Verve Therapeutics’ Base Editing Therapy VERVE-102 Reduces LDL-C in Patients With HeFH and CAD
Verve noted that a patient treated at the 0.6 mg/kg dose showed the maximum decrease in LDL-C levels: 69%.
Verve Therapeutics’ VERVE-102, an investigational in vivo base editing therapy that uses a lipid nanoparticle (LNP) delivery system, has demonstrated the ability to reduce low-density lipoprotein cholesterol (LDL-C) and PCSK9 protein levels in patients with heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD) being treated in the phase 1b HEART-2 clinical trial (NCT06164730).1
As of the March 13, 2025, data cut-off, 14 patients had been treated across 3 cohorts in HEART-2 and reached at least 28 days of follow-up. For the 4 patients treated in the 0.3 mg/kg cohort, LDL-C levels were decreased by 21% and PCSK9 levels were decreased by 46%. For the 6 patients treated at a dose of 0.45 mg/kg, LDL-C levels were decreased by 41% and PCSK9 levels were decreased by 53%. For the 4 patients treated in the 0.6 mg/kg cohort, LDL-C levels decreased by 53% and PCSK9 levels decreased by 60%. Verve noted that a patient treated at the 0.6 mg/kg dose showed the maximum decrease in LDL-C levels: 69%.
Verve also reported the results in terms of total RNA dose. From day 28 through the last available follow-up, a time-averaged percent change for mean LDL-C decreases from baseline was reported. For the 4 patients who received less than 25 mg total RAN dose, a –21% mean LDL-C reduction from baseline was observed; for the 7 patients who received a 25 mg to less than 50 mg total RNA dose, a –41% mean LDL-C reduction from baseline was observed; and for the 3 patients who received 50 mg to less than 60 mg total RNA dose, a –59% mean LDL-C reduction from baseline was observed.
“Verve was founded 7 years ago with a vision of 1 treatment dose potentially leading to a lifetime of LDL-C lowering,” Sekar Kathiresan, MD, the cofounder and chief executive officer of Verve Therapeutics, said in a statement.1 “The data presented today suggest that this game-changing, 1 dose future is possible. We are pleased by the safety VERVE-102 has demonstrated so far, and our proprietary GalNAc-LNP delivery technology is showing a potentially best-in-class safety profile. The initial efficacy data suggest that VERVE-102 has the potential to match or exceed the LDL-C reduction provided by currently available PCSK9-targeting therapies. Among participants who received a dose greater than 50 mg total RNA, we observed a mean LDL-C reduction of 59% and a maximum LDL-C reduction of 69%. Furthermore, VERVE-101 has continued to show excellent durability for the base editing mechanism out to nearly 2 years, with follow-up ongoing.In sum, VERVE-102 has the potential to solve the urgent need for enduring efficacy in patients living with HeFH or ASCVD. We are incredibly grateful to the patients and healthcare professionals who believe in our mission and participate in our clinical trials. Together, we are striving to revolutionize cardiovascular disease treatment and deliver a one dose future.”
With regard to safety, Verve characterized VERVE-102 as “well-toleratred” and reported that there were no treatment-related serious adverse events (AEs), dose-limiting toxicities, or cardiovascular events seen in the study. A single patient experienced a grade 2 infusion-related reaction with transient symptoms, but the AE was resolved following treatment with acetaminophen. The company also noted that across all dose levels, there were no changes in alanine aminotransferase, aspartate aminotransferase, bilirubin, or platelets that were deemed clinically significant and no dose-dependent trends in these changes emerged.
Verve stated that the fourth cohort of HEART-2, which is using a dose of 0.7 mg/kg, is currently recruiting patients in the United Kingdom, Canada, Israel, Australia, and New Zealand. Two patients have already been dosed in this cohort as of April 7, 2025, and the company noted that early laboratory and safety findings seem to be consistent with the previous cohorts. Verve anticipates that in the second half of this year it will report final data from the trial’s dose escalation portion. Pending regulatory clearance, Verve expects that a planned phase 2 clinic for VERVE-102 will dose its first patient in the second half of this year.
Verve originally announced the dosing of the first patient in HEART-2 in May 2024.2 Verve Therapeutics previously announced that it would be prioritizing the further development of VERVE-102 in April 2024.3 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.
In May 2024, CGTLive® interviewed Kethiresan about Verve’s decision to follow up VERVE-101 with next-generation editing approaches. He discussed VERVE-102 and the company’s gene editing strategy to help address unmet needs in the field of cardiovascular disease.
“We have a second investigational medicine called VERVE-102 that also targets PCSK9 but differs in the delivery vehicle, in the lipid nanoparticle formulation,” Kethiresan told CGTLive. “In this second product VERVE-102, we're using a ligand called GalNAc that targets this lipid nanoparticle even more specifically to the liver. And so that's the main difference.”
