Enlicitide’s Phase 3 Triumphs Herald New Era for PCSK9 Inhibitors and Cholesterol Management

On September 2, 2025, Merck announced that its oral PCSK9 inhibitor, enlicitide decanoate (MK-0616), achieved all primary and key secondary endpoints in the Phase 3 CORALreef Lipids trial, marking its third successful Phase 3 study following CORALreef HeFH and AddOn [1]. As the first oral PCSK9 inhibitor to demonstrate significant low-density lipoprotein cholesterol (LDL-C) reductions in Phase 3, enlicitide could transform cholesterol management. With cardiovascular disease claiming 18 million lives globally, including significant burdens in the US and China [2], this SinoDrugWatch review provides an overview of the PCSK9 inhibitor landscape, Merck’s milestone, and comparisons with AstraZeneca’s AZD0780, highlighting opportunities for oral therapies in a competitive market.

Understanding PCSK9 Inhibitors

PCSK9 inhibitors target the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which inhibits LDL receptor activity in the liver, reducing LDL-C clearance [3]. By blocking PCSK9, these drugs enhance LDL-C removal, lowering the risk of atherosclerotic cardiovascular disease (ASCVD), such as heart attacks and strokes [3]. Since 2015, PCSK9 inhibitors have evolved across three main types:

• Monoclonal antibodies (e.g., Amgen’s Repatha [evolocumab], Sanofi/Regeneron’s Praluent [alirocumab]) bind circulating PCSK9, preventing its interaction with LDL receptors, but require biweekly or monthly injections [4].
• siRNA therapies (e.g., Novartis’ Leqvio [inclisiran]) use small interfering RNA to reduce PCSK9 production in hepatocytes, offering twice-yearly dosing [5].
• Oral inhibitors (e.g., Merck’s enlicitide, a macrocyclic peptide; AstraZeneca’s AZD0780, a small molecule) inhibit PCSK9 via daily pills, improving convenience [1, 6].

Despite their efficacy, injectables face challenges: needle-based delivery reduces adherence, and high costs limit access, impacting the 86 million US adults and millions in China with hypercholesterolemia [2, 7]. Oral inhibitors promise to address these barriers, potentially reshaping treatment for high-risk patients by simplifying administration and improving compliance [6].

PCSK9 Inhibitor Landscape: US and China

The global PCSK9 inhibitor market, valued at USD 2.5–3 billion in 2024, is projected to reach USD 7–8 billion by 2030 (CAGR 16–20%) [8, 9]. Monoclonal antibodies dominate, but oral and siRNA therapies are gaining traction.

United States

The US holds 46% of global market share, driven by high CVD prevalence (86 million adults) [8]. Key drugs include:

• Evolocumab (Repatha, Amgen): Monoclonal antibody, approved 2015 for hypercholesterolemia/ASCVD [4].
• Alirocumab (Praluent, Sanofi/Regeneron): Monoclonal antibody, approved 2015, expanded for pediatric use [4].
• Inclisiran (Leqvio, Novartis): siRNA, approved 2021, dosed twice yearly [5].

High costs (~$14,000/year initially, now lower) and insurance rejections (~31%) are challenges [8]. Pipeline candidates include LIB Therapeutics’ lerodalcibep (Fc-fusion PCSK9, BLA accepted Feb 2025) and enlicitide [10].

China

China leads the Asia-Pacific market (23.5% global share, CAGR 22%), driven by rising CVD rates [8, 9]. PCSK9 uptake remains underpenetrated, with fewer than 5% of eligible patients receiving therapy due to high costs and injection burden [7]. Sanofi’s withdrawal of Praluent in August 2025 due to supply issues and competition from domestic drugs like Innovent’s Sintbilo shifts the landscape [11]. The table below details marketed therapies in China:

Marketed PCSK9 Therapies in China

Praluent’s exit creates opportunities for domestic players like Innovent and oral therapies like enlicitide, especially if they secure National Reimbursement Drug List (NRDL) inclusion [11].

Merck’s CORALreef Program: Three Phase 3 Triumphs

Merck’s CORALreef program includes three Phase 3 trials for enlicitide: CORALreef Lipids, HeFH, and AddOn [1]. The CORALreef Lipids trial (NCT05952856), announced on September 2, 2025, tested enlicitide in adults with hypercholesterolemia on statins (or statin-intolerant) and at risk for ASCVD. It met its primary endpoint, achieving a statistically significant and clinically meaningful LDL-C reduction at 24 weeks versus placebo, with reductions in non-HDL cholesterol, apolipoprotein B (ApoB), and lipoprotein(a) [Lp(a)] [1]. CORALreef HeFH and AddOn trials also showed significant LDL-C reductions, though specific numerical results for all three trials are pending presentation at a scientific congress [1]. Phase 2b data showed LDL-C reductions of 41.2–60.9% across doses (6 mg, 12 mg, 18 mg, 30 mg), among the strongest for PCSK9 therapies [12]. Safety was robust, with adverse events (AEs) comparable to placebo and low discontinuation rates [1]. Merck is engaging global regulators, and the CORALreef Outcomes trial (14,500+ participants) will assess cardiovascular event prevention [1].

Comparing Enlicitide and AZD0780

Enlicitide leads the oral PCSK9 race, but AstraZeneca’s AZD0780 is competitive. The table below compares their trial data:

Key takeaway: Enlicitide’s macrocyclic peptide design delivers robust LDL-C lowering, while AZD0780’s small-molecule profile offers potential manufacturing and cost advantages [6, 12].

Global Oral PCSK9 Pipeline

Why This Matters

With 70% of ASCVD patients missing LDL-C goals, oral PCSK9 inhibitors could improve adherence, especially in China, where high costs (¥19,976–¥49,088 annually) limit access [7]. Enlicitide’s Phase 3 successes position it for potential market entry, while AZD0780 remains competitive [1, 6]. LIB Therapeutics’ lerodalcibep and Novartis’ inclisiran add to a crowded pipeline, pressuring payers for competitive pricing [5, 10]..

Looking Ahead

Enlicitide’s triumphs in CORALreef Lipids, HeFH, and AddOn trials signal a potential first-mover advantage, but pricing and outcomes data from CORALreef Outcomes will be critical [1]. In China, oral PCSK9 inhibitors could capitalize on market shifts, provided they secure NRDL listing [11]. If Merck replicates its US momentum in China, where adherence and affordability dominate, the first oral PCSK9 could reset the standard of care within five years.

References

1. Merck & Co., Inc. Merck’s Investigational Oral PCSK9 Inhibitor Enlicitide Decanoate Met All Primary and Key Secondary Endpoints in Adults with Hypercholesterolemia in Pivotal CORALreef Lipids Study. https://www.merck.com/news (accessed September 3, 2025).
2. World Health Organization. Cardiovascular Diseases (CVDs). https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (accessed September 3, 2025).
3. Sabatine, M. S.; Giugliano, R. P.; Keech, A. C.; et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med. 2017, 376, 1713–1722.
4. Schwartz, G. G.; Steg, P. G.; Szarek, M.; et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N. Engl. J. Med. 2018, 379, 2097–2107.
5. Ray, K. K.; Wright, R. S.; Kallend, D.; et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N. Engl. J. Med. 2020, 382, 1507–1519.
6. Rider, D.; Bhatt, D. L.; Nicholls, S.; et al. Oral PCSK9 Inhibitor, AZD0780, Reduces LDL-C in Patients with Dyslipidemia: The PURSUIT Trial. J. Am. Coll. Cardiol. 2025, 85, A123 (abstract).
7. Li, J.; Zhang, X.; Zhao, S. PCSK9 Inhibitors in China: Current Status and Future Prospects. Cardiovasc. Drugs Ther. 2024, 38, 1001–1010.
8. Mordor Intelligence. PCSK9 Inhibitors Market Size & Share Analysis - Growth Trends & Forecasts (2024–2030). https://www.mordorintelligence.com (accessed September 3, 2025).
9. DataM Intelligence. Global PCSK9 Inhibitors Market - 2024–2030. https://www.datamintelligence.com (accessed September 3, 2025).
10. LIB Therapeutics. LIB Therapeutics Announces FDA Acceptance of Biologics License Application for Lerodalcibep. https://www.libtherapeutics.com (accessed September 3, 2025).
11. Reuters. Sanofi Halts Praluent Supply in China Amid Supply Constraints, Competition. https://www.reuters.com (accessed August 12, 2025).
12. Ballantyne, C. M.; Banka, P.; Mendez, G.; et al. Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616. J. Am. Coll. Cardiol. 2023, 81, 1553–1564.