Denali Therapeutics has become the latest on a growing list of biotechs to experience an FDA review delay in recent months.
The agency in July accepted an application for Denali’s enzyme replacement therapy, called tividenofusp (tivi), to treat a rare genetic disorder called Hunter syndrome. At the time, the FDA scheduled a decision date for Jan. 5, 2026, but the regulator has just informed Denali that this has been pushed back three months to April 5.
The biotech put the decision in the context of the updated clinical pharmacology information it had supplied to the FDA as part of the application review process. While this information was not related to tivi’s efficacy, safety or biomarkers and did not involve supplying any additional clinical data, according to Denali, the FDA classified the submission as a major amendment to the application, which requires a three-month extension to the deadline.
“Denali believes that the updated information submitted in the amendment does not affect the clinical pharmacology or benefit-risk conclusions of the BLA,” the company explained in an Oct. 13 release.
“We appreciate the FDA’s continued collaboration throughout the review process,” Denali CEO Ryan Watts, Ph.D., said in the release. “We continue to prepare for the potential approval and commercial launch of tividenofusp alfa.”
In separate notes Monday evening, analysts with William Blair and Evercore ISI wrote that the delay came after Denali flagged an incorrect molecular weight for the drug shown on a public source. Because the FDA often uses such sources to inform its pharmacokinetic analyses, Denali “proactively” flagged the discrepancy, according to Evercore ISI’s note, and the FDA responded by asking for “updated molecular weight info directly” from the biotech.
“Management believes that, due to the nature that the discrepancy was identified late in the review cycle, procedurally it made sense for the agency to issue a major amendment, extending the PDUFA by three months,” the William Blair analysts wrote.
Tivi is a version of the iduronate 2-sulfatase enzyme that is engineered to penetrate the blood-brain barrier by binding to transferrin receptor 1, which normally shuttles iron into the brain.
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William Blair analysts labeled the delay “disappointing” but said they viewed it as a “technicality” that is unlikely to affect the eventual decision.
Denali submitted the application on the back of a phase 1/2 open-label trial that enrolled 47 boys around the age of 5. The study noted a sharp decline of the biomarker heparan sulfate in both their cerebrospinal fluid and urine after 24 weeks, with levels dropping by an average of about 90% from baseline.
Hunter syndrome, also called mucopolysaccharidosis type II (MPS II), is characterized by patients’ inability to break down certain sugars, which leads to tissue and organ damage that ultimately causes stiff joints, delayed growth and enlarged spleens and livers, among other symptoms. The disease can also lead to cognitive and behavioral problems, and, in severe cases, patients may not survive beyond their teenage years.
There is one approved enzyme replacement therapy for Hunter syndrome in Takeda’s Elaprase, which the Japanese drugmaker secured as part of its acquisition of Shire Pharmaceuticals in 2019.
In August, the FDA pushed back the approval decision deadline for another Hunter syndrome treatment in the form of Regenxbio’s gene therapy clemidsogene lanparvovec after requesting additional data.
While FDA Commissioner Marty Makary, M.D., pledged in June that the agency was on track to meet all of its PDUFA deadlines despite deep staffing cuts, the regulator has delayed or missed various decision dates this year for various reasons for the likes of Stealth Therapeutics’ rare disease candidate, KalVista Pharmaceuticals’ angioedema asset and Omeros’ transplant drug, among others.
