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Apr 15 2025
5Verve Therapeutics has taken a significant step forward in its efforts to develop a one-time gene editing treatment for high cholesterol. The biotech company has released promising early-stage clinical data for VERVE-102, its latest PCSK9-targeted candidate, suggesting that it has successfully addressed prior safety issues without sacrificing efficacy.
The development of VERVE-102 follows the discontinuation of VERVE-101, Verve’s first attempt at PCSK9 base editing. That program was halted during a phase 1 trial after one of six participants who received a 0.45 mg/kg dose experienced grade 3 elevations in liver enzymes and a severe drop in platelet count. Verve attributed these adverse events to the lipid nanoparticle (LNP) delivery system, prompting the company to reformulate the therapy using a different LNP with a new ionizable lipid.
VERVE-102 retains the same therapeutic payload as its predecessor but is delivered using the updated LNP. The reformulation appears to have paid off. In a phase 1b study involving 14 patients with heterozygous familial hypercholesterolemia or premature coronary artery disease, Verve reported no clinically significant changes in key laboratory markers, including bilirubin, liver enzymes, and platelets. Importantly, no dose-related safety trends emerged across the three dosing levels tested.
Only one patient experienced a grade 2 infusion-related reaction, which resolved quickly with acetaminophen. There were no serious adverse events, dose-limiting toxicities, or cardiovascular complications reported.
From an efficacy standpoint, VERVE-102 delivered strong LDL-C and PCSK9 reductions. In the cohort receiving the 0.45 mg/kg dose—matching the dose used in the VERVE-101 trial—participants saw an average 41% decrease in LDL cholesterol and a 53% drop in PCSK9 levels over time. These results closely mirror the 42% LDL-C reduction seen with VERVE-101 at the same dose, but without the earlier safety issues.
Higher doses yielded even better outcomes. At the 0.6 mg/kg dose, the four treated participants experienced time-averaged LDL-C and PCSK9 reductions of 53% and 60%, respectively. For comparison, a single patient who received the same dose of VERVE-101 saw a 57% LDL-C reduction sustained for up to 18 months.
Verve has now begun dosing patients at 0.7 mg/kg. The early safety and lab data from the first two individuals in this group are consistent with earlier results, and the company anticipates potentially deeper cholesterol reductions at this higher dose.
The latest results suggest that VERVE-102 may outperform Novartis’ approved siRNA-based Leqvio (inclisiran), which targets a 40% to 50% LDL-C reduction range. Analysts at William Blair described the updated LNP approach as a “best-case scenario” for Verve, addressing safety concerns while maintaining therapeutic benefit.
With regulatory clearance now in place to expand into U.S. sites, Verve plans to begin a phase 2 trial in the second half of 2025. The ongoing phase 1b study is enrolling patients in the U.K., Canada, Israel, Australia, and New Zealand.
Crucially, Verve also expects to share an opt-in package with Eli Lilly in the same timeframe. Lilly secured the right to opt into the program through a 2023 deal with Beam Therapeutics. If the pharmaceutical giant chooses to proceed, it will cover one-third of global development costs and co-commercialize VERVE-102 with Verve in the U.S., while Verve retains exclusive rights elsewhere.
VERVE-102 enters a competitive but evolving field. Existing PCSK9-targeted therapies such as Amgen’s Repatha and Sanofi-Regeneron’s Praluent rely on antibody-based approaches, while newer entrants like Leqvio and oral drugs from AstraZeneca and Merck & Co. are in various stages of development. Verve’s candidate stands out for its potential to offer a durable, single-dose gene editing solution for long-term cholesterol management.
Source: https://www.fiercebiotech.com/biotech/verves-second-swing-pcsk9-editing-yields-clean-safety-profile-teeing-lilly-opt-decision
This is non-financial/medical advice and made using AI so could be wrong.
