FDA halts BioMarin’s PKU gene therapy trial
pharmafile | September 7, 2021 | News story | Manufacturing and Production, Medical Communications, Research and Development |
BioMarin Pharma has announced that the FDA has slapped a clinical hold on its Phase 1/2 trial of its candidate for phenylketonuria (PKU) while it investigates a safety signal.
The pause was ordered after liver tumours were seen in mice given the therapy in preclinical testing.
Patients in the Phearless study of BMN 307 – an adeno-associated virus (AAV) gene therapy designed to replace the phenylalanine hydroxylase (PAH) deficient in people with PKU – are, however, getting a lower dose than was used in the animal studies.
But BioMarin said that the “translatability of these findings to humans is uncertain and under further investigation”.
BioMarin’s preclinical study was carried out to explore the durability of BMN 307 activity in mice with two germline mutations which may predispose them to the development of cancer.
One mutation eliminated the PAH gene that’s missing in PKU, while the second rendered the animals immunodeficient, which could also raise the risk of malignancy.
Of 63 animals treated, six of seven animals administered BMN 307 at the highest dose group – 2e14 Vg/kg – developed liver tumours. Five of the mice had adenomas and one had a hepatocellular carcinoma (HCC).
Currently subjects in the Phearless study have received doses of either 2e13 vg/kg or 6e13 vg/kg of BMN 307, although the protocol does include a third, higher-dose group.
With gene therapies such as these, cancer is a perennial fear as altering DNA in cells in this way leaves a risk that the viruses used to deliver genes into patient cells could inadvertently trigger a mutation or disrupt a mechanism that guards against a cell becoming cancerous.
PKU is a rare genetic disease that manifests at birth and is marked by an inability to break down phenylalanine, an amino acid that is commonly found in many foods. Left untreated, high levels of the amino acid become toxic to the brain and may lead to serious neurological and neuropsychological issues.
The FDA’s decision stemmed not from safety but on a lack of data on the durability of the gene therapy, which is designed to provide a functional copy of factor VIII, the clotting protein deficient in people with haemophilia A.
Since then, BioMarin has reported data showing that functional factor VII expression has been declining over time in patients treated with valrox, although they still seem to be protected from bleeding episodes.
Hank Fuchs, head of R&D at BioMarin, said: “More than 3,000 patients have been treated with gene therapy, and there are no reports of cancers emerging as a consequence.
“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.”
Kat Jenkins
