FDA Slaps a Hold on BioMarin's PKU Gene Therapy

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A string of gene therapy clinical trials have been paused due to safety concerns. The most recent is BioMarin Pharmaceutical, which announced that the U.S. Food and Drug Administration (FDA) had placed a clinical hold on its BMN 307 Phearless Phase I/II study. The trial investigates BMN 307, an AAV5-phenylalanine hydroxylase (PAH) gene therapy in adults with phenylketonuria (PKU).

Biomarin’s study was paused based on interim safety data from a preclinical, non-GLP pharmacology study that found liver tumors in laboratory animals receiving the therapy. The studies were in mice with two germline mutations, which predisposed them to the development of malignancy. One of the mutations eliminated the PAH gene that is missing in PKU. The second mutation made the mice immunodeficient. Of 63 treated animals, six of seven animals receiving BMN 307 at the highest dose were found to have tumors when necropsied at 52 weeks after dosing. And there was data suggesting that parts of the adenovirus (AAV) vector had integrated into the genome of the animals. No cancers were seen in mice at 24 weeks.

Humans in the Phearless study have received lower doses, either 2e13 vg/kg or 6e13 vg/kg. BioMarin indicates it will work with the Data Review Board and the principal investigators to study the people who have been dosed in the trial and will continue to monitor them long-term.

“More than 3,000 patients have been treated with gene therapy, and there are no reports of cancers emerging as a consequence,” said Hank Fuchs, M.D., president, Worldwide Research and Development at BioMarin. “Acknowledging the complexity of the issue as highlighted in this week’s FDA discussion, integrational mutagenesis and resultant cancer formation has been observed in mice using other AAV vectors. Therefore, we plan to investigate these findings. For patients who have already received lower doses of these vectors, we will continue to carefully evaluate and monitor their health. We are committed to understand and mitigate any risk of cancer causation.”

PKU patients lack the PAH required to metabolize Phe, an essential amino acid in most protein-containing foods. These patients tend to accumulate abnormally high Phe blood levels, which can become toxic to the brain, resulting in severe intellectual disability, seizures, tremors, behavioral and psychiatric problems. The disease can be managed with severe Phe-restricted diets, supplemented by low-protein modified foods and Phe-free medical foods.

On August 16, the FDA lifted a clinical hold on Rocket Pharmaceuticals’ gene therapy for Danon disease. The hold was placed on the company’s RP-A501 in May. That trial was not halted over safety issues but to ensure that Rocket modified the trial protocol, as well as supporting documents that included revised guidelines for patient selection and safety management.

On August 9, the FDA placed a clinical hold on bluebird bio’s trials of elivaldogene autotemcel (eli-cel) gene therapy for cerebral adrenoleukodystrophy (CALD). That hold was related to a report of a Suspected Unexpected Serious Adverse Reaction (SUSAR) of myelodysplastic syndrome in a patient receiving the gene therapy in a Phase III trial. The patient received the dose more than a year ago.

On August 3, the FDA lifted a partial hold on Novartis’ OAV-101 intrathecal clinical trials for spinal muscular atrophy (SMA). The hold had been placed in 2019 after the Novartis’ subsidiary AveXis found dorsal root ganglia mononuclear cell inflammation associated with the therapy in preclinical animal studies. The hold was lifted after Novartis presented comprehensive nonclinical toxicology data addressing the concerns.

In February 2020, the FDA placed a clinical hold on LogicBio’s proposed gene therapy for methylmalonic acidemia (MMA). The hold was made before the Phase I/II trial began after the FDA demanded answers to undisclosed clinical and nonclinical questions.

This clinical hold is just another setback that BioMarin has faced in the gene therapy space. In August 2020, the FDA issued a Complete Response Letter (CRL) for its Biologics License Application (BLA) for its gene therapy for severe hemophilia A, valoctocogene roxaparvovec. The agency indicated that the BLA wasn’t ready for approval in its present form and had recommended the company gather two years of data from its ongoing 270-301 Phase III study to provide more evidence of durable effects using Annualized Bleeding Rate (ABR) as the primary endpoint.

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