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BioMarin to Delay Seeking FDA Approval for Hemophilia A Gene Therapy by Three Months to Address FDA Request for Data and Analysis

May 31, 2022

BioMarin reported more than six years of positive data for its experimental hemophilia A gene therapy Roctavian from an ongoing phase 1/2 study but said it does not expect to file for U.S. Food and Drug Administration approval until September because the FDA has requested it include additional data and analysis in its application.

The company said the FDA has not requested additional pre-clinical or clinical studies. While at present, no requests have been made concerning evaluation of efficacy and safety three years after dosing from the GENEr8-1 study, BioMarin said that such data will become available during the anticipated BLA review. Based on these new information requests, the company said the Biologics Application License resubmission is now expected by the end of September. Previously, the company expected to file the application by the end of June 2022. In August 2020, the FDA said it wouldn’t approve the gene therapy without additional data demonstrating the durability of the therapy.

“The thorough feedback recently provided by the FDA increases our ability to support the FDA’s review of our application and hopefully makes Roctavian available as a choice for patients in the United States,” said Hank Fuchs, president of worldwide research and development at BioMarin. “We are encouraged after six years of data in this phase 1/2 study by the consistent and durable bleed control following a one-time treatment with Roctavian. These data demonstrate the potential to change the treatment paradigm by providing severe hemophilia A patients hope for longer intervals free from prophylactic therapy.”

The European Medicines Agency continues the review of BioMarin’s Marketing Authorization Application for Roctavian. The company expects a Committee for Medicinal Products for Human Use opinion mid-year 2022. BioMarin has provided the EMA with two-year follow-up safety and efficacy data from the GENEr8-1 study.

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 (FVIII levels <1%) 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. People with hemophilia A with moderate (FVIII 1-5%) or mild (FVIII 5-40%) disease show a much-reduced propensity to bleed.

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.

The updated results from its ongoing open-label phase 1/2 study represents the longest duration of clinical observation for Roctavian. It showed six-year post-treatment follow-up of the 6e13 vg/kg and five-year 4e13 vg/kg cohorts demonstrated sustained hemostatic efficacy of Roctavian. The company plans to share the data during an oral presentation at the upcoming International Society on Thrombosis and Haemostasis (ISTH) 2022 Congress July 9 to 13.

All participants in the 6e13 vg/kg cohort remain off prophylactic Factor VIII treatment at the time of the data cut. The mean cumulative annualized bleed rate (ABR) remains less than one and substantially below baseline levels; the mean ABR in year six was 0.7 with a mean cumulative ABR reduction of 95 percent and Factor VIII use reduction of 96 percent through six years, compared to baseline.

All participants in the 4e13 vg/kg cohort were off prophylactic Factor VIII at the time of the data cut. Six months prior to the data cut, one participant temporarily resumed prophylactic Factor VIII treatment for one month, after which he was bleed free through the last follow up. The mean annualized bleed rate in year five for the 4e13 vg/kg cohort was 0.7 with a mean cumulative ABR reduction of 91 percent and Factor VIII use reduction of 93 percent through five years, compared to baseline.

Overall, the safety profile of Roctavian in the phase 1/2 study remains consistent with previously reported data with no delayed-onset treatment related adverse events. All participants continue to remain off corticosteroids since the first year. No participants developed inhibitors to Factor VIII, and no participants withdrew from the study. No participants have developed thrombotic events. The most common adverse events associated with Roctavian occurred early after a single infusion and included short-lived infusion-associated reactions and transient, asymptomatic, and mild to moderate rise in the levels of certain proteins and enzymes measured in liver function tests with no long-lasting clinical sequelae.

A serious adverse event of a parotid acinic cell carcinoma was identified in one study participant, who was treated more than five years ago, and was reported as unrelated to Roctavian by the investigator. The study participant was successfully treated. The relevant health authorities were notified, and all studies remain ongoing without modification. The independent Data Monitoring Committee (DMC) further reviewed the case. A genomic analysis was conducted as prespecified in the clinical trial protocol and the findings from the completed analysis showed a comparable pattern of integration between healthy and tumor containing tissues, with no evidence emerging that vector integration contributed to the salivary gland mass.

The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to Roctavian in March 2021. RMAT is an expedited program intended to facilitate development and review of regenerative medicine therapies, such as Roctavian, that are intended to address an unmet medical need in patients with serious conditions. The RMAT designation is complementary to Breakthrough Therapy designation, which the Company received in 2017. In addition to the RMAT and Breakthrough Therapy designations, BioMarin’s Roctavian also has received orphan drug designation from the FDA and EMA for the treatment of severe hemophilia A. The Orphan Drug Designation program is intended to advance the evaluation and development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.

Author: Rare Daily Staff

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