Verve Reports Details of FDA Hold of Experimental Gene Editing Trial in Patients with HeFH; Shares Slide

Verve Therapeutics’ shares slide 11 percent after the company reported details of the reason behind the U.S. Food and Drug Administration hold on starting a clinical trial in the United States of its experimental gene editing therapeutic VERVE-101, in patients with heterozygous familial hypercholesterolemia, a prevalent and potentially life-threatening subtype of atherosclerotic cardiovascular disease, had been placed on hold on November 4.

In patients with heterozygous familial hypercholesterolemia (HeFH), a genetic mutation in the LDLR gene down-regulates LDLR expression, which leads to extremely high LDL-C levels in the blood. Over time, high LDL-C builds up in the arteries, resulting in reduced blood flow or blockage, and ultimately heart attack or stroke. Inactivation of the PCSK9 gene can increase LDLR expression, resulting in lower LDL-C levels and reduced risk for heart attack and ASCVD.

VERVE-101 is a novel, investigational in vivo gene editing medicine designed to be a single-course treatment to permanently turn off the PCSK9 gene in the liver to reduce disease-driving low-density lipoprotein cholesterol. VERVE-101 is currently being evaluated in the ongoing heart-1 phase 1 clinical trial in New Zealand and the United Kingdom.

On December 2, 2022, Verve said, in a SEC document, that it received a clinical hold letter from the FDA that outlined the information required to resolve the clinical hold, including additional preclinical data relating to potency differences between human and non-human cells, risks of germline editing, and off-target analyses in non-hepatocyte cell types. The FDA also requested available clinical data from the ongoing heart-1 trial. In addition, the FDA has requested that Verve modify the trial protocol in the United States to incorporate additional contraceptive measures and to increase the length of the staggering interval between dosing of participants. Verve intends to submit a response as expeditiously as possible.

Clinical data from the ongoing heart-1 study in New Zealand and the U.K. were not included in the IND package submitted to the FDA. At the time that the U.S. hold was placed, Verve had completed dosing of VERVE-101 in the first dose cohort of the dose-escalation portion of the heart-1 trial, which was well tolerated in all three patients. No treatment-related adverse events had been reported to date, and all adverse events observed were Grade 1 in nature. The independent Data Safety Monitoring Board had reviewed safety data from the first cohort and recommended dose escalation to the planned second dose level, which is expected to begin soon.

Verve said it continues to enroll patients in the heart-1 clinical trial in New Zealand and the United Kingdom and plans to report initial safety and pharmacodynamic data from the dose-escalation portion of the heart-1 trial in the second half of 2023.

Author: Rare Daily Staff