The Golden Waterway for Innovative Drugs Is Now Open
Update time:
2026-04-10 19:31
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The value potential of PCSK9 medicines continues to rise.
Recently, at the annual meeting of the American College of Cardiology, Merck unveiled the latest Phase III clinical data for enlicitide, convincing the industry that a pivotal era shift is underway.
Data showed that among patients already on statin therapy, enlicitide reduced levels of LDL-C — the so-called "bad cholesterol" — by more than 64%, a far greater reduction than existing oral lipid-lowering drugs. Published in The New England Journal of Medicine, the results sent ripples across the global pharmaceutical industry.
This marks enlicitide’s third successful Phase III study. Previously, it achieved a 58.2% LDL-C reduction in patients with heterozygous familial hypercholesterolemia and a 57.1% reduction in a broader high-risk cardiovascular population.
With three mutually corroborating studies, enlicitide is poised to become a blockbuster drug. Analysts at RBC Capital Markets project that, if approved, enlicitide could reach $5 billion in annual sales by 2034.
The competitive landscape of the global cardiovascular drug market has been reshuffled. And behind Merck, Chinese innovative players are rising rapidly.
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A Hat-Trick of Successes
The story of enlicitide begins with a scientific breakthrough.
Decades ago, Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center discovered the LDL receptor, explaining how the liver clears "bad cholesterol" from the bloodstream.
This work earned them the 1985 Nobel Prize in Physiology or Medicine and laid the foundation for the rise of statins.
In the 2000s, researchers from the same institution — Helen Hobbs and Jonathan Cohen — identified a unique population with natural mutations in the PCSK9 gene. These mutations lowered PCSK9 protein levels, kept LDL-C persistently low throughout life, and significantly reduced heart disease risk.
As a result, the PCSK9 target moved into the spotlight of lipid-lowering drug development.
PCSK9 protein acts by "disabling" LDL receptors on the liver surface. When PCSK9 levels are excessive, LDL receptors are degraded in large numbers, and cholesterol cannot be efficiently cleared from the blood. Inhibiting PCSK9 allows LDL receptors to recover, accelerating cholesterol metabolism.
In 2015, Regeneron and Amgen launched the PCSK9 monoclonal antibodies Praluent and Repatha respectively. Administered by injection, these agents achieved LDL-C reductions of over 60%. Yet their commercial performance fell far short of expectations.
Due to high pricing, inconvenient injection administration, and reimbursement restrictions, these "scientifically successful" products never became commercial blockbusters. It took seven years after approval for Repatha to surpass $1 billion in annual sales.
Merck’s enlicitide aims to break the commercial logjam of PCSK9 drugs with an oral formulation.
Over the past year, results from three Phase III trials of enlicitide have been released one after another, and Merck is poised to begin its formal regulatory journey.
The first study, CORALreef HeFH, focused on patients with heterozygous familial hypercholesterolemia. Three hundred and three subjects received once-daily oral enlicitide or placebo on top of statin therapy. After 24 weeks, the enlicitide group achieved a 58.2% LDL-C reduction, while the placebo group saw a 2.6% increase. The reduction remained stable at 55.3% at week 52.
The second trial, CORALreef Lipids, enrolled a much larger sample of 2,909 patients with established cardiovascular disease or high risk. At week 24, enlicitide reduced LDL-C by 57.1%, representing a 55.8% difference from placebo. After 52 weeks of follow-up, the reduction held at 52.4%, with mean LDL-C falling to 45.7 mg/dL (approximately 1.18 mmol/L), demonstrating potent and durable lipid-lowering effects.
Importantly, the second study also confirmed that enlicitide significantly reduces non-HDL cholesterol and apolipoprotein B levels — two key markers for assessing cardiovascular risk.
The recently released latest data pushed LDL-C reduction to over 64%.
Behind this "hat-trick" lies Merck’s distinctive technological approach. Enlicitide is a macrocyclic peptide drug identified and optimized via mRNA display technology. This platform offers unique advantages over traditional approaches for "undruggable" targets relying on protein–protein interactions and intrinsically disordered proteins.
Mechanistically, enlicitide binds to the LDL receptor-binding site on PCSK9, preventing degradation of LDL receptors and enhancing LDL-C clearance.
However, there is a trade-off. Reports have noted that enlicitide requires patients to fast for eight hours before dosing, which could pose an adherence barrier. In comparison, AstraZeneca’s oral PCSK9 inhibitor AZD0780 carries no such restriction.
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Clash of Multinational Pharma Giants
Merck’s breakthrough has undoubtedly electrified the entire industry.
Cardiovascular disease is the world’s leading cause of death, and the lipid-lowering drug market continues to expand. For instance, data from Menet shows that in the first three quarters of 2025, sales of lipid regulators across China’s three major terminal and six market segments exceeded 20 billion yuan, representing a year-on-year increase of 15.7%.
In this vast blue ocean, the PCSK9 target has become a fiercely contested battleground.
Novartis has reaped substantial rewards. In November 2019, Novartis acquired The Medicine Company for $9.7 billion, gaining the PCSK9-targeting siRNA therapy inclisiran. Two years later, inclisiran was approved by the FDA under the brand name Leqvio.
Leqvio uses RNA interference to suppress PCSK9 protein synthesis at the genetic level. Its greatest advantage is dosing frequency: a second injection three months after the initial dose, followed by just two injections per year. In 2025, Leqvio generated global sales of $1.198 billion, up 57% year-on-year, becoming the first small nucleic acid chronic disease drug to cross the blockbuster threshold.
Established multinational corporations (MNCs) such as Regeneron and Amgen have not stood idle, pursuing differentiated strategies to expand PCSK9 monoclonal antibodies from "statins adjunctive therapy" to broader primary prevention populations.
Yet Novartis shows no signs of backing down. In July 2025, the FDA approved an updated label for Leqvio, allowing its use as first-line monotherapy combined with diet and exercise, no longer mandating combination with statins. This indication expansion further solidified Leqvio’s leading position.
Active investment and deal-making also reflect MNCs’ fierce competition in this sector.
In June 2025, Eli Lilly acquired gene-editing firm Verve Therapeutics for a total of $1.35 billion. Early data showed that Verve’s one-time PCSK9 gene-editing therapy maintained LDL-C reductions of around 60% two years after administration.
Prior to the Verve acquisition, Lilly paid Beam Therapeutics a $200 million upfront fee and a $50 million equity investment, securing an option to jointly develop base-editing programs for cardiovascular diseases.
Steve Nissen, a researcher at the Cleveland Clinic, commented: "Gene therapy changes everything." For young patients with inherited high cholesterol, a single DNA edit could eliminate the burden of lifelong medication — opening a new frontier in lipid-lowering treatment.
Even so, oral administration remains highly attractive. Beyond Merck, AstraZeneca has also bet heavily on oral PCSK9 inhibitors. Phase IIb data released in 2025 showed that AZD0780 reduced LDL-C by 50.7% in patients with an inadequate response to statins.
Analysts predict that, with positive follow-up data, AZD0780 could reach annual peak sales of more than $5 billion.
MNCs are now engaged in an all-out battle: seizing more adherent patient groups with oral formulations, achieving ultra-long-acting dosing with small nucleic acid technologies, and exploring one-time cures with gene therapies. The entry of Chinese players has added a new dimension to this "infinite game".
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Rise of Domestic Players
In the monoclonal antibody sector, domestic PCSK9 inhibitors have already broken through.
Products including Innovent’s tuczisumab, Akeso’s inulitsumab, Junshi’s ongaricizumab, and Hengrui’s recaticizumab have been approved successively, breaking the monopoly of MNC products in the Chinese market.
Although monoclonal antibodies still require injections every 2–4 weeks, domestic pricing advantages and insurance coverage are improving accessibility.
In the small nucleic acid race, the pace of catching up has accelerated sharply.
CSPC Pharmaceutical’s SYH2053 injection is the first domestic PCSK9 siRNA drug to enter Phase III clinical trials. This siRNA agent, delivered to the liver via GalNAc technology, is indicated for adult primary hypercholesterolemia or mixed dyslipidemia, with patient recruitment recently initiated.
If successful, SYH2053 is expected to become the first approved domestic PCSK9 siRNA drug, going head-to-head with Novartis’ Leqvio.
RiboBio’s RBD7022, developed in partnership with Qilu Pharmaceutical, completed Phase II patient enrollment in May 2025, enrolling 204 patients with hyperlipidemia. Discovered using RiboBio’s proprietary RiboGALSTARTM platform, Qilu obtained Greater China rights for a total of 700 million yuan.
Shengyin Biomedical, backed by Lilly and Roche, has advanced its lead candidate SGB-3403 — another PCSK9-targeting siRNA drug — with the first patient dosed in Australia.
HK Healthcare, traditionally focused on generic drugs, has initiated a Phase Ib trial for its self-developed siRNA drug YKYY015 injection in November 2025.
Domestic companies are also active in the oral small-molecule PCSK9 inhibitor space.
Early R&D of oral small molecules is far more challenging than that of monoclonal antibodies and siRNAs, which can be rapidly developed through standardized processes. Small molecules require lengthy screening and rational design to achieve stronger binding, better safety, and higher stability.
CiviBio has taken a critical step forward. As the first domestic oral PCSK9 small molecule to enter the clinic, CVI-LM001 reduced LDL-C by 26.3% from baseline after 28 consecutive days of 300 mg oral dosing in Phase I.
Some companies are pursuing even more promising dual-target and novel mechanism therapies.
In February 2026, Betta Pharmaceuticals’ BEBT-701 injection received NMPA clinical trial approval for the treatment of mild-to-moderate hypertension combined with elevated LDL-C.
Developed using the company’s proprietary GalNAc dual oligonucleotide conjugation platform, this agent targets both AGT (angiotensinogen) and PCSK9, enabling synergistic regulation of blood pressure and lipid metabolism. If successful, BEBT-701 will be the world’s first-in-class AGT/PCSK9 dual-target siRNA drug.
In the same month, Frontier Biotech entered an exclusive licensing agreement with Austria’s AFFiRiS, obtaining Greater China rights to the PCSK9 active immunotherapy AT04.
Unlike traditional passive immunotherapies such as antibodies, AT04 stimulates the body to produce its own anti-PCSK9 antibodies via vaccination, theoretically offering less frequent dosing and more controllable costs.
— Epilogue —
The release of enlicitide’s latest data has lifted expectations for oral PCSK9 inhibitors to new heights. Yet looking at China’s fast-following players, the race is far from decided.
From monoclonal antibodies and siRNAs to oral small molecules, and from single targets to multi-pathway approaches, Chinese innovative pharma companies are deploying diverse technical routes to solve the same challenges facing MNCs: how to make lipid-lowering therapy more effective, convenient, and accessible.
In an increasingly crowded market, commercialization capabilities will become a decisive factor. For example, small nucleic acid drugs, though seemingly well ahead, face competition not only from expensive innovative therapies but also from established small-molecule drugs as they expand from rare diseases to common conditions.
Especially with Novartis’ Leqvio now covered by Chinese national medical insurance and priced below 3,000 yuan per injection, it has become even more urgent for latecomers to establish pricing and accessibility advantages.
Merck expects to file enlicitide for marketing approval as early as mid-2026, with a potential launch by the end of the year if approved. Meanwhile, domestic PCSK9 siRNA drugs are advancing rapidly into Phase III trials, and oral small molecules continue to progress, with a harvest period expected in the coming years.
The gap is narrowing, but the real test has only just begun.
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