Ultragenyx scored a belated regulatory win with the FDA approval of a first-in-disease gene therapy, giving the company a boost after a previous regulatory rejection and a recent late-stage setback.
The FDA has approved Ultragenyx’s Fayuvi as the first treatment for children with mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome type A, a rare genetic disorder.
MPS III is a neurodegenerative disorder, with MPS IIIA as the most common form. Due to a change in the SGSH gene, patients with MPS IIIA cannot make enough of an enzyme called sulfamidase. Without the enzyme, complex sugar molecules called heparan sulfate build up in cells and damage the brain, causing children to lose cognitive, language and other developmental abilities over time.
According to Ultragenyx, an estimated 3,000 to 5,000 patients in the developed world are affected by Sanfilippo syndrome type A.
Fayuvi, previously known as UX111, uses an adeno-associated viral vector to deliver a working copy of the SGSH gene into the patient’s cells. It marks the first FDA-approved therapy designed to address the underlying disease; previously, treatment for MPS IIIA focused on managing symptoms.
“The approval of Fayuvi marks a historic moment for children and families living with MPS IIIA, which is a disease that has, until now, offered no approved treatment to alter its devastating course,” Acting FDA Commissioner Kyle Diamantas said in a Sept. 17 statement. “Gene therapy holds tremendous promise for rare diseases like Sanfilippo syndrome type A, and this milestone reflects the FDA's commitment to action.”
The road to this milestone was not without hurdles for Ultragenyx. Last year, the FDA declined to approve the one-time gene therapy due to manufacturing-related issues at Ultragenyx’s own gene therapy production facility and a third-party manufacturer. The California biotech has publicly stated that it’s producing Fayuvi at its facility in Bedford, Massachusetts, and through Andelyn Biosciences in Columbus, Ohio.
The FDA accepted the company’s resubmission in April and put it under priority review.
The FDA evaluated data from a small group of patients from a single-arm trial, which measured levels of heparan sulfate in cerebrospinal fluid as a biomarker, as well as neurodevelopmental outcomes and compared them with natural history.
Among 17 children under 2 years of age or with earlier-stage of the disease at the time of treatment, a one-time intravenous infusion of Fayuvi led to a positive 23.2-point treatment effect in cognitive score as measured by Bayley-III compared to natural history data.
Eight children reached a 36-month cognitive development age, whereas no one in the natural history cohort reached this milestone.
Among 10 older or later-stage children, retention of functional abilities was observed in at least one of three areas at the time of their last assessment, exceeding typical decline patterns in untreated children with Sanfilippo syndrome Type A.
The above data were presented in February and submitted to the FDA as part of Ultragenyx’s application for Fayuvi.
“We recognize the profound urgency of making this therapy available to families, and our focus now is on supporting timely access in the U.S. as we work closely with treatment centers and payers to support families on the gene therapy treatment journey,” Ultragenyx CEO Emil Kakkis, M.D., Ph.D., said in a Sept. 17 statement.
Fayuvi marks Ultragenyx’s second FDA approval in less than a month, following an FDA accelerated approval for its other AAV gene therapy, Genglycos, for the rare genetic disorder glycogen storage disease type Ia (GSDIa).
However, the company is still reeling from a major clinical setback earlier this month, which saw its Angelman syndrome candidate, an antisense oligonucleotide therapy called apazunersen, crash out in phase 3 development. Following the phase 3 Aspire trial flop, Ultragenyx’s stock price hit its all-time low this month, as the company mulls potential “significant expense reductions.”
Fayuvi’s approval also comes in the wake of a turbulent time, during which the FDA’s former leadership took a stringent approach to rare disease approvals. The heightened regulatory scrutiny led to a demonstration co-staged by National MPS Society at the FDA’s White Oak campus in March. Since then, the FDA has approved Denali Therapeutics’ enzyme replacement therapy Avlayah for Hunter syndrome, or MPS II.
The agency also walked back a previous request for Regenxbio to incorporate a control arm for its MPS II gene therapy candidate RGX-121, although the Maryland biotech’s FDA refiling plan was recently stalled because of a clinical hold following a safety signal in a sister program designed for MPS I.