BioMarin Prepares for PDUFA Delay for Val-Rox Hemophilia Gene Therapy


Recent communication with the FDA suggests that the agency's decision might be delayed past Q1 2023.

In a status update for its biologics license application (BLA) for valoctocogene roxaparvovec (val-rox), BioMarin disclosed that the gene therapy's PDUFA target action date may be delayed if the FDA deems the submission of new data from a phase 3 analysis as a major amendment to the application.1

The AAV gene therapy, which is under review for the treatment of severe hemophilia A in adults, currently has a PDUFA date of March 31, 2023. In recent communications with the FDA, BioMarin noted that the agency has scheduled its inspection of the company's manufacturing facility in California and has requested the submission of expected 3-year data from on the ongoing phase 3 GENEr8-1 clinical trial. These data, once reviewed by the agency, could be considered a major amendment and therefore extend the review period by 3 months.

"We appreciate the level of engagement from FDA this early in their BLA review cycle and are pleased to share that the inspection of our gene therapy manufacturing facility has now been scheduled. Additionally, with their request related to the upcoming three-year data analysis from our Phase 3 GENEr8-1 study, FDA stated that these data are expected to provide longer-term efficacy and safety information and would thus be useful to people with Hemophilia A and healthcare providers in making better and more informed decisions when considering valoctocogene roxaparvovec as a treatment choice should it be approved," said Hank Fuchs, MD, president of worldwide research and development, BioMarin, in a statement.

The FDA accepted BioMarin's resubmitted BLA for val-rox in October 2022, following marketing authorization by the European Commission in August 2022. The gene therapy has received RMAT, breakthrough therapy, and orphan drug designations from the FDA.

Full 52-week results from the GENEr8-1 study were published earlier this year in the New England Journal of Medicine,2 demonstrating that a single dose of the infused gene therapy resulted in statistically significant increases in endogenous Factor VIII production (P <.001) and signficantly reduced bleeding events and use of factor VIII concentrate (P <.001 for both), all while maintaining a relatively good safety profile (N = 134).

Data released in January 20223 from a subset of the modifiend intent-to-treat population (n=17) of patients who had been dosed at least 3 years prior to data cutoff showed a mean factor VIII activity of 16.8 IU/dL by CS assay and 27 IU/dL by OS assay, with a mean cumulative annualized bleeding rate of 0.7 over the 174-week evaluation period and 0.6 during year 3.

BioMarin is expected to publish its full 3-year data analysis from the entire cohort in early 2023.

The FDA isn't the only agency waiting on long-term benefits of the drug. In its final evidence report, The Institute for Clinical and Economic Review (ICER) has concluded that the price of valoctocogene roxaparvovec (val-rox; Roctavian; BioMarin) should be capped at $1.9 million and the price of etranacogene dezaparvovec (EtranaDez; uniQure and CSL Behring) should be capped at $2.9 million,4 noting the unknown long-term benefits of val-rox.

"The new gene therapies can result in successfully-treated patients appearing ‘cured’ for at least a period of time. During this period these gene therapies will eliminate the need for expensive prophylactic treatment," David Rind, MD, chief medical officer, ICER, said in a statement.5 "However, the duration of this ‘cure’ and the safety of therapies remain important uncertainties. At least with val-rox, patients will eventually return to needing prophylaxis.”

1. BioMarin Announces Incremental Progress on Biologics License Application (BLA) Review for Valoctocogene Roxaparvovec AAV Gene Therapy for Adults with Severe Hemophilia A Program. News release. BioMarin Pharmaceutical. November 7, 2022.
2. Ozelo MC, Mahlangu J, Pasi J, et al. Valoctocogeneroxaparvovec gene therapy for hemophilia A. New Eng J Med. 2022; 386: 1013-1025. doi: 10.1056/NEJMoa2113708
3. BioMarin Announces Stable and Durable Annualized Bleed Control in the Largest Phase 3 Gene Therapy Study in Adults with Severe Hemophilia A; 134-Participant Study Met All Primary and Secondary Efficacy Endpoints at Two Year Analysis. News release. BioMarin Pharmaceutical. January 9, 2022.
4. Institute for Clinical and Economic Review. Gene therapy for hemophilia B and an update on gene therapy for hemophilia A: Effectiveness and value. November 3, 2022.
5. ICER Publishes Evidence Report on Gene Therapies for Hemophilia A and B. News release. ICER. November 3, 2022.
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