Verve Therapeutics reports new data from study of VERVE-201

Verve Therapeutics reported new preclinical data in non-human primates demonstrating potent, durable and well-tolerated editing of the ANGPTL3 gene following administration of VERVE-201. To support advancement of VERVE-201 toward clinical development, Verve is evaluating the candidate in numerous preclinical studies and reported preclinical data in NHPs. VERVE-201cyn, the NHP surrogate of VERVE-201, was studied in 34 wild-type NHPs, across three groups: control, 1.5 mg/kg dose and 3.0 mg/kg dose. Key results showed: Mean whole liver DNA editing at the ANGPTL3 gene of 55% and 63% and mean blood ANGPTL3 protein reduction from baseline of 89% and 96%, at 1.5mg/kg and 3.0mg/kg doses, respectively, with durable effects observed out to six months following treatment. Decreased liver triglyceride mass, a nonclinical surrogate for hepatic fat accumulation, in NHPs treated with either 1.5 mg/kg or 3.0 mg/kg of VERVE-201cyn as compared to vehicle control, when assessed six months following treatment. VERVE-201cyn was well-tolerated with only transient impacts on alanine aminotransferase and aspartate aminotransferase that resolved by day 14 and there was no observed impact on total bilirubin levels. On-target ANGPTL3 editing was detected primarily in the liver, with a lower degree of ANGPTL3 editing in adrenal and spleen tissues and minimal ANGPTL3 editing elsewhere, consistent with the biodistribution of LNPs. In an additional study, Verve evaluated VERVE-201’s potential in an LDL receptor-deficient NHP model designed to mimic the physiology of patients with HoFH. Patients with HoFH have severe or complete LDLR deficiency, which limits the ability of traditional LNPs to deliver base editing medicines to the liver. Verve has developed its proprietary GalNAc-LNP to allow for uptake via an additional receptor, the asialoglycoprotein receptor, which is expected to enable delivery independent of LDLR. Verve first developed LDLR-deficient NHPs, resulting in an increase in mean LDL-C from 55 to 458 mg/dL. Subsequent treatment in these NHPs with VERVE-201cyn at a dose of 3.0 mg/kg led to: Mean whole liver DNA editing at the ANGPTL3 gene of 60% and a mean 84% reduction in blood ANGPTL3 protein. Mean 46% decrease in LDL-C and a mean 54% decrease in circulating triglycerides. Verve also reported preclinical findings in Ldlr-knockout mice fed a high-fat Western diet, in which administration of VERVE-201mu, as compared to control, led to a 97% reduction in blood ANGPTL3 protein, a 47% reduction in LDL-C and a 72% reduction in triglycerides.