BioMarin Says Cancer Case in Trial Not Tied to Roctavian Gene Therapy

No holds called for by regulators in ongoing hemophilia A clinical trials

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by Steve Bryson, PhD |

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A participant in a Phase 3 clinical trial evaluating Roctavian (valoctocogene roxaparvovec), a gene therapy for hemophilia A, has been diagnosed with leukemia.

A genetic assessment of the case, conducted by the therapy’s developer, BioMarin Pharmaceutical, suggested the cancer diagnosis was not linked to Roctavian.

Details of the assessment were submitted to regulators in the U.S. and others worldwide. As a result, none of the authorities, including independent safety data monitors, have called for a hold or modifications to ongoing Roctavian clinical trials.

According to a recently issued regulatory filing, the company is still on track to resubmit an application requesting Roctavian’s approval in the U.S. by the end of the month.

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BioMarin’s initial approval request to the U.S. Food and Drug Adminstration (FDA), submitted in December 2019, was not decided by the regulatory agency, which instead said it would require more safety and efficacy data. The FDA specifically requested two years of follow-up data on participants in a Phase 3 trial that was used as the basis for the filing.

Roctavian — given via a single infusion into the bloodstream — is designed to restore the production of factor VIII (FVIII), the blood clotting protein that is missing or is defective in hemophilia A.

The treatment uses a harmless adeno-associated virus (AAV5) to deliver a shorter but functional copy of the F8 gene, which contains instructions to make FVIII, to liver cells — the main producers of clotting factors in the body.

The modified F8 genetic material is delivered to the nucleus of liver cells, but does not permanently integrate into the patient’s genome — the DNA sequence of all human genes — which may potentially cause cancer. Regardless, a detailed assessment of cancer cases in gene therapy trials is required by regulators.

In this case, genetic testing of blood cells collected from the patient showed that 85% of the individual’s leukemic cells carried a type of mutation that is a well-known leukemia driver.

In addition, leukemia cells contained negligible levels of Roctavian’s vector DNA — less than one copy per 500 cells — indicating that the delivered genetic material is not being actively copied when new cells divide and grow, the company noted.

Earlier this year, BioMarin had reported another patient, who had received Roctavian five years earlier, had developed a salivary gland tumor. However, the genomic analysis had determined that case was also unrelated to the gene therapy.

The overall rate of cancers seen in all Roctavian trials — two in about 400 patient-years of observation — is “consistent with expected rates of cancer in persons with hemophilia,” BioMarin noted in the regulatory filling.

A patient-year is a composite measure that takes into account the number of patients and the time they were followed in a study. In this case, 400 patient-years refers to 400 patients who were followed for one year.

Additional testing is ongoing to determine whether the vector DNA has integrated into the genome of leukemic cells and contributed to their growth.

News of the leukemia case came on the heels of Roctavian’s conditional approval in Europe. In the EU, the treatment is available to patients with severe hemophilia A who do not have inhibitors to standard replacement therapy or detectable antibodies against AAV5.

The therapy’s conditional approval was mainly supported by data from the ongoing Phase 3 GENEr8-1 trial (NCT03370913). Data demonstrated that more than 80% of the 134 men with severe hemophilia A involved in the study were bleed-free after two years, and most stopped using standard replacement therapies.

A small Phase 1/2 study (NCT02576795) with 15 severe hemophilia A patients also contributed to the decision. That trial showed that Roctavian reduced bleed rates and the need for replacement therapies for up to six years among participants.

BioMarin’s initial approval request in the U.S. had been based on six-month data from GENEr8-1, and three-year findings from the Phase 1/2 study.