Verve Therapeutics Doses First Patient in Phase 1b Trial for Gene Therapy VERVE-102


VERVE-102 is intended to reduce LDL-C in patients with heterozygous familial hypercholesterolemia or premature coronary artery disease.

Verve Therapeutics has dosed the first patient in Heart-2, a phase 1b clinical trial (NCT06164730) evaluating VERVE-102, an investigational in vivo base editing therapy that uses a lipid nanoparticle (LNP) delivery system, for the treatment of heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD).1

VERVE-102 is intended to lower levels of low-density lipoprotein cholesterol (LDL-C), which drives disease symptoms in the aforementioned indications, by permanently inactivating the PCSK9 gene in the cells of the liver. The gene editing product, which is intended to serve as a one-time treatment, targets PCSK9 with the use of an optimized guide RNA and delivers mRNA coding for an adenine base editor. Furthermore, it is directed to the cells of the liver via a GalNAc-LNP delivery technology

The open-label, single-ascending dose study is recruiting adult patients who need additional lowering of LDL-C, and will assess outcomes by measuring pharmacokinetics and changes in levels of the PCSK9 protein and LDL-C in the blood. Four dose cohorts, which will each include 3 to 9 patients with either eligible disease, are planned.

“Dosing the first patient in the Heart-2 phase 1b clinical trial for VERVE-102 is an important step in the continued progress of our pipeline,” Sekar Kathiresan, MD, the cofounder and chief executive officer of Verve Therapeutics, said in a statement.1 “We are focused on transforming the care of atherosclerotic cardiovascular disease (ASCVD) through gene editing medicines that can lead to sustained reductions in blood cholesterol after a single course of treatment. VERVE-102 is designed to turn off the PCSK9 gene with a goal of durably lowering LDL-C in patients living with either HeFH or premature CAD, and we look forward to evaluating the safety and preliminary efficacy data of VERVE-102 in the Heart-2 trial. With clinical trial applications cleared in Canada and the United Kingdom, we are actively enrolling patients in the Heart-2 trial and expect to provide a data update on our PCSK9 program in 2025.”

Verve Therapeutics announced that it would be prioritizing the further development of VERVE-102 in April 2024.2 The announcement came alongside news that the company would be pausing enrollment in its phase 1b Heart-1 clinical trial (NCT05398029) evaluating VERVE-101, a CRISPR base-editing therapy intended to treat HeFH and ASCVD by reducing LDL-C levels. VERVE-101 uses CRISPR/Cas9 to inactivate the PCSK9 gene in hepatic cells via a single base pair change. VERVE-101 is delivered in an engineered LNP that uses a different ionizable lipid from VERVE-102 and does not include the company’s liver-targeting GalNAc ligand.

Heart-1's enrollment was paused after the sixth patient to receive treatment in the study experienced a grade 3 treatment-induced transient increase in serum alanine aminotransferase (ALT) and a serious AE of grade 3 treatment-induced thrombocytopenia within 4 days of administration of 0.45 mg/kg of VERVE-101. Verve noted that the patient’s laboratory abnormalities resolved fully within a few days and the participant did not experience any related bleeding or other symptoms.

“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,” Kathiresan said in an April 2024 statement.2 “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. 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.”

1. Verve Therapeutics Announces Dosing of First Patient in Heart-2 Phase 1b Clinical Trial Evaluating VERVE-102. News release. Verve Therapeutics. May 7, 2024. Accessed May 14, 2024.
2. Verve therapeutics announces updates on its PCSK9 program. Verve Therapeutics. April 2, 2024. Accessed May 14, 2024.
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