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FDA halts tests of BioMarin drug amid heightened focus on gene therapy safety

The theoretical risk that gene therapy may cause cancer in humans has hung over the field for decades. Those worries resurfaced last year when a liver tumor was spotted in a patient who had received an experimental treatment for hemophilia from the biotech company UniQure.

But a definitive link between the adeno-associated viruses, or AAVs, that commonly deliver gene therapies and tumor formation has never been established in humans. Though preclinical tests dating back more than 20 years have shown AAVs can slip into the genomes of mice and cause liver cancer, those findings have never been replicated in larger animals or in people. UniQure’s hemophilia treatment was exonerated this year, for instance. And testing of BioMarin’s own hemophilia gene therapy, which uses the same type of virus as its PKU treatment, has never been halted because of such problems.

“More than 3,000 patients have been treated with gene therapy, and there are no reports of cancers emerging as a consequence,” asserted BioMarin research chief Hank Fuchs, in a statement.

Nonetheless, concerns have persisted among regulators, particularly amid a boom in gene therapy research that has led to wider use of AAVs than ever before. In response, the FDA convened a meeting last week in which it asked a panel of experts to discuss ways to prevent or mitigate the risks of cancer and other potential gene therapy side effects.

At the meeting, panel members agreed that any link between AAVs and cancer in humans remains theoretical given the current evidence. They also didn’t recommend major changes to gene therapy research, proposing instead more thorough patient monitoring, careful scrutiny of gene therapy components and longer animal tests.

Still, BioMarin’s disclosure early on Monday suggests the FDA is taking a “conservative” stance regarding such issues, wrote Brian Abrahams, an analyst at RBC Capital Markets, in a note to clients.

Abrahams said he believes the program’s suspension is a “precautionary” move, citing the history of cancer observations in mouse tests of gene therapy and the high dose BioMarin used in the experiment. Abrahams speculated the FDA’s concerns could be addressed if BioMarin moves forward with a lower dose and agrees to stricter monitoring.

The program might be stuck in limbo for some time, however. BioMarin didn’t estimate how long the program could be delayed. But because the onset of tumors occurred 52 weeks after treatment, “whatever experimental work [BioMarin] and [the] FDA agree on may take up to a year to understand,” wrote Christopher Raymond, an analyst at Piper Sandler, in a note.

Raymond also noted that the similarities between BioMarin’s PKU gene therapy, its hemophilia treatment Roctavian and a preclinical program for hereditary angioedema mean the situation has added “important new risk” to the company’s gene therapy portfolio.

BioMarin shares fell by nearly 9% in pre-market trading Tuesday.