Verve’s Hypercholesterolemia Gene-Editing Therapy VERVE-101 Cleared for US Trial After Rocky Start


The US IND application, on hold since November 2022, was cleared with the help of data from a clinical trial being conducted in New Zealand.

Verve Therapeutics’ investigational new drug (IND) application for VERVE-101, an investigational gene-editing therapy intended to treat heterozygous familial hypercholesterolemia (HeFH), has been cleared by the FDA.1

Verve originally submitted the IND application to the FDA in October 2022, but it was placed on hold by the agency in November 2022.2 At the time, the company was already evaluating the gene-editing therapeutic in the ongoing phase 1b heart-1 clinical trial (NCT05398029) in New Zealand. Heart-1, which is currently recruiting patients in New Zealand and the United Kingdom, dosed its first patient in New Zealand in July 2022.1,3 At the time the hold was placed, the company reported that no sudden unexpected serious adverse events (AEs) had been observed in the heart-1 study and that the therapy was well-tolerated in the 3 patients treated in the first dose cohort, with all AEs being grade 1.2 The independent Data Safety Monitoring Board recommended dose escalation to the second dose level after reviewing safety data from the first cohort.

“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,” Andrew Bellinger, MD, PhD, the chief scientific officer of Verve, said in a statement.1 “This clearance, for the first time, enables clinical development of an in vivo base editing product candidate in the United States. Our interactions with the FDA have been valuable, and we plan to incorporate our learnings from this regulatory process to execute a global regulatory strategy across the rest of our pipeline. With the clearance of this IND, we plan to begin the process of activating US clinical trial sites for the heart-1 clinical trial.”

According to Fierce Biotech, which recently interviewed Verve’s CEO Sekar Kathiresan, MD, the hold placed by the FDA was related to concerns about the gene edits being transferred to patients’ future children.4 The agency requested additional data, with specific concerns including the potential for editing in germline and other nonhepatocyte cell types. In response, the company submitted both clinical data from heart-1's ongoing activities outside the US and additional preclinical data intended to assuage these concerns.

“The combination of the human data and addressing the preclinical questions did the trick,” Kathiresan told Fierce Biotech. “Some areas can be addressed with human data, but some of the theoretical concerns can't be addressed by human data and needs to be addressed in preclinical models. So we've done both... We know that the US will play an important role in the development of this medicine as well as our other pipeline programs... We were the first in front of them with this technology, in vivo-based editing, and being first is good in some things. Sometimes you have to work with the party on the other side to develop a set of standards for the technology and what it's going to take to move forward... It's been a process—a very good process, working with them—but a process.”

The novel, investigational in-vivo base-editing CRISPR therapy is designed to permanently turn off the PCSK9 gene in the liver to reduce levels of low-density lipoprotein cholesterol in patients with HeFH, a subtype of atherosclerotic cardiovascular disease (ASCVD).3 The heart-1 trial is expected to enroll approximately 44 adult patients with HeFH and established ASCVD.

1. Verve Therapeutics announces clearance of investigational new drug application by the U.S. FDA for VERVE-101 in patients with heterozygous familial hypercholesterolemia. News release. October 23, 2023. Accessed October 23, 2023.
2. Verve Therapeutics provides regulatory update on VERVE-101 investigational new drug application and reports third quarter 2022 financial results. News release. November 7, 2022. Accessed October 23, 2023.
3. Verve Therapeutics doses first human with an investigational in vivo base editing medicine, VERVE-101, as a potential treatment for heterozygous familial hypercholesterolemia. News release. Verve Therapeutics. Verve Therapeutics. July 12, 2022. Accessed October 23, 2023.
4. Fierce Biotech. Verve's base editing hold lifted, starting a thaw on a regulatory blockade that sent peers ex-US. Website. October 23, 2023. Accessed October 23, 2023.
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