FDA Lifts Verve’s Clinical Hold on Base Editing Therapy for Rare Heart Disease

Rare Daily Staff

The U.S. Food and Drug Administration has lifted its clinical hold on Verve Therapeutics study of its VERVE-101 base editing therapy for the treatment of heterozygous familial hypercholesterolemia, a rare, genetic form of heart disease.

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 an experimental, in vivo base editing medicine designed to be a single-course treatment that inactivates the PCSK9 gene in the liver to durably lower blood low-density lipoprotein cholesterol (LDL-C). HeFH is a prevalent and life-threatening inherited disease characterized by lifelong elevations in blood LDL-C and accelerated atherosclerotic cardiovascular disease. VERVE-101 consists of an adenine base editor messenger RNA and an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle. By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 aims to inactivate the target gene. Inactivation of the PCSK9 gene has been shown to up-regulate LDL receptor expression, which leads to lower LDL-C levels, thereby reducing the risk for ASCVD.

In December 2022, Verve said 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.

Verve submitted interim clinical data from the dose-escalation portion of the ongoing heart-1 phase 1b clinical trial and addressed the FDA’s preclinical questions in its response to the clinical hold. The heart-1 trial is evaluating the safety, tolerability, pharmacokinetic and pharmacodynamic profile of VERVE-101 in patients with HeFH and is currently being conducted at sites in the United Kingdom and New Zealand.

“The clearance of our IND application by the FDA is a significant milestone in our effort to offer patients living with HeFH a transformative alternative to the chronic care model of disease management. This clearance, for the first time, enables clinical development of an in vivo base editing product candidate in the United States,” said Andrew Bellinger, chief scientific officer of Verve. “With the clearance of this IND, we plan to begin the process of activating U.S. clinical trial sites for the heart-1 clinical trial.”

Photo: Andrew Bellinger, chief scientific officer of Verve