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BioMarin Reports Hemophilia A Gene Therapy Produced Stable and Durable Annualized Bleed Control in Two Year Analysis

January 10, 2022

BioMarin Pharmaceutical reported positive results from its ongoing global phase 3 GENEr8-1 study of valoctocogene roxaparvovec, an experimental gene therapy for the treatment of adults with severe hemophilia A.

In 2019, the U.S. Food and Drug Administration said it would not approve the gene therapy without additional data to further demonstrate its durability.

People living with hemophilia A lack sufficient functioning Factor VIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Additionally, people with the most severe form of hemophilia A often experience painful, spontaneous bleeds into their muscles or joints. Individuals with the most severe form of hemophilia A make up approximately 50 percent of the hemophilia A population.

The standard of care for individuals with severe hemophilia A is a prophylactic regimen of replacement Factor VIII infusions administered intravenously up to two to three times per week or 100 to 150 infusions per year. Despite these regimens, many people continue to experience breakthrough bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.

Valoctocogene roxaparvovec is an AAV-factor VIII gene therapy designed to restore adequate levels of factor VIII for normal clotting. The therapy is being developed as a one-time treatment for adults with severe hemophilia A and could eliminate the need for ongoing factor VIII treatments.

In the GENEr8-1 phase 3 study, Annualized Bleeding Rate (ABR) was significantly reduced by 4.1 treated bleeds per year, or 85 percent from a baseline mean of 4.8 (median 2.8), in the pre-specified primary analysis in participants from a prior non-interventional study. The mean ABR was 0.8 through the entire efficacy evaluation period, 0.9 during year one, and 0.7 during year two.

Valoctocogene roxaparvovec also significantly reduced the mean annualized Factor VIII infusion rate in the rollover population by 133 infusions per year or 98 percent from baseline. The mean annualized infusion rate was 2.6 through the entire efficacy evaluation period, 1.5 (median 0.0) during year one, and 3.4 during year two.

At the end of the second-year post-infusion with valoctocogene roxaparvovec, participants in the modified intent-to-treat (mITT) population had a mean endogenous Factor VIII activity level of 23.0 IU/dL, as measured by the chromogenic substrate assay and 36.1 IU/dL, as measured by the one-stage assay.

In a subset of the mITT population that had been dosed at least three years prior to the data cut, mean Factor VIII activity was 16.8 IU/dL by CS assay and 27.0 IU/dL by OS assay at the end of year three. The mean cumulative ABR for this subpopulation was 0.7 through the entire efficacy evaluation period and 0.6 during year three.

BioMarin plans to present additional data from this study at upcoming medical meetings.

“A potential single treatment that provides a durable response for years could be a game-changer by offering a transformative treatment choice beyond existing therapies and addressing an unmet medical need for people with hemophilia A,” said Steven Pipe, professor of Pediatrics and Pathology at the University of Michigan and investigator in the phase 3 study. “As a principal investigator, I have witnessed the transformative liberating potential of valoctocogene roxaparvovec for hemophilia A in my own clinical trial participants.”

Overall, in the phase 3 study, valoctocogene roxaparvovec has continued to be well tolerated. All participants received a single 6e13 vg/kg dose. No participants developed inhibitors to Factor VIII, malignancy, or thromboembolic events. During year two, no new safety signals emerged, and no treatment-related serious adverse events (SAE) were reported. Most patients had discontinued any corticosteroid use in year one, and there was no corticosteroid -related SAEs in the remaining patients being tapered off corticosteroid in year two.

Overall, the most common adverse events (AE) associated with valoctocogene roxaparvovec occurred early and included transient infusion associated reactions and mild to moderate rise in liver enzymes with no long-lasting clinical sequelae. Alanine aminotransferase (ALT) elevation (119 participants, 89 percent), a laboratory test of liver function, remained the most common AE. Other common adverse events were headache (55 participants, 41 percent), arthralgia (53 participants, 40 percent), nausea (51 participants, 38 percent), aspartate aminotransferase (AST) elevation (47 participants, 35 percent), and fatigue (40 participants, 30 percent).

“These results show that valoctocogene roxaparvovec could profoundly change the way hemophilia A is treated,” said Hank Fuchs, president of Worldwide Research and Development at BioMarin. “We are looking forward to continuing to work with health authorities to bring this therapy to patients with hemophilia A.”

The European Medicines Agency (EMA) validated BioMarin’s resubmission of a Marketing Authorization Application (MAA) and a Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) opinion is anticipated in the first half of 2022.

In the United States, BioMarin intends to submit two-year follow-up safety and efficacy data on all study participants from the phase 3 GENEr8-1 study to support the benefit/risk assessment of valoctocogene roxaparvovec, as previously requested by the FDA. Based on these results, BioMarin is planning to meet with FDA to discuss the resubmission of a Biologics License Application targeted for the second quarter of 2022, followed by an expected six-month review by the FDA.

Valoctocogene roxaparvovec has received both Regenerative Medicine Advanced Therapy (RMAT) designation and Breakthrough Therapy designation from FDA, which are intended to expedite development of drugs for serious or life-threatening diseases and conditions. In addition to the RMAT designation and Breakthrough Therapy designation, valoctocogene roxaparvovec also has received Orphan Drug designation from the FDA and EMA for the treatment of severe hemophilia A.

Photo: Hank Fuchs, president of Worldwide Research and Development at BioMarin

Author: Rare Daily Staff

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