Largest Phase III Hemophilia Gene Therapy Trial Yields Positive Results

BioMarin Pharmaceutical shared positive results from its ongoing Phase III GENEr8-1 trial on the viability of valoctocogene roxaparvovec as a treatment for patients diagnosed with severe hemophilia A.

The study has a total of 134 adult participants, the largest of its kind to date. In the second year of the trial, the researchers saw that valoctocogene roxaparvovec caused an 85% reduction in the annualized bleeding rate (ABR), or by 4.1 treated bleeds per year, from a baseline of 4.8. The mean ABR was 0.8 throughout the entire evaluation period, starting at 0.8 in the first year and then 0.7 in the second year.

In addition to ABR, the drug significantly reduces the annualized Factor VIII infusion rate by 98%, or 133 infusions per year, from the baseline data. The mean annualized infusion rate throughout the duration was 2.6, starting at 1.5 in year one and then 3.4 in year two. At the end of the second year, the participants demonstrated a mean endogenous Factor VIII activity level of 23 IU/dL (measured by chromogenic substrate assay) and 36.1 IU/dL (measured using the one-stage assay).

In summary, the results over the two-year evaluation period showed consistent clinical benefit from using valoctocogene roxaparvovec. The company also posted positive year one results in July 2021.

All participants received a single 6e13 vg/kg dose of the drug and none of them experienced any thromboembolic events, malignancies, or developed inhibitors to Factor VIII. No new safety signals and treatment-related serious adverse events also surfaced. Across the period, the most common adverse event observed were mild to moderate liver enzyme increases with no lasting impacts and transient infusion-associated reactions. Some participants reported headaches, arthralgia, fatigue, and nausea.

Hemophilia A is characterized by a lack of Factor VIII protein for blood clotting, putting those suffering from it at risk from even the most minor injuries. They also often experience painful and spontaneous bleeds into the joints or muscles. Patients with the severe form of the disease make up about 50% of the hemophilia A population. Despite the prophylactic regimen to replace Factor VIII, many patients still experience bleeds, leading to poor quality of life. About one in 10,000 people suffer from this disease.

“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 Dr. Steven W. Pipe, an investigator in the Phase III study and professor of pediatrics and pathology at the University of Michigan, in a statement.

From the trial’s positive results, the European Medicines Agency (EMA) accepted the resubmission of a Marketing Authorization Application (MAA). BioMarin will also be placing the drug for review by the Committee for Advanced Therapies and Committee for Medicinal Products for Human Use within the first half of 2022.

In the U.S., BioMarin will be submitting follow-up efficacy and safety data from the study to comply with the U.S. Food and Drug Administration (FDA)‘s request. The company will be meeting with the FDA soon for its Biologics License Application, which it hopes to obtain by the second quarter of this year after the FDA’s review. Valoctocogene roxaparvovec already has Breakthrough Therapy and Regenerative Medicine Advanced Therapy designations. It also has an Orphan Drug Designation from both the EMA and the FDA for severe hemophilia A.