FDA Issues Complete Response Letter to BioMarin for Hemophilia A Gene Therapy

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BioMarin received the complete response letter for valoctocogene roxaparvovec, its gene therapy intended for treating severe hemophilia A.

FDA has issued a complete response letter (CRL) to BioMarin Pharmaceutical for the company’s biologics license application (BLA) for valoctocogene roxaparvovec, a gene therapy for treating severe hemophilia A. The CRL was issued on Aug. 18, 2020 and indicates that BioMarin’s application is not ready for regulatory approval as it presently stands. BioMarin plans to meet with the agency in the coming weeks to work through the next steps needed for approval, the company announced in an Aug. 19, 2020 press release.

Although the company had a previous agreement with FDA on the extent of data required in the BLA, FDA introduced a new recommendation for two years’ worth of data from an ongoing Phase III trial the company is conducting. The new recommendation is meant to allow for the collection of data, using annualized bleeding rate as the primary endpoint, to provide substantial evidence that the therapy has a durable effect. FDA informed BioMarin of this new recommendation in the CRL.

FDA’s recommendation involves BioMarin completing the Phase III study and submitting two-year follow-up safety and efficacy data on all study participants. FDA also concluded in its CRL that differences between a Phase I/II study and the ongoing Phase III study limited the agency’s ability to determine the durability of the gene therapy’s effect. The Phase III study was fully enrolled in November 2019. The company expects the last patient in that study to complete two years of follow up in November 2021.

BioMarin’s BLA was based on an interim analysis of study participants in the Phase III study who were treated with investigational gene therapy product that was manufactured by a yet-to-be-commercialized process as well as three-year data from the Phase I/II study. FDA had granted valoctocogene roxaparvovec priority review status and breakthrough therapy and orphan drug designations. The therapy maintains its breakthrough therapy and orphan drug designations.

"We remain committed to the hemophilia community and to leading the way to the first ever gene therapy in hemophilia A," said Jean-Jacques Bienaimé, chairman and CEO of BioMarin, in the press release."We are surprised and disappointed that [FDA] introduced new expectations for the first time in the [c]omplete [r]esponse [l]etter. We are confident in valoctocogene roxaparvovec gene therapy and its potential to redefine the treatment paradigm for people with hemophilia A."

The company will continue with ongoing clinical trials while it explores the next steps to obtain FDA approval. The company’s marketing authorization application with the European Medicines Agency remains ongoing.


The product was expected to be the first-to-market hemophilia gene therapy in the United States, with the hope of launching in 2020, according to an Aug. 20, 2020 GlobalData analyst statement. FDA’s CRL, however, delays the US launch to 2022.

“The introduction of gene therapies will revolutionize the hemophilia treatment landscape and despite an initially slow uptake, will be a major driver for the hemophilia market, which is expected to reach $9.3 [billion] by 2028, according to GlobalData. However, it comes as no surprise that these treatments will face market access issues due to the lack of long-term safety and efficacy data and the high cost of gene therapies targeting a small patient population,” said Tajekesa Chapman, a senior pharma analyst at GlobalData, in the statement.

“Curative options such as gene therapies provide permanent expression of clotting factor and are highly anticipated to eradicate the need for prophylactic factor replacement therapies—which severe hemophilia A patients heavily depend on to prevent spontaneous bleeding. A single gene therapy administration removes the burden of frequent dosing and administration by intravenous infusion and avoids the risk of developing inhibitors against replacement factors,” Chapman added in the statement.

Source: BioMarin Pharmaceutical and GlobalData