Hopes of a Food and Drug Administration approval of the first gene therapy to treat hemophilia A were dashed Wednesday as the agency issued a rejection for one that had been seen as a likely winner.
San Rafael, California-based BioMarin Pharmaceutical said Wednesday that the FDA had the day before issued a complete response letter, or CRL, for its approval application for valoctocogene roxaparvovec, a gene therapy that it had developed for severe hemophilia.
Shares of BioMarin were down 35% on the Nasdaq following the news.
The company said that despite its agreement with the agency on the data necessary for the gene therapy’s approval, the FDA introduced a new recommendation that, as the primary endpoint, the company use two years of data to provide substantial evidence of durable effect using annualized bleeding rate and suggested it submit two-year follow-up data on all study participants. The Phase III study completed enrollment in November 2019, and the last patient will complete two years of follow-up in November 2021, the company added. In other words, it may not win approval until at least 2022.
BioMarin said the FDA had first informed it of the recommendation in the CRL despite not having raised it at any time during development or review and that it planned to meet with the agency in the coming weeks to determine the next steps to obtain approval. The agency had told the company that differences between the Phase III study and the prior Phase I/II study limited its ability to rely on the latter to support durability of effect.
“We are surprised and disappointed that the FDA introduced new expectations for the first time in the complete response letter,” BioMarin CEO Jean-Jacques Bienaime said in a statement. “We are confident in valoctocogene roxaparvovec gene therapy and its potential to redefine the treatment paradigm for people with hemophilia A.”
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
In a note to investors following the news, RBC Capital Markets analyst Kennen MacKay called the CRL a “massive surprise” and “thesis-changing,” meaning it substantially affects analysts’ outlook on the company. The letter, he wrote, results in concerns about reduced credibility on the part of BioMarin’s management, delay to the gene therapy’s launch and increased concern and risk regarding the therapy itself.
With respect to the differences between the Phase I/II and Phase III studies, MacKay noted that the products in the respective trials used different manufacturing techniques and facilities, which combined with slightly different results in efficacy based on Factor VIII expression, “likely underscore FDA’s concern that manufacturing changes may result in different product characteristics over time,” specifically differences in durability. He noted that in conversations with BioMarin, the company had suggested there were no concerns previously raised about comparability of the data.
Valoctocogene roxaparvovec, also known as valrox and Roctavian, is not the only gene therapy under development for hemophilia A – Roche’s Spark Therapeutics also has one, SPK-8011, in Phase I/II development.
In a note to investors, Cowen analyst Phil Nadeau called the CRL disappointing, surprising and “seemingly not consistent with the strategy BioMarin initially agreed upon with the Agency.” However, he added that the company’s apparent weakness appears overdone, and the agency could institute similar two-year data requirements for all gene therapies in hemophilia A. If that were the case, he wrote, BioMarin’s product would still likely be the first such product to hit the market.
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