P069 - INITIAL RESULTS FROM THE PHASE 1B HEART-2 STUDY OF VERVE-102, AN INVESTIGATIONAL BASE EDITING MEDICINE DESIGNED TO INACTIVATE PCSK9 IN THE LIVER AND DURABLY LOWER LDL CHOLESTEROL

Background: Long-term clinical studies and human genetic data show that the cardiovascular benefits of LDL-C lowering accumulate over time. Lipid-lowering therapies that require chronic administration for years or decades place a substantial burden on patients, and their efficacy is limited in real world use by inconsistent adherence and frequent discontinuation. VERVE-102 is an investigational base editing medicine designed to address the unmet medical need for durable LDL-C control. VERVE-102 consists of an mRNA encoding an adenine base editor and guide RNA targeting PCSK9 packaged in a GalNAc-lipid nanoparticle for in vivo delivery to hepatocytes. The goal of treatment with VERVE-102 is permanent inactivation of PCSK9 in the liver and durable LDL-C lowering after a single course of treatment.

METHODS AND RESULTS: Heart-2 is an ongoing, Phase 1b, single ascending dose study of VERVE-102 in adults with heterozygous familial hypercholesterolemia and/or premature coronary artery disease who require additional LDL-C lowering despite maximally tolerated oral therapy. Participants receive premedication with dexamethasone and antihistamines before a single 2- to 4-hour infusion of VERVE-102 via peripheral IV infusion. The primary objective is to assess safety and tolerability. Changes in blood PCSK9 and LDL-C are being evaluated as a secondary objective and are presented here as time-averaged percent changes from baseline from day 28 through the last available follow-up.

As of a 13 March 2025 data cut, 14 participants with ≥28 days of follow up had been treated with VERVE-102 across three weight-based dose cohorts: 0.3 mg/kg (n=4), 0.45 mg/kg (n=6), 0.6 mg/kg (n=4) (Table 1). VERVE-102 was well-tolerated across all cohorts with no treatment-related serious adverse events, no cardiovascular events, and no clinically significant or dose-responsive laboratory changes. There was a single infusion-related reaction (grade 2) in one participant (0.6 mg/kg) that resolved with acetaminophen. Changes from baseline in blood PCSK9 and LDL-C were dose-dependent, reaching mean reductions of 60% and 53%, respectively, in the 0.6 mg/kg cohort. LDL-C lowering was highly correlated with the total RNA dose (Pearson r=-0.79; P< 0.0001). All three participants who received a total RNA dose ≥50 mg had >50% LDL-C lowering, with a mean reduction of 59% and a maximum reduction of 69% (Table 2).

Conclusion: In this initial analysis, VERVE-102 was well-tolerated and led to a mean 59% reduction in LDL-C for participants receiving a total RNA dose ≥50 mg. Dose escalation in Heart-2 is ongoing with open sites in Canada to further characterize the safety and lipid-lowering potential of VERVE-102.