Key Points:
- Despite the advent of PCSK9 inhibitors, the majority of patients with familial hypercholesterolemia do not meet their LDL-C targets with standard therapies.
- VERVE-1 is a novel CRISPR base editing medication which was designed to inactivate hepatic PCKS9 with a single DNA base pair change, thus reducing LDL-C.
- In this study, the highest dose of VERVE-101 treatment resulted in a sustained >55% LDL-C reduction at 180 days. VERVE-101 was generally well tolerated, with mild infusion reactions at high doses and two observed severe adverse CV events which were attributed to underlying severe ASCVD.
Heterozygous familial hypercholesterolemia is an inherited disease resulting in lifelong, severe LDL-c elevations; however, few patients ever meet their LDL-C goal. Given the success of PCSK9 inhibitors, there has been great interest in developing base-editing technology to inactivate hepatic PCSK9. VERVE-101 is a novel CRISP base editing medication which was designed to reduce LDL-C via inactivation of hepatic PCKS9 using a single DNA base pair change. Prior studies in non-human primates have demonstrated durable LDL-C reductions up to 2.5 years following a single infusion. In a breaking presentation at the 2023 AHA Scientific Sessions today, Dr. Andrew Bellinger and his team presented the interim first-in-human Phase 1b results of their study: “Safety and Pharmacodynamic Effects of VERVE-101: An Investigational DNA Base Editing Medicine Designed to Durably Inactivate the PCSK9 Gene and Lower LDL Cholesterol,” or the heart-1 study.
The heart-1 study included 10 participants treated with VERVE-101 across 4 dose cohorts, from 0.1mg/kg (3 patients) to 0.6 mg/kg (1 patient). Participants were required to be age 18-75 with known heterozygous familial hypercholesterolemia and established ASCVD, on maximally tolerated lipid lowering therapy without having reached their lipid targets. Participants were pre-medicated with dexamethasone and anti-histamines, and VERVE-101 was delivered in a single infusion. The primary endpoint was safety and tolerability. Additional endpoints included pharmacokinetics of VERVE-101, blood PCSK9, and blood LDL-C.
The mean age was 54, with 20% women. VERVE-101 infusion did not result in a significant change in PCSK9 levels at the first two doses, but the three participants who received 0.45 or 0.6 mg/kg dosing had a reduction of 47%, 59%, and 84% respectively within 28 days of dosing. Similarly, in the three participants in the two higher dose cohorts there was an observed LDL-C reduction of 39%, 48%, and 55% participants by 28 days. The participant receiving 0.6 mg/kg had a durable 55% LDL-C reduction up to 180 days post administration. From a safety perspective, mild infusion reactions were common at doses of 0.45 mg/kg and above (identified in 100% of participants). Two patients experienced severe cardiovascular severe adverse events, both of which were determined to be related to the participants’ underlying ASCVD by an independent data safety monitoring board. Transient reversible ALT increases at higher doses were common and self-resolved.
When discussing the clinical implications of the study at the Scientific Sessions, Dr. Bellinger stated: “In conclusion, VERVE-101 provides the first proof-of-concept for in vivo DNA base editing in humans…in patients who require deep LDL-C lowering over decades, single course gene editing medicines may emerge as an option to overcome limitations of the chronic care model.”
