Gene Therapy Trial Participant’s Cancer Unrelated to Therapy says BioMarin

BioMarin Pharmaceutical reported in an SEC filing that a participant in the late-stage study of its investigational gene therapy to treat hemophilia was diagnosed with B-cell acute lymphoblastic leukemia, which the company believes is not related to the treatment based on initial genetic testing of the leukemic cells.

The company said the overall rate of all cancers observed in all the BMN 270 gene therapy trial patients (2 in approximately 400 patient years of observation) appears consistent with expected rates of cancer in persons with hemophilia.

BioMarin said it has begun a comprehensive assessment of the case. According to the filing: “The preliminary results of genetic testing performed at the site revealed that 85 percent of leukemic cells carried a Philadelphia-like (Ph-like) chromosomal translocation, which is a well-known driver-mutation in leukemic cells. Further, testing on leukemic cells enriched to 90 percent purity from peripheral blood carried negligible levels of BMN 270 vector DNA (less than 1 copy per 500 cells). These negligible, near background levels of BMN 270 indicate that BMN 270 is not clonally expanding in these leukemic cells.”

The company said it is conducting additional genomic analyses, which it expects to confirm the absence of BMN 270 vector integration events contributing to leukemic growth, as well as to provide further insights into the underlying genetic etiology of this case.

BioMarin has submitted an IND safety report to the U.S. Food and Drug Administration and communicated these findings to international health authorities on September 2, 2022, and no authority has requested a hold on any trial at this time. Currently, all trials of BMN 270 are ongoing, including additional enrollments, with no modifications, and BioMarin said it does not expect to make any modifications in the future due to this event. The Company’s independent Data Safety Monitoring Board agreed that this case did not require any modification to BioMarin’s ongoing trials at this time.

BioMarin received conditional marketing authorization from the European Commission at the end of August for BMN 270, marketed as Roctavian, for adults with severe hemophilia A without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5.

Though BioMarin had hoped to win U.S. approval for Roctavian, the U.S. Food and Drug Administration notified the company in August 2020 that it would not approve the gene therapy without additional data to demonstrate the durability of the gene therapy. The concern was that event though all of the participants in an open-label phase 1/2 study of the gene therapy remained off prophylactic therapy after a single dose, the data also showed that factor VIII activity levels declined with the most recent year’s data, even though the participants maintained high enough levels of factor VIII to prevent spontaneous bleeding events.

The agency said it wanted to see two years of data from the phase 3 study to provide substantial evidence of a durable effect using annualized bleeding rate, the endpoint of the study. BioMarin said it is still working to bring Roctavian to eligible patients with severe hemophilia A in the United States and said it is targeting a Biologics License Application resubmission for Roctavian by the end of September 2022. Typically, BLA resubmissions are followed by a six-month review procedure. However, the company anticipates three additional months of review may be necessary based on the number of data read-outs that will emerge during the procedure.

Author: Rare Daily Staff