concerns are addressed.

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

Regulatory Uncertainty in the Gene Therapy Landscape

The rejection of UX111 comes at a time of significant change within the FDA's leadership, particularly in the realm of cell and gene therapies. The appointment of Vinay Prasad, M.D., as the new director of the Center for Biologics Evaluation and Research, coupled with recent administrative changes in the FDA's cell and gene therapy office, has introduced uncertainty into the regulatory process.

Industry analysts, including those at Jefferies and Leerink Partners, view the complete response letter as a "speed bump" rather than a significant setback for Ultragenyx. However, the decision delays an important test case for the new FDA leadership's approach to cell and gene therapies targeting rare diseases.

As the pharmaceutical industry navigates these regulatory challenges, the outcome of Ultragenyx's efforts to address the FDA's concerns will be closely watched. The company's ability to swiftly resolve manufacturing issues and resubmit its application could provide valuable insights into the evolving landscape of gene therapy development and approval.