Cancer Fears Puts BioMarin’s Phearless Study on Hold

On September 6th, the FDA placed a clinical hold on BioMarin’s gene therapy for phenylketonuria (PKU), citing safety signals from the preclinical studies.

Biomarin’s Phearless study is evaluating BMN 307, its candidate for gene therapy for phenylketonuria, a rare hereditary disorder. The disease is caused by defects in the phenylalanine hydroxylase (PAH) gene, which breaks down phenylalanine, an amino acid that is toxic when it accumulates in the body.

BMN 307 uses AAV5 (a strain of adeno-associated virus) vectors to deliver the healthy PAH gene, which could theoretically restore the ability to break down phenylalanine and thus treat PKU.

Cancer in Mice Raises Safety Concerns

It wasn’t the results of the Phase 1/2 Phearless study that sparked the FDA’s concern, but safety signals from an interim analysis of pre-clinical findings in mice. Of the 63 mice treated, six of seven mice given the highest dose (2e14 Vg/kg) developed cancer. Tumors were found in the liver of these mice when a necropsy was taken a year after dosing; there were no telltale signs at six months.

It’s possible these mice were predisposed to develop cancer. The animals possessed two germline mutations, one that knocked out the PAH gene defunct in PKU and another that rendered them immunodeficient.

Patients in the Phearless study were also given lower treatment doses, while the protocol did include a higher dose group. The company has promised to evaluate and monitor their health carefully.

“More than 3,000 patients have been treated with gene therapy, and there are no reports of cancers emerging as a consequence,” said Hank Fuchs, M.D., BioMarin’s head of R&D. He acknowledged that other AAV vectors did cause mutations after integrating into mice DNA which resulted in cancer.

Potential Side Effects of Gene Therapy Complicates Regulatory Approvals

The pause imposed by the FDA marks another setback in BioMarin’s gene therapy development program. In August 2020, the agency had rejected its Hemophilia A gene therapy, citing the need for more long-term data to prove the effectiveness of the treatment.

There have long been worries that viral vectors used in gene therapy might integrate into the genome and cause mutations that lead to cancer. While the integration and subsequent development of cancer have been observed in mice models, the link between gene therapies and cancer in humans is far more uncertain.

Last December, UniQure’s hemophilia B AAV-based gene therapy was put on hold by the FDA after one case of hepatocellular carcinoma was detected in a trial participant. The concerns were largely dispelled when a follow-up investigation found that the AAVs did not integrate into regions of the DNA associated with cancer and was therefore unlikely to have caused it.

Earlier this year, clinical trials testing Bluebird Bio’s LentiGlobin, its gene therapy for sickle cell disease, were put on clinical hold after two patients developed blood cancers.

At around the same time, Bluebird also withdrew Zynteglo, its gene therapy for beta-thalassemia, from the European market as it uses the same lentiviral vector technology as LentiGlobin. The marketing hiatus for Zynteglo lasted five months, ending after Bluebird confirmed the lentivirus vectors used in LentiGlobin did not cause the blood cancers. The confirmation also allowed the trials to resume.

In August, Bluebird was hit with another clinical hold, from the FDA this time, for Lenti-D, its lentiviral vector-based gene therapy for cerebral adrenoleukodystrophy. The order to pause was issued after a patient developed myelodysplastic syndrome (a form of blood cancer) despite receiving the gene therapy a year ago. This time, Bluebird suspected the cancer was caused by Lenti-D lentiviral vector insertion.

Author

Joy Lin

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