Ultragenyx is going through a rough patch. Days after reporting a disappointing mid-term phase 3 readout for an antibody drug, the company has received an FDA rejection for its rare disease gene therapy.
The FDA has declined to approve UX111, Ultragenyx’s gene therapy for Sanflilippo syndrome type A, a rare disease that causes progressive damage to the central nervous system.
In a complete response letter issued to the company, the FDA requested additional information and improvements around manufacturing-related issues and observations from production facility inspections, Ultragenyx said in a July 11 press release.
“The company believes that these observations are readily addressable, related to facilities and processes, and are not directly related to the quality of the product,” the company said.
The letter didn’t raise any problems with the data package or clinical inspections, but the FDA asked that Ultragenyx include updated clinical data from current trial patients in its resubmission, according to the company.
“[T]he FDA has acknowledged that the neurodevelopmental outcome data provided to date are robust and the biomarker data provide additional supportive evidence,” Ultragenyx said in its release Friday.
The manufacturing-related rejection for UX111 is more than a setback for Ultragenyx, as it also delays a key test of the new FDA leadership’s much-touted support for cell and gene therapies against rare diseases.
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 to address the underlying sulfamidase (SGSH) enzyme deficiency responsible for Sanflilippo syndrome type A, which has no approved treatment. The neurodegenerative disease manifests in early childhood and is estimated to affect about 3,000 to 5,000 patients in commercially accessible geographies, according to Ultragenyx.
As was the case with many other rare disease therapies, Ultragenyx’s FDA application for UX111 was based on data from a small group of patients from a single-arm trial. The company filed for accelerated approval using a surrogate biomarker endpoint measuring levels of heparan sulfate in cerebrospinal fluid.
In February, the FDA accepted Ultragenyx’s application and granted it a priority review with a target action date of Aug. 18.
But the FDA has undergone major changes since February, which have added significant uncertainties to UX111’s regulatory future. Notably, Vinay Prasad, M.D., who has blasted the FDA’s previous approval of Sarepta Therapeutics’ Duchenne muscular dystrophy gene therapy Elevidys, has become the new director of the Center for Biologics Evaluation and Research, overseeing reviews of gene therapies. Then Nicole Verdun, M.D., who led the FDA’s super office of cell and gene therapy, and her deputy Rachel Anatol, Ph.D., were reportedly put on administrative leave.
A decision on UX111 could give the industry an early understanding of the new FDA’s regulatory approach to gene therapies after U.S. health officials, including Prasad, indicated continued support for the field.
Following the recent FDA leadership changes, Jefferies analysts had given UX111 a 50-50 chance at approval, citing “uncertainty with the new administration and the risk inherent in small n, single-arm gene therapy datasets.”
Because the rejection appears to be about manufacturing, the Jefferies team said in a Friday note that they “don’t see today’s update as negative” for Ultragenyx.
Similarly, in a separate Friday note, analysts at Leerink Partners called the complete response letter “a speed bump to approval, rather than a roadblock.”
Cell and gene therapies face significant manufacturing hurdles thanks to their complex constructs and highly bespoke nature.
“In contrast to traditional drug review, where 80% of the review is focused on the clinical portion of that process, and maybe 20% is focused on the product issues, I’d say that this general principal is almost completely inverted when it comes to cell and gene therapy,” former FDA Commissioner under the previous Trump administration, Scott Gottlieb, M.D., said in 2018.
Back in 2020, Sarepta’s then-investigational Elevidys was hit with a regulatory delay as the FDA requested an additional potency assay before the company could start a phase 3 trial.
More broadly speaking, manufacturing issues were among the most commonly cited in the FDA’s past rejections of drug applications. Among the more than 200 past complete response letters for since-approved drugs that the FDA released to a database last week, manufacturing problems were mentioned in 51% of cases, a Jefferies analysis found.