FDA Delays Decision on Roctavian, Potential Hemophilia A Gene Therapy, for a Year or More

The U.S. Food and Drug Administration (FDA) has pushed back by more than one year a decision on Roctavian, the potential first gene therapy for adults with hemophilia A.

In a complete response letter that took the therapy’s developer, BioMarin by surprise, the FDA said it needed more and longer-term data to consider Roctavian’s approval.

Specifically, the agency now has requested complete results from two years of follow-up on the 134 patients in the company’s Phase 3 GENEr8-1 trial (NCT03370913), investigating the safety and effectiveness of a single infusion of Roctavian in adults with severe disease. An interim analysis, released last year, included 26-week data on 16 treated patients.

The final patient in this fully enrolled trial will finish two years of post-treatment evaluation in November 2021, meaning a decision by the FDA is not possible until late next year or in 2022.

“We are surprised and disappointed that the FDA introduced new expectations for the first time in the Complete Response Letter.  We are confident in valoctocogene roxaparvovec [Roctavian] gene therapy and its potential to redefine the treatment paradigm for people with hemophilia A,” Jean-Jacques Bienaimé, BioMarin’s chairman and CEO, said in a press release.

“We remain committed to the hemophilia community and to leading the way to the first ever gene therapy in hemophilia A,” he added.

In its letter, the FDA also stated that differences between the two studies supporting the approval request — a Phase 1/2 trial and the Phase 3 study — limited its ability to rely on the earlier trial’s results, which stretch out years, to support the durability of Roctavian in raising factor levels.

After discussions with the FDA, BioMarin first submitted a biologics license application (BLA) requesting Roctavian’s approval in December 2019. The agency accepted the BLA in February and placed it under priority review,  setting Aug. 21 as a decision date.

BioMarin plans to meet with FDA officials in the coming weeks to discuss its best future steps.

The company filed a similar request in November — in the form of a marketing authorization application — to the European Medicines Agency (EMA), which also was accepted for evaluation under accelerated assessment. The company is awaiting an opinion from the EMA’s Committee for Medicinal Products for Human Use regarding possible approval.

Roctavian, formerly known as BMN 270 and Valrox, is a one-time gene therapy aimed at durably restoring the production of factor VIII (FVIII), which is the blood-clotting protein missing in people with hemophilia A.

By doing so, the therapy is expected to reduce and possibly eliminate the need for repeated FVIII infusions, a current standard treatment to avoid spontaneous bleeding episodes.

Roctavian uses a harmless version of an adeno-associated virus (AAV), called AAV5, to deliver a shorter, but functional, copy of F8 — the gene that provides instructions to make FVIII — to liver cells. The activity of this shorter version of F8, known as B-domain deleted human FVIII, is controlled by a liver-specific gene promoter that ensures the production of FVIII happens only in liver cells, the main producers of blood-clotting factors in the body.

BioMarin’s application to the FDA was supported by interim data from the GENEr8-1 trial, as well as three-year data from the Phase 1/2 trial (NCT02576795), called Study 270–201, in 15 men with severe hemophilia A.

GENEr8-1, an open-label safety and effectiveness study, is treating patients with a single infusion of Roctavian at a dose of 6e13 vector genomes per kilogram (vg/kg). All patients had been using prophylactic (preventive) FVIII replacement therapy for at least one year before enrolling in the study.

Its main goal is treatment effects on FVIII activity levels over the course of one year. Secondary goals include assessments of Roctavian on the number of spontaneous bleeds and FVIII infusions in the year following treatment.

Early data from 16 men, followed for 23 to 26 weeks by April 30, 2019, showed that Roctavian for seven patients increased FVIII activity levels to more than 40 international units per deciliter (IU/dL), a pre-specified requirement for regulatory drug submissions in the U.S. and Europe. An eighth patient was reported to reach this same milestone shortly after the April cutoff date.

Treatment also lowered the number of spontaneous annual bleeds patients experienced by 85% since the start of the study, and the annual median usage of FVIII by 84%.

BioMarin has reported that all 134 GENEr8-1 patients have been treated, and one-year study data is expected in early 2021.

Data from the Phase 1/2 trial, assessing the five-year safety and effectiveness of four different doses of Roctavian given through a single infusion to 15 men with severe hemophilia A, also was part of the approval application.

In the two men who received the two lowest doses (6e12 vg/kg and 2e13 vg/kg), Roctavian failed to increase FVIII activity levels beyond 1 IU/dL.

Three-year data from the other 13 patients, including six who received Roctavian at a dose of 4e13 vg/kg and seven treated with the highest 6e13 vg/kg dose, showed the therapy led to clinically meaningful improvements in FVIII activity levels.

In the first year of follow-up, patients given Roctavian at the lower of these doses saw their mean FVIII activity levels increase to 21 IU/dL, while those in the highest dose group had their mean FVIII activity levels increase to 64.3 IU/dL.

FVIII activity levels dropped gradually over time in both groups, however, reaching a minimum of 32.7 IU/dL at the end of the third year in the 6e13 vg/kg dose group, and a minimum of 14.7 IU/dL in the 4e13 vg/kg by the end of the second year of follow-up.

Roctavian also lowered the frequency of annual bleeding episodes by at least 92% in patients in both dose groups. By the end of the second year, more than half (67%) remained free of bleeds requiring additional FVIII treatment.

More recently, the company released data from a four-year update on the seven patients in the highest dose group, along with a three-year update on those treated at the 4e13 vg/kg dose.

This analysis showed that six men (86%) in the 6e13 vg/kg dose group and five (83%) in the 4e13 vg/kg dose group remained free of bleeding events in the past year. Although FVIII activity levels continued to drop in both groups, they remained within a therapeutic range.

Roctavian’s safety profile was consistent with that of previous studies. No new adverse events (side effects) or patient withdrawals were reported. None of the men participating in the study developed factor VIII inhibitors or thrombotic events (blood clots that can obstruct blood vessels).

The FDA previously granted breakthrough therapy and orphan drug status to Roctavian. In Europe, the EMA also named Roctavian an orphan drug and granted it the designation of priority medicines, or PRIME, which is meant to facilitate the development of new medications that address an unmet medical need.