Rare Daily Staff

The U.S. Food and Drug Administration placed a clinical hold on BioMarin Pharmaceutical’s phase 1/2 study evaluating BMN 307, an experimental AAV5 gene therapy, in adults with phenylketonuria, based in interim safety findings from a preclinical, non-GLP pharmacology study in mice.

BioMarin carried out this preclinical study to understand the durability of BMN 307 activity in mice bearing two germline mutations, which may predispose the mice to the development of cancerous tumors. 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 highest 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. The translatability of these findings to humans is uncertain and under further investigation.

PKU, or phenylalanine hydroxylase (PAH) deficiency, is a rare genetic disorder caused by a deficiency of the enzyme PAH. This enzyme is required for the metabolism of Phe, an essential amino acid found in most protein-containing foods. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, resulting in a variety of complications including severe intellectual disability, seizures, tremors, behavioral problems, and psychiatric symptoms. As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all individuals with PKU under the age of 40 in countries with newborn screening programs are diagnosed at birth and treatment is implemented soon after.

PKU can be managed with a severe Phe-restricted diet, which is supplemented by low-protein modified foods and Phe-free medical foods; however, it is difficult for most patients to adhere to the life-long strict diet to the extent needed to achieve adequate control of blood Phe levels. Dietary control of Phe in childhood can prevent major developmental neurological toxicities, but poor control of Phe in adolescence and adulthood is associated with a range of neurocognitive disabilities with significant functional impact.

To date, BioMarin 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 preclinical 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.

“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. “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.”

Hank Fuchs, president of Worldwide Research and Development at BioMarin

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