- BioMarin Pharmaceutical will need to run additional preclinical studies to assess the "theoretical" cancer risk of a rare disease gene therapy it's developing, information the Food and Drug Administration requested to resolve a clinical hold the agency placed on human tests of the treatment last fall.
- Running those studies and collecting the asked-for data will take "several quarters," BioMarin said in a statement Thursday. The company will disclose next steps "when available."
- The FDA's hold came after a study in mice run by BioMarin found the virus used to shuttle functional copies of the target gene into cells fused into the genomes of six mice which had developed liver cancer. The mice were given a much higher dose by weight of the gene therapy than used in initial human testing, however. While other studies have shown similar risks in mice, they haven't been observed in larger animals or in people.
With more and more gene therapies advancing into clinical testing, the FDA has paid close attention to signs of safety risks, issuing orders to stop testing in a number of recent cases involving developers like UniQure, Bluebird bio, Pfizer and Astellas Pharma.
But the FDA has stayed alert, convening last September a meeting of outside experts to discuss some of the most notable safety risks with one common type of gene therapy. In particular focus was whether gene therapy using adeno-associated viruses as a delivery vehicle have potential to spur cancer growth, as has been observed in mice studies over the past two decades.
FDA advisers, however, noted that risk remains theoretical in humans and, while expressing caution, didn't advocate for any significant scale back of gene therapy research.
Since then, the agency has reimposed a hold on tests of Bluebird's sickle cell gene therapy and issued the halt for BioMarin's therapy, which is meant to treat a rare disease called phenylketonuria, or PKU.
BioMarin had hoped to resolve the hold as soon as later this quarter, but the new requests from the FDA will mean a more extended pause on testing. Previously, the company had said it believed it was unlikely that the virus integration observed in mice directly caused the cancer that was later found.
"While integration can be demonstrated to have occurred it is by no means a monolithic event, meaning it's not present in every tumor, the same integration," said Hank Fuchs, BioMarin's head of R&D, in a Jan. 9 interview. "So it looks like integration is more of a passenger than it is a cause."
Thursday's announcement from the company, however, caused some analysts to wonder about the FDA's viewpoint, and whether the requests for additional preclinical testing might indicate further caution on the part of the regulator.
"[O]ne does have to wonder about the 'knock on' effect here," said Christopher Raymond, an analyst at Piper Sandler, in a Feb. 17 note to clients. "BMN 307 may be the only [BioMarin] gene therapy with this issue, but it's not the only gene therapy upon which FDA has placed a clinical hold recently," he added, using the company's designation for the treatment.
"We continue to believe that the clinical hold on BMN 307 is representative of the FDA taking a highly cautious approach toward the development of gene therapies," wrote Kennen MacKay, an analyst at RBC Capital Markets, in a separate investor note.
While BioMarin did not specify what studies it needs to conduct, MacKay suggested toxicology studies in mice are likely what the FDA requested.
Alongside the announcement related to its PKU gene therapy, BioMarin said studies of a more advanced treatment for hemophilia A are continuing. The company intends to file for approval of that therapy later this year.
Shares in BioMarin slid by 5% in Friday morning trading.