Merck & Co. Inc. / Jiangsu Hengrui Pharmaceuticals Co. Ltd.

Cardiovascular disease driven by elevated lipoprotein(a)

64M US cases/yr · $10.0B Global Lp(a)-lowering therapy addressable market (peak projected)

Disease Overview

Lipoprotein(a) - Lp(a) - is a genetically determined, LDL-like particle with an attached apolipoprotein(a) tail that functions as an independent, causal cardiovascular risk factor. Roughly 20% of the global population and an estimated 64 million US adults carry elevated Lp(a) (>=50 mg/dL or >=125 nmol/L), conferring 2-3x increased risk of premature myocardial infarction, ischemic stroke, and calcific aortic valve stenosis. Unlike LDL-C, Lp(a) is not meaningfully modified by lifestyle, statins, ezetimibe, or PCSK9 inhibitors, leaving a massive untreated risk population. The commercial hypothesis driving Merck's up-to-$1.97B license of Hengrui's HRS-5346 is that an oral small molecule Lp(a) inhibitor could unlock the primary-care prescriber channel at a scale injectable siRNAs and antisense oligonucleotides cannot reach. HRS-5346 would enter an active Phase 2/3 competitive field in which Novartis's pelacarsen, Amgen's olpasiran, Eli Lilly's lepodisiran, and Silence Therapeutics' zerlasiran are all pursuing injectable Lp(a)-lowering in cardiovascular outcomes trials.

Competitive Landscape

The Lp(a) competitive landscape spans three MOA families. Antisense oligonucleotides (ASO) are led by Novartis/Ionis's pelacarsen (TQJ230, monthly SC, Phase 3 HORIZON outcomes trial, FDA filing expected 2026). siRNA Lp(a) lowering is the largest cohort: Amgen's olpasiran (AMG 890, quarterly SC, Phase 3 OCEAN(a) outcomes trial), Eli Lilly's lepodisiran (SC every 6 months, Phase 3 ACCLAIM-Lp(a)), and Silence Therapeutics/Novartis's zerlasiran (SC biannual, Phase 2). Oral small molecule Lp(a) inhibitors - HRS-5346's class - include Merck's own muvalaplin (MK-0616 combination context, Phase 2 KRAKEN), Hengrui's HRS-5346 as the newly licensed asset, and emerging programs at CSPC Pharmaceutical and Shanghai Pharmaceuticals. Upstream/adjunct approaches include PCSK9 inhibitors (alirocumab/Praluent, evolocumab/Repatha) with modest 20-30% Lp(a) reduction, and CETP inhibitors (obicetrapib/NewAmsterdam Pharma) showing Lp(a) reduction as secondary benefit. Merck's thesis with HRS-5346 layered on its muvalaplin program is to own the oral Lp(a) franchise with convenience, scale, and cardiometabolic cross-franchise leverage against injectable siRNA competitors.