The US Food and Drug Administration (FDA) has placed a clinical hold on the phase 1/2 Phearless study investigating BMN 307, a gene therapy from California-based rare disease biotech, BioMarin Pharmaceutical.
The Phearless study was investigating the AAV5-phenylalanine hydroxylase (PAH) gene therapy in adults with phenylketonuria (PKU), a genetic disorder affecting approximately 70,000 diagnosed patients in the regions of the world where BioMarin operates.
The hold was based on interim safety findings from a pre-clinical study that tested BMN 307 in mice with mutations that made them predisposed to develop malignancy. Six of the seven animals administered BMN 307 at the highest dose group developed liver tumours, five had adenomas and one a hepatocellular carcinoma.
The translatability of these findings to humans is uncertain and under further investigation, said BioMarin in a statement.
The Phearless study has already seen patients dosed with BMN 307, although the company stresses that this is at lower doses than in the mice studies, and that, due to previously identified risks, the liver health of participants is being monitored regularly.
“More than 3,000 patients have been treated with gene therapy, and there are no reports of cancers emerging as a consequence,” said BioMarin head of R&D, Hank Fuchs. However, he said that in acknowledgment of “the complexity of the issue” the company would investigate further. “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.”
PKU is caused by a deficiency of the enzyme PAH, which is needed required for the metabolism of essential amino acid phenylalanine. Without active enzyme, the amino acid accumulates and becomes toxic to the brain, resulting in complications including severe intellectual disability, seizures, tremors, behavioural problems and psychiatric symptoms.
The core of BioMarin’s business is a portfolio of drugs for the treatment of mucopolysaccharidosis (MPS), which saw a rise in revenues of 17% in the second quarter of 2021. It’s products include Vimizim (elosulfase alfa) for MPS type IVA (Morquio A syndrome), Naglazyme (galsulfase) for MPS VI (Maroteaux-Lamy syndrome) and Kuvan (sapropterin dihydrochloride) in children with PKU.