Merck Invests $2 Billion in Novel Lipoprotein(a) Inhibitor Amidst Competitive Landscape

On March 25, Merck announced a significant investment of nearly $2 billion to acquire rights to HRS-5346, a novel oral small molecule inhibitor targeting lipoprotein(a) [Lp(a)], developed by Hengrui Medicine. This deal includes an upfront payment of $200 million, drawing substantial attention to the emerging target of Lp(a) in lipid-lowering therapies.

Lp(a) is recognized as a critical risk factor for cardiovascular disease, yet no approved medications specifically aim to lower Lp(a) levels globally. According to the Insight database, 12 Lp(a)-targeted drugs are currently in clinical development, with major players including Merck, Novartis, Eli Lilly, and Amgen, as well as domestic firms like Hengrui and Boehringer Ingelheim.

Cardiovascular diseases (CVD) remain the leading cause of death worldwide, particularly in China, where the number of affected individuals exceeds 330 million. Atherosclerotic cardiovascular disease (ASCVD) is a significant manifestation of CVD, with dyslipidemia being a key pathogenic risk factor. Historically, low-density lipoprotein cholesterol (LDL-C) has been the primary target for lipid-lowering therapy. However, research has shown that even optimal control of LDL-C does not eliminate residual cardiovascular risk.

Recent findings highlight the role of Lp(a) in the development of ASCVD. Composed of LDL-like particles and apolipoprotein(a) [Apo(a)], Lp(a) is synthesized mainly in the liver and exhibits significant concentration variability. Elevated levels of Lp(a) are causally linked to an increased risk of cardiovascular diseases, independent of baseline LDL-C levels.

The 2023 Chinese Lipid Management Guidelines explicitly recognize elevated Lp(a) as an independent risk factor for conditions such as coronary heart disease and ischemic stroke.

Currently, eight of the 12 Lp(a)-targeted drugs in clinical trials are nucleic acid-based, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO). These drugs function by inhibiting the translation of target mRNA, effectively preventing Lp(a) formation.

Prominent examples include:

• Pelacarsen: Developed by Novartis and Ionis, this ASO targets Apo(a) mRNA and is currently in Phase III trials for secondary prevention of cardiovascular events in hyperlipidemic patients. Phase II results indicated that Pelacarsen reduced Lp(a) levels by 35%-80% in various dosage groups.

• Olpasiran: An siRNA molecule from Amgen, showing promising results in Phase II studies, with Lp(a) levels decreasing significantly after treatment.

• Muvalaplin: A small molecule inhibitor by Eli Lilly, which breaks the assembly of Lp(a) particles. In Phase II trials, it demonstrated a dose-dependent reduction in Lp(a) levels, highlighting its potential for convenient oral administration.

Merck's acquisition of HRS-5346 represents a strategic move in this competitive landscape, as companies race to develop effective treatments for Lp(a). While progress has been made, many of these drugs remain in clinical trials, and their broader application in clinical practice is still a considerable challenge. The future potential of Lp(a) targeted therapies awaits further clinical validation and data.