FDA requests manufacturing changes for UX111 gene therapy
Ultragenyx works to resolve issues with experimental Sanfilippo A treatment
The U.S. Food and Drug Administration (FDA) is requesting changes to Ultragenyx Pharmaceutical’s manufacturing process before it will consider accelerated approval of UX111, the company’s experimental gene therapy for Sanfilippo syndrome type A.
In a corporate update earlier this week, Ultragenyx stated it “believes the observations are readily addressable and many have been addressed.”
The company plans to meet with the FDA to agree on a plan for resolving the issues. Once an agreement is reached, Ultragenyx is planning to resubmit its application seeking accelerated approval of UX111. It will take up to six months for the FDA to review the resubmission.
UX111 application submitted based on clinical trial findings
Sanfilippo type A is caused by mutations in the SGSH gene. These mutations lead to the toxic buildup of a molecule called heparan sulfate in brain cells, which ultimately drives disease symptoms.
UX111 is designed to deliver a healthy copy of the SGSH gene to cells in the brain, thereby addressing the underlying genetic deficit that causes the disease and clearing out toxic heparan sulfate buildups. The therapy is administered by a one-time infusion into the bloodstream.
An ongoing clinical trial called Transpher A (NCT02716246) is testing UX111 in people with Sanfilippo A. The study, which is open to patients of all ages, is still recruiting participants at two sites in Spain. Participants who complete the trial have the option to enter a Phase 3 extension study (NCT04360265), where they will be followed for at least five years.
Available data from the Transpher A trial have indicated UX111 treatment leads to reductions in heparan sulfate levels in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, and that it may improve cognitive and motor skills. Based on these findings, last year Ultragenyx submitted an application asking the FDA to grant UX111 accelerated approval.
FDA seeks additional information, improvements
Accelerated approval is a form of conditional approval where the FDA allows a medication to be brought to market based on early clinical data that it is likely effective, while still requiring drug developers to run additional tests to prove efficacy. Ultragenyx’s application specifically asked the FDA to grant accelerated approval based on the findings that UX111 treatment can reduce heparan sulfate levels in the CSF, which the FDA has previously agreed could serve as a surrogate marker for likely efficacy in Sanfilippo A.
The FDA granted priority review to Ultragenyx’s application, and a decision was expected this month. However, last month the FDA issued a complete response letter — which is effectively a refusal to approve the application at this time.
According to Ultragenyx, the FDA asked for “additional information and improvements related to specific aspects of chemistry, manufacturing and controls (CMC) procedures and validation, as well as observations from the recently completed manufacturing facility inspections.” The company noted that the FDA did not raise any issues with the clinical data, though it did request that updated data from the ongoing trials be included in a resubmission.
Ultraegyx is now working to address these concerns in hopes of resubmitting the application.
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