FDA grounds BioMarin gene therapy trial for months with demand for tumor risk data

BioMarin Pharmaceutical faces a long clinical hold on its phenylketonuria (PKU) gene therapy trial. After stopping the trial over tumors in mice, the FDA has asked BioMarin to run additional nonclinical studies that are expected to take “several quarters” to assess the risk of BMN 307.

To get the hold lifted, BioMarin needs to run nonclinical studies to “assess the theoretical oncogenic risk to human study participants.” The expected timeline for the completion of the studies suggests the hold on the phase 1/2 study, which the FDA imposed in September, could drag on for more than one year. The delay could give an advantage to rival programs such as Homology Medicines’ midphase gene therapy.

The FDA’s concerns about the theoretical oncogenic risk are underpinned by data from a preclinical study of the durability of BMN 307 in mice. Six of the seven mice that received the highest BMN 307 dose had liver tumors 52 weeks after dosing.

BioMarin also saw evidence for integration of portions of the vector into the genome. Tumors caused by insertional mutagenesis are a long-standing theoretical worry about adeno-associated virus (AAV) gene therapies in general. Yet, clinical data from multiple assets have supported development despite evidence of vector insertion in mice. 

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Evidence that AAV vectors can cause tumors is based on mice and typically involves vector integration in a locus absent from the human genome. Studies in non-rodent species and humans have delivered more encouraging safety data, but the preclinical BMN 307 study nonetheless raises the question of whether the tumor risk applies to patients.

BioMarin had begun dosing PKU patients with BMN 307 before seeing the safety signal in mice. However, the study was still giving two lower doses and was yet to escalate to the dose that was linked to tumors in six out of seven mice. BioMarin now needs to try to find out whether BMN 307 poses a tumor risk to patients before it can proceed.