FDA Places Clinical Hold on BioMarin’s Phase I/II Gene Therapy Study

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FDA placed a clinical hold on the BMN 307 Phearless Phase I/II study, which was evaluating an investigational PAH gene therapy in adults with PKU.

BioMarin Pharmaceutical announced in a Sept. 5, 2021, press release that FDA placed a clinical hold on the BMN 307 Phearless Phase I/II study. The study was evaluating BMN 307, an investigational AAV5-phenylalanine hydroxylase (PAH) gene therapy, in adults with phenylketonuria (PKU).

The clinical hold was based on interim safety findings from a pre-clinical, non-GLP pharmacology study. Tumors developed in some of the mice receiving the highest dose of BMN 307 with evidence for integration of portions of AAV vector into the genome.

The pre-clinical study was to determine the durability of BMN 307 activity in mice with two germline mutations, which may predispose the mice to the development of malignancy. One mutation eliminated the PAH gene missing in PKU, and the second rendered the animals immunodeficient.

Of the 63 animals that were treated, six of seven animals that received the highest dose of BMN 307 (2e14 Vg/kg) had tumors on liver necropsy 52 weeks after dosing with evidence for integration of portions of AAV vector into the genome. No lesions were observed in any mice at 24 weeks. Five mice had adenomas and one had a hepatocellular carcinoma. The translatability of these findings to humans is uncertain and under further investigation.

To date, BioMarin has dosed humans in the Phearless Phase I/II clinical study with lower doses of either 2e13 vg/kg or 6e13 vg/kg. The liver health of Phearless study participants is regularly monitored. The company said it will work with the data review board and principal investigators to further evaluate the study participants who received BMN 307 and will continue to monitor them over the long-term.


"More than 3,000 patients have been treated with gene therapy, and there are no reports of cancers emerging as a consequence. 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," said Hank Fuchs, president of worldwide research and development at BioMarin, in a company press release. "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."

BioMarin has paused further enrollment of additional participants outside the United States in Phearless Phase I/II study and are working with FDA and other health authorities. In the company press release, they said they will communicate next steps when available.

Source: BioMarin