Eli Lilly and Company / Verve Therapeutics, Inc.

Heterozygous Familial Hypercholesterolemia (HeFH) and Established ASCVD - one-time gene editing

1.3M US cases/yr · $5.2B 2024 global PCSK9 inhibitor market (Repatha $2.2B + Praluent + Leqvio ~$1.5B combined, plus biosimilars/other) · ~40-60% Real-world non-adherence to chronic injectable PCSK9 therapies within 12 months

Disease Overview

Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal-dominant genetic disorder affecting approximately 1 in 250-300 Americans (~1.3 million people), characterized by lifetime elevation of LDL-cholesterol (often 200-400 mg/dL) due to mutations in LDLR, APOB, or PCSK9 genes. HeFH patients carry 3-4x the lifetime risk of premature coronary heart disease compared to the general population, and despite statin, ezetimibe, and PCSK9 inhibitor therapy, many remain above LDL goals due to adherence, intolerance, or insufficient response. More broadly, atherosclerotic cardiovascular disease (ASCVD) secondary-prevention patients - approximately 20 million US adults with coronary artery disease - represent an adjacent target population where durable LDL-C reduction could prevent recurrent MACE. The CDC and American Heart Association project that cardiovascular disease costs the US over $400 billion annually. A one-time in vivo base-editing therapy that permanently inactivates hepatic PCSK9, analogous to the approved PCSK9 mAbs (Repatha, Praluent) and siRNA (Leqvio), could eliminate the need for chronic injections and address non-adherence, which drives a substantial share of real-world treatment failure.

Competitive Landscape

PCSK9 inhibition is a validated LDL-lowering mechanism anchored by Amgen's Repatha (evolocumab, 2024 global sales $2.2B), Regeneron/Sanofi's Praluent (alirocumab), and Novartis' Leqvio (inclisiran siRNA, 2024 sales ~$754M, twice-yearly dosing). The next wave targets one-time durability via gene editing or oral small molecules. Verve Therapeutics' VERVE-102 is an in vivo liver-targeted CRISPR base editor (adenine base editing) delivered via GalNAc-LNP that permanently inactivates hepatic PCSK9 - Phase 1b Heart-2 and Heart-1 data have demonstrated durable LDL-C reductions of 40-60% with single IV dose. Direct gene-editing competitors include Beam Therapeutics' BEAM-302 (base-editing, AAT deficiency; CVD programs earlier), Intellia Therapeutics' NTLA-2001/2002 (CRISPR-Cas9, TTR/HAE focus), Prime Medicine (prime editing, preclinical CVD), and CRISPR Therapeutics' CTX320 (Lp(a)-lowering gene edit). Oral PCSK9 competitors include Merck's MK-0616 enlicitide (Phase 3) and AstraZeneca's AZD0780 (Phase 2). Lilly's acquisition of Verve consolidates a leading CVD gene-editing platform alongside its existing Lipoprotein(a) siRNA lepodisiran (Phase 3) and oral GLP-1/obesity cardiometabolic franchise.