Do Verve's gene edits pass down to patients' children? The FDA wants to know

The FDA has set out its reasons for putting Verve Therapeutics’ high cholesterol gene editing therapy on hold. Officials want additional data to allay concerns that patients could pass on the edited genes to their children before they lift the clinical hold.

Last month, the FDA put Verve’s application on hold and vowed to send an official letter setting out its questions within 30 days. Verve now has the letter—and knows what needs to be done to get the clinical trial of its PCSK9-deactivating drug candidate VERVE-101 off the ground. 

The FDA has asked for more preclinical data on potency differences between human and non-human cells, the risks of germline editing and off-target analyses in non-hepatocyte cell types. Officials also want Verve to share data from the heart-1 trial, which continues to enroll patients in New Zealand and the U.K., and to tweak the protocol to mitigate the risks of the therapy.

Specifically, the FDA has asked Verve to incorporate additional contraceptive measures and to increase the length of the staggering interval between dosing of participants. Verve plans to submit a response “as expeditiously as possible” but is yet to set out a timeline for resolving the request.

The FDA’s questions cover subjects that Verve has been researching. Sequencing of sperm samples from six sexually mature male nonhuman primates before and after treatment with VERVE-101 showed no evidence of PCSK9 gene editing. Similarly, genotyping of the 436 offspring of female mice treated with the murine surrogate of VERVE-101 showed that the PCSK9 gene edit was not transmitted to the babies.

Verve can also use heart-1 data, which was absent from the IND filing, to try to allay the FDA’s concerns. The biotech has completed dosing of VERVE-101 in the first three-patient cohort of the dose-escalation portion of the heart-1 trial. No patients suffered treatment-related adverse events, and all adverse events so far have been grade 1. Verve got the green light to dose the second cohort, and data are due in 2023. 

Investors sent shares in Verve down 10% to $21.50 in premarket trading in the wake of the FDA update. The stock traded above $40 in late October, but news of the clinical hold sent it down to around $20.