FDA Approves BioMarin’s Hemophilia A Gene Therapy Roctavian
The FDA’s decision to approve this first gene therapy in hemophilia A was based on data from the phase 3 GENEr8-1 clinical trial.
Steven Pipe, MD
The FDA has approved BioMarin’s valoctocogene roxaparvovec (val-rox) for the treatment of adults with severe hemophilia A defined as congenital factor VIII (FVIII) deficiency with FVIII activity of less than 1 IU/dL who do not have antibodies to adeno-associated virus serotype 5 (AAV5) according to an FDA-approved test.1 Val-rox will be marketed in the United States under the name Roctavian; it is the first gene therapy for hemophilia A to be approved in the US.
The decision was based on data from the phase 3 GENEr8-1 clinical trial (NCT03370913)1,2 Val-rox is contraindicated for patients with acute or uncontrolled chronic infections, significant hepatic fibrosis, cirrhosis, or hypersensitivity to mannitol. The gene therapy is being manufactured at a facility in Novato, California. BioMarin noted that it will offer an outcomes-based warranty for val-rox to insurance companies in the United States that includes a provision for full reimbursement in the event that a patient's disease does not respond to the treatment. The company also announced during their conference call after the approval that val-rox will be priced at $2.9 million.
"Adults with severe hemophilia A face a lifelong burden, with frequent infusions and a high risk of health complications, including uncontrolled bleeding and irreversible joint damage," Steven Pipe, MD, an investigator on GENEr8-1 and the director of the Pediatric Hemophilia and Coagulation Disorders Program at CS Mott Children’s Hospital, said in a statement.1 "The approval of Roctavian, as the first gene therapy for severe hemophilia A, has the potential to transform the way we treat adults based on years of bleed control following a single, 1-time infusion."
In January 2023, BioMarin reported that GENEr8-1 had met all of its primary and secondary efficacy end points.3 The 3-year data analysis included findings from 112 patients for annualized bleeding rate (ABR) and annualized Factor VIII (FVIII) utilization (AFR) and findings from 132 patients for FVIII activity. The mean ABR for treated bleeds was 1.9 (median, 0.0), the mean AFR was 8.4 (median, 0.0), and the mean FVIII activity was 18.8 IU/dL (median, 8.4). Two of the patients included in the analysis discontinued participation before reaching 3 years of follow-up; FVIII activity was imputed as 0 IU/dL. BioMarin noted that 92% of participants had not resumed prophylaxis at the 3-year timepoint; resumption was safe for the patients who did restart prophylaxis with FVIII or emicizumab. All patients included in the study received val-rox at a dose of 6x1013 vg/kg.
READ MORE: FDA Accepts BLA Filing for Hemophilia B Gene Therapy Fidanacogene Elaparvovec
The FDA-approved labeling includes the prospective data from 112 patients in whom 6-month baseline ABR was collected, who reported a mean ABR reduction of 52% (2.6 bleeds per year) through the end of follow-up (median, 3 years) compared with baseline ABR while receiving routine FVIII prophylaxis (5.4 bleeds per year). Those data were based on an FDA analysis that imputed an ABR of 35 in 13 patients for the periods when these patients were on prophylaxis. Those individuals additionally reported a substantial reduction in the rate of spontaneous bleeds and joint bleeds following treatment, for an observed mean ABR of 0.5 bleeds per year for spontaneous bleeds and 0.6 bleeds per year for joint bleeds, in comparison with their baseline rate while receiving routine FVIII prophylaxis (spontaneous: mean ABR, 2.3 bleeds per year; joint: mean ABR, 3.1 bleeds per year).
"Today's approval of Roctavian builds on BioMarin's proven track record of advancing treatments that target the underlying cause of life-threatening genetic conditions, which has produced 8 best- or first-in-class commercial therapies," Jean-Jacques Bienaimé, MBA chairman and chief executive officer of BioMarin, added to the statement.1 "We are proud to now offer adults with severe hemophilia A, a 1-time, single-dose treatment option. We are especially grateful to the bleeding disorders community for its support of this program, and to all the patients and healthcare providers who participated in our clinical trials."
In terms of safety, val-rox was reported to be well-tolerated at the GENEr8-1 dose as of the 3-year data analysis announcement. Transient infusion-associated reactions and mild to moderate rises in liver enzymes were among the most common adverse events (AEs) reported in patients receiving val-rox that were deemed associated with the treatment. The most common AE related to val-rox was increased levels of alanine aminotransferase. Increased levels of aspartate aminotransferase were observed in 101 patients (63%), 55 patients (34%) experienced cases of nausea, 54 patients (34%) experienced headaches, and 44 patients (28%) experienced fatigue; all of these AEs were deemed related to treatment. No cases of inhibitors to FVIII, thromboembolic events, or malignancy associated with val-rox were reported.
BioMarin originally submitted a BLA for val-rox in August 2020, which was rejected with a request for 2-year follow-up data.4 A resubmission in June 2022 was delayed with requests for additional durability and safety data.5 Meanwhile, val-rox was approved for hemophilia A in the EU in August 2022 with conditional marketing authorization.6 Ultimately, BioMarin submitted the BLA leading to today’s decision in September 2022; the submission included 2-year results from GENEr8-1.7 The Prescription Drug User Fee Act target date for the most recent BLA submission was originally set for March 31, 2023, but was extended to June 30, 2023, following BioMarin’s submission of a 3-year data analysis from GENEr8-1, which the FDA considered a major amendment to the application.8
This landmark news in hemophilia A comes on the heels of momentum in the development of gene therapies in hemophilia overall. Just a few days ago, Pfizer’s biologics license application (BLA) for fidanacogene elaparvovec, an investigational AAV vector-based gene therapy intended to treat adult patients with hemophilia B, was accepted by the FDA for filing with a Prescription Drug User Fee Act (PDUFA) date set for Q2 2024.9 Months before, in late 2022, the FDA approved the first gene therapy for hemophilia B, with UniQure and CSL Behring’s etranacogene dezaparvovec (Hemgenix), for treating adults with hemophilia B who currently use Factor IX prophylaxis therapy, have a current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.10
