FDA Halts BioMarin’s Trial Assessing Gene Therapy in Rare Disease

FDA recently placed a clinical hold on BioMarin Pharmaceuticals Phase 1/2 trial evaluating its AAV5-phenylalanine hydroxylase (PAH) gene therapy in adults with the rare disease, phenylketonuria (PKU).

The agency based its decision on interim safety findings from a pre-clinical, non-GLP pharmacology study. The study assessed the durability of the gene therapy, BMN 307, in mice bearing two germline mutations. 

In the study, one mutation eliminated the PAH gene missing in PKU, while the second rendered the animals immunodeficient. 

Researchers found that of the 63 animals treated, six of seven animals administered BMN 307 at the highest dose group developed tumors on liver necropsy 52 weeks after dosing, with evidence for the integration of portions of AAV vector into the genome. 

Notably, researchers reported no lesions in any mice at 24 weeks. Five of these mice had adenomas, and one had hepatocellular carcinoma (HCC). 

PKU, or PAH deficiency, is a genetic disorder affecting nearly 70,000 diagnosed patients in various regions of the world where BioMarin operates. 

BioMarin has already dosed participants in its Phase 1/2 Phearless clinical study with lower doses than in the mice studies. Researchers regularly monitor the liver health of patients enrolled in the Phearless study due to the risk previously identified by mice studies. 

The company stated that it will work with the data review board and principal investigators to further evaluate the study participants already dosed and continue to monitor them over the long term. 

Additionally, BioMarin is pausing further enrollment into the Phearless study until the mice trial findings are investigated.

“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,” Hank Fuchs, MD, president of worldwide research and development at BioMarin, said in the announcement. 

“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,” Fuchs concluded.