A gene therapy designed to treat the severest cases of the most common type of hemophilia has been rejected by the FDA, which wants more data on the durability of the investigational treatment developed by BioMarin Pharmaceutical.
Letters issued by the FDA turning down experimental treatments aren’t made public, but BioMarin (NASDAQ: BMRN) says the missive requested data that the agency hadn’t previously told it the company would need to support approval of the bleeding disorder drug, valoctocogene roxaparvovec (Roctavian).
Shares of San Rafael, CA-based BioMarin closed down 35 percent Wednesday at $76.71. In an SVB Leerink research note analysts called the announcement a “major negative surprise” because the company and the regulator had previously agreed on the extent of data required to support review of the gene therapy.
The company’s marketing application was based on three-year data from a Phase 1/2 study and interim data from a Phase 3 study. According to information relayed by BioMarin about the FDA’s decision, differences between those studies hampered the agency’s ability to rely on the earlier study as evidence of durability of effect.
Hemophilia A, a disorder that can be inherited or occur as a result of a spontaneous mutation, is characterized by too little of a protein called factor VIII, which plays a key role in helping blood clot. Low levels of the blood-clotting protein mean even modest injuries can cause life-threatening bleeding.
About 1 in 10,000 people have hemophilia A. The most severe form of the condition occurs in those who make less than 1 percent of typical levels of factor VIII, and these patients—who comprise about 50 percent of those with hemophilia A—may experience painful, spontaneous bleeds into their muscles or joints. To reduce those episodes, patients are treated with frequent intravenous infusions of a substitute for naturally produced factor VIII. Even with those infusions, some patients still experience “breakthrough” bleeding episodes, according to BioMarin.
The biotech’s gene therapy, administered as a single infusion, delivers a functioning version of the gene that codes for factor VIII. Valrox, as the therapy is called for short, is intended to increase patients’ levels of that clotting protein in order to reduce or eliminate such bleeding episodes.
BioMarin said the FDA’s letter, issued Tuesday, recommended more data than the agency had previously informed it would be necessary—specifically, two years of data from the Phase 3 study. The biotech says the agency wants it to finish the Phase 3 trial and submit two-year follow-up safety and efficacy data from those patients. The last patient added to the trial, which enrolled 134 patients, will reach the two-year mark in November 2021, BioMarin says.
The FDA plans to use those data to determine whether there is enough evidence to show valrox has a durable effect based on the number of bleeding episodes patients experience yearly, a measure known as the annualized bleeding rate. Currently a secondary goal in the late-stage trial, the agency recommends the company consider using the measure as a main goal, BioMarin said.
Last May the company announced it planned to ask the FDA to approve the gene therapy, and it released data from the earlier study that it said indicated valrox should stop hemophilia A patients’ spontaneous bleeding for at least eight years. The estimate took into consideration data from a group of seven patients who had been on the therapy for three years as well as early data from the Phase 3 trial.
Company CEO Jean-Jacques Bienaimé, in a prepared statement, said the firm was “surprised and disappointed” by what the firm described as the FDA’s new expectations, and he added that the company will continue evaluating valrox in clinical trials as it determines how to proceed. In the meantime, valrox remains under review by the European Medicines Agency.
Other companies are also working on potential genetic fixes for patients with hemophilia, including partners Sangamo Therapeutics (NASDAQ: SGMO) and Pfizer (NYSE: PFE), and Roche, which inherited a gene therapy program being developed for patients with hemophilia Awhen it acquired Spark Therapeutics. This summer Regeneron Pharmaceuticals (NASDAQ: REGN) and Intellia Therapeutics (NASDAQ: NTLA) added the bleeding disorders to their existing gene-editing alliance.
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