Verve Therapeutics has generated evidence its PCSK9 pivot could pay off. One year after dropping a base editing candidate over a safety signal, the biotech has shown its Eli Lilly-partnered successor can achieve similar cholesterol reductions without raising any red flags.
Boston-based Verve stopped a phase 1 trial of VERVE-101 last year after one of six patients treated with the 0.45-mg/kg dose had grade 3 rises in a liver enzyme and a grade 3 case of low blood platelets. The biotech pointed to the lipid nanoparticle (LNP) as the likely cause of the adverse events. VERVE-102, a drug candidate that uses a different LNP to deliver the same payload, became Verve’s lead PCSK9 program.
Since then, analysts have questioned Verve about why it believes VERVE-102 will be free from the issues that sank its predecessor. Monday, the biotech published data to support its argument that the use of a LNP with a different ionizable lipid has squashed the risk of laboratory abnormalities.
Verve shared results from 14 people with heterozygous familial hypercholesterolemia and/or premature coronary artery disease who received one of three doses of VERVE-102 in a phase 1b trial. The biotech saw no clinically significant changes in bilirubin, platelets or two liver enzymes. There were no dose-dependent trends in any of the laboratory measurements.
One patient had a grade 2 infusion-related reaction. The reaction involved transient symptoms that resolved with acetaminophen. There were no treatment-related serious adverse events, dose-limiting toxicities or cardiovascular events.
Verve’s data suggest it has mitigated the safety concern without compromising efficacy. The biotech reported a 41% reduction in LDL cholesterol and 53% reduction in PCSK9 in the six patients who received a 0.45-mg/kg dose. The figures are time-averaged changes from Day 28 through the last follow-up. Verve saw a time-averaged LDL-C reduction of 42% in the six patients who received 0.45 mg/kg of VERVE-101.
The biotech reported data on four patients who received 0.6 mg/kg of VERVE-102. At that dose, Verve saw time-averaged reductions in LDL-C and PCSK9 of 53% and 60%, respectively. This compares to a 57% reduction in LDL-C in the one patient who received 0.6 mg/kg of VERVE-101. That reduction was sustained out to 18 months after a single dose, supporting Verve’s claims about the durability of effects.
The company is now enrolling people to receive 0.7 mg/kg of VERVE-102. The early laboratory and clinical safety profile for the first two patients to receive the higher dose is in line with the first three cohorts, Verve said. The dose-dependent LDL-C reductions seen so far suggest patients on 0.7 mg/kg may experience deeper declines in cholesterol.
The data suggests that VERVE-102 exceeds the 40% to 50% LDL-C reduction goals set by Novartis' approved siRNA Leqvio (inclisiran) and corrects for safety concerns with VERVE-101 by swapping out the LNP, "which is a best-case scenario for Verve shares," analysts at William Blair said in an April 14 note.
Verve plans to dose the first patient in a phase 2 trial of VERVE-102 in the second half of 2025. While the phase 1b study is enrolling patients in the U.K., Canada, Israel, Australia and New Zealand, the biotech expects to include U.S. sites in the phase 2. The FDA recently cleared Verve to study the candidate in the U.S.
The biotech also plans to share the opt-in package in the second half of 2025 with Lilly, which acquired the opt-in right from Beam Therapeutics in 2023. If Lilly takes up its option, the Big Pharma will pay one-third of global development costs in return for an equal split of profits in the U.S. Lilly and Verve would jointly commercialize VERVE-102 in the U.S., while Verve holds all product rights in other territories.
Other companies are targeting PCSK9 to lower LDL-C. Amgen’s Repatha, and Sanofi and Regeneron’s Praluent, which are antibodies that inhibit PCSK9, were first to market. Later, Novartis won approval for Leqvio. AstraZeneca and Merck & Co. have oral PCSK9 inhibitors in clinical development. The potential for VERVE-102 to provide durable reductions in LDL-C after a single dose sets the candidate apart.
Editor's note: This article was updated at 12 p.m. ET on April 14 to include analyst insight.