The Food and Drug Administration has placed a clinical hold on the phase 1/2 Phearless study evaluating BMN 307 for the treatment of phenylketonuria in adults.

BMN 307 is an investigational adeno-associated virus type 5 (AAV5)-phenylalanine hydroxylase (PAH) gene therapy designed to normalize phenylalanine concentration levels. The open-label, dose escalation phase 1/2 Phearless study ( Identifier: NCT04480567) was evaluating the safety, efficacy and tolerability of 3 doses of BMN 307 in adults with phenylketonuria.

The clinical hold was based on interim safety findings from a preclinical pharmacology study that evaluated the durability of BMN 307 activity in 63 mice with 2 germline mutations: 1 mutation eliminated the PAH gene and the other caused the mice to be immunodeficient. Results showed that 6 out of 7 mice treated with BMN 307 at the highest dose had tumors on liver necropsy at 52 weeks (5 with adenomas and 1 with hepatocellular carcinoma). There were no lesions observed in any mice at 24 weeks. 

The clinical significance of these findings to humans has not been established. The Company is pausing further enrollment in the phase 1/2 study until further investigation is completed. To date, patients had only been administered lower doses of the AAV gene therapy.

“More than 3000 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, MD, President, Worldwide Research and Development at BioMarin.  “For patients who have already received lower doses of these vectors, we will continue to carefully evaluate and monitor their health.”


US FDA placed a clinical hold on BMN 307 Phearless phase 1/2 gene therapy study in adults with PKU based on interim pre-clinical study findings. News release. BioMarin Pharmaceutical Inc. Accessed September 8, 2021.