BioMarin Pharmaceutical Inc. announced that the U.S Food and Drug Administration (FDA) placed a clinical hold on the BMN 307 Phearless Phase 1/2 study. The Phearless study is evaluating BMN 307, an investigational AAV5-phenylalanine hydroxylase (PAH) gene therapy, in adults with phenylketonuria (PKU). The FDA's clinical hold was based on interim safety findings from a pre-clinical, non-GLP pharmacology study. The Company carried out this pre-clinical study to understand the durability of BMN 307 activity in mice bearing two germline mutations, which may predispose the mice to the development of malignancy. One mutation eliminated the PAH gene that's missing in PKU and the second rendered the animals immunodeficient. Of 63 animals treated, six of seven animals administered BMN 307 at the dose group (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 of these animals had adenomas and one had a hepatocellular carcinoma (HCC). The translatability of these findings to humans is uncertain and under further investigation. To date, the Company has only dosed humans in the Phearless Phase 1/2 clinical study with lower doses of either 2e13 vg/kg or 6e13 vg/kg. Due in part to the risk previously identified by historical rodent studies, the liver health of Phearless study participants is regularly monitored. The Company will work with the Data Review Board and Principal Investigators to further evaluate the study participants who have been dosed and will continue to monitor them over the long-term. The clinical significance of these pre-clinical rodent findings has not been established and cancers due to AAV integration have not been observed in larger animals or humans. BioMarin is pausing further enrollment into this global Phase 1/2 study until the investigation of these findings is completed. The company is working with the FDA and other health authorities and will communicate next steps for the program when available.