FDA issues Ultragenyx CRL for Sanfilippo syndrome gene therapy

The U.S. FDA has issued a complete response letter for Ultragenyx Pharmaceutical’s BLA for UX111, an AAV gene therapy as a treatment for patients with Sanfilippo syndrome type A (MPS IIIA).

The CRL cited specific chemistry, manufacturing and controls (CMC)-related observations from recently completed manufacturing facility inspections that Ultragenyx says are resolvable as they are “related to facilities and processes and are not directly related to the quality of the product.”

“We believe the CMC observations are readily addressable and many have already been addressed. While the CRL will delay the potential approval of UX111 to 2026, we are working with urgency to respond and resubmit,” said Emil D. Kakkis, MD, Ph.D., CEO and president of Ultragenyx.

The FDA accepted Ultragenyx’s BLA for UX111 back in February, granting it priority review and assigning a PDUFA action date of August 18, 2025. The agency did not hold an advisory committee meeting to discuss the application.

UX111 is a novel in vivo gene therapy in phase 1/2/3 development for Sanfilippo syndrome type A (MPS IIIA), a rare fatal lysosomal storage disease that primarily affects the brain and currently has no approved treatment. The therapy is designed to address the underlying SGSH enzyme deficiency responsible for abnormal accumulation of heparan sulfate, a glycosaminoglycan, in the brain that results in progressive cell damage and neurodegeneration. UX111 is dosed in a one-time intravenous infusion using a self-complementary AAV9 vector to deliver a functional copy of the SGSH gene to cells.

The BLA submission for UX111 is supported by the latest data from the pivotal Transpher A and long-term follow-up studies presented at WORLDSymposium 2025, demonstrating treatment with UX111 resulted in rapid and sustained decreased levels of heparan sulfate in cerebrospinal fluid in patients with Sanfilippo syndrome type A irrespective of age or stage of disease progression at the time of treatment.

Ultragenyx says it will be working with the FDA over the next few months to resolve the observations. Once resolution is achieved, the company expects to resubmit the BLA and anticipates up to a six-month review period to follow the resubmission.

This marks the second CRL issued by the agency in less than a week. On Friday, Capricor Therapeutics said it had received a CRL regarding its BLA for deramiocel, the company’s lead cell therapy candidate for the treatment of cardiomyopathy associated with Duchenne muscular dystrophy. In the CRL, the FDA said that the BLA didn't meet the requirement for substantial evidence of effectiveness and cited the need for additional clinical data. The CRL also referenced certain outstanding items in the CMC section of the application, but, according to a press release from Capricor, the company believes it has addressed these issues in prior communications with the FDA.