Verve Moves on to Second Gen Cardiovascular CRISPR Therapy After Adverse Events


The sixth participant dosed experienced grade 3 treatment-induced ALT increases and thrombocytopenia.

Verve Therapeutics is pausing enrollment in its phase 1b heart-1 clinical trial (NCT05398029) of VERVE-101 CRISPR-editing therapy in consultation with the study’s independent data and safety monitoring board (DSMB) after the sixth participant treated experienced asymptomatic grade 3 adverse events (AEs).1

Within 4 days of receiving 0.45 mg/kg VERVE-101, the participant experienced a Grade 3 treatment-induced transient increase in serum alanine aminotransferase (ALT) and a serious AE of Grade 3 treatment-induced thrombocytopenia. The laboratory abnormalities resolved fully within a few days and the participant did not experience any related bleeding or other symptoms.

Verve also announced that it would be prioritizing its preclinical therapy, VERVE-102, also for the treatment of heterozygous familial hypercholesterolemia (HeFH), going forward. VERVE-102 uses a different lipid nanoparticle delivery system, with a different ionizable lipid and incorporation of GalNAc, than VERVE-101 but delivers the same base editor and guide RNA for PCSK9.The aptly named Heart-2 clinical trial is set to initiate for patients with HeFH or premature coronary artery disease in the second quarter of 2024 in the United Kingdom and Canada.

“The Heart-1 clinical trial continues to support proof-of-concept for in vivo base editing of the PCSK9 gene in the liver, with a meaningful and durable lowering of LDL-C,” Sekar Kathiresan, MD, cofounder and CEO, Verve, said in the statement.1 “However, at potentially therapeutic dose levels of VERVE-101, we have observed certain asymptomatic laboratory abnormalities, which we believe are attributable to the LNP delivery system. The safety of patients in our clinical trials is of the utmost importance."

READ MORE: Gene Editing Investigations Mature With heart-1 Trial for Familial Hypercholesterolemia

"We plan to further investigate the laboratory abnormalities observed in the Heart-1 clinical trial in order to inform the next steps for VERVE-101. At this time, we are prioritizing the initiation of the Heart-2 clinical trial of VERVE-102 due to its proximity to the clinic and its use of a different LNP that incorporates an ionizable lipid which has been well-tolerated in third-party clinical trials. We are grateful to our study participants and to our investigators, who share our belief in the promise of single-course gene editing medicines for the treatment of cardiovascular disease. We look forward to initiating the Heart-2 clinical trial in the second quarter of this year," Kethiresan continued.

The announcement comes less than 5 months after the first data from heart-1 made a splash at the American Heart Association’s Scientific Sessions 2023. At the meeting, Verve’s chief scientific officer, Andrew Bellinger, MD, PhD, presented data from 10 participants across 4 dose cohorts: 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 0.45 mg/kg (n = 3), and 0.6 mg/kg (n = 1). With a data cutoff of October 16, 2023, results of the trial pointed to an LDL-C reduction of 55% with just a single treatment at the greatest dose.2 The company also announced plans to expand the trial to the United States around the same time.3

"These first signs and signals from heart-1 in terms of the effective LDL lowering, I think, are promising and open a new door research in cardiovascular medicine and one that could result in therapeutics that are extremely useful,” Deepak Bhatt, MD, MPH, director, Mount Sinai Fuster Heart Hospital and Dr. Valentin Fuster Professor of Cardiovascular Medicine, Icahn School of Medicine, Mount Sinai, told CGTLive.

1. Verve therapeutics announces updates on its PCSK9 program. Verve Therapeutics. April 2, 2024. Accessed April 2, 2024.
2. Vafai SB, Gladding PA, Scott R, et al. Safety and pharmacodynamic effects of VERVE-101 an investigational DNA Base editing medicine designed to durably inactivate the PCSK9 gene and lower LDL cholesterol – interim results of the phase 1b heart-1 trial. Presented at: AHA Scientific Sessions 2023; November 10-13; Philadelphia, Pennsylvania.
3. 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.
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