FDA slaps clinical hold on BioMarin gene therapy trial after tumors seen in mice 

The gene therapy space has taken yet another hit. Labor Day, just days after the FDA convened a panel to discuss the cancer risk of gene therapies, BioMarin revealed the regulator has slapped a clinical hold on a phase 1/2 study over a safety signal seen in mice. 

BioMarin gave seven mice with mutations that could raise their risk of tumors the highest dose of the gene therapy it is testing in patients with phenylketonuria, a rare genetic disorder that renders people unable to break down an amino acid. At that dose, which is yet to be given to humans, six of the mice had tumors one year after dosing. Five mice had benign tumors, and one had liver cancer. BioMarin also found evidence that parts of the vector integrated into the genome.

Vector integration is a long-standing concern about the safety of gene therapies. In mice, researchers have linked vectors that integrate into certain parts of the genome, such as an area that encodes for regulatory RNAs, to the development of liver cancer. A more recent study saw vector integration in the livers of dogs, but, to date, there is no evidence of tumor development outside of rodents.

Even so, the theoretical risk is one of the FDA’s chief concerns about the safety of gene therapies. The BioMarin mice study, which the biotech ran to assess the durability of BMN 307, triggered the alarm at the FDA, leading the regulator to put the phase 1/2 trial on clinical hold. BioMarin has also stopped enrollment at sites outside of the U.S.

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The pause will give BioMarin time to investigate the findings. BioMarin is already monitoring the liver health of recipients of BMN 307 and will work with the data review board and principal investigators on the long-term monitoring of their health. The biotech will disclose the next steps after working with the FDA on how to proceed with the study.

The FDA goes into the talks armed with the latest thinking on the risks posed by vector integration. At the two-day advisory committee meeting held last week, one of the four sessions focused on the cancer risk of vector integration. Lisa Butterfield, Ph.D., the vice president of the Parker Institute for Cancer Immunotherapy who chaired the meeting, summarized the views of the other experts on safety monitoring in clinical trials.

“There are a number of standards here that could be followed. And there were no recommendations to change the standards, other than to consider for the young children that some of the monitoring would be more challenging,” Butterfield said. The standard discussed by the experts is ultrasound scans every six months.

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Several factors point to the potential for BioMarin to resolve the clinical hold. The cancer risk outside of rodents remains theoretical, and BioMarin has previously said the current highest dose tested in humans, which is far lower than that given in the mice study, could be the one it takes forward. 

If BioMarin gets the hold lifted, it will resume its effort to add a gene therapy to its portfolio of phenylketonuria treatments. BioMarin already has two drugs approved in the indication, but neither product is a panacea, leading multiple groups to target the market. Homology Medicines has a rival gene therapy, based on a different vector, in a phase 1/2 study.