The value potential of PCSK9 drugs continues to rise.

Recently, at the annual meeting of the American College of Cardiology, Merck unveiled latest Phase III clinical data for enlicitide, convincing the industry that a generational shift is underway.

This marks enlicitide’s third successful Phase III study. Previously, it achieved a 58.2% LDL‑C reduction in patients with heterozygous familial hypercholesterolemia (HeFH) and a 57.1% reduction in a broader high‑risk cardiovascular population.

With three mutually validating studies, enlicitide’s status as a blockbuster is all but confirmed. Analysts at RBC Capital Markets predict that, if approved, enlicitide could reach $5 billion in sales by 2034.

The story of enlicitide begins with a scientific breakthrough.

Decades ago, Drs. Michael Brown and Joseph Goldstein at UT 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 at the same institution—Helen Hobbs and Jonathan Cohen—identified a unique population with natural mutations in the PCSK9 gene. Lower PCSK9 protein levels kept LDL‑C persistently low and significantly reduced heart disease risk.

Thus, the PCSK9 target moved into the spotlight of lipid‑lowering drug development.

In 2015, Regeneron and Amgen launched the PCSK9 monoclonal antibodies Praluent and Repatha, injectable agents achieving over 60% LDL‑C reduction. Yet their commercial performance fell far short of expectations.

High pricing, inconvenient injection, and reimbursement barriers prevented these scientifically successful products from becoming commercial blockbusters. Repatha did not surpass $1 billion in sales until seven years after approval.

Merck’s enlicitide aims to solve PCSK9’s commercial dilemma via an oral formulation.

Over the past year, three Phase III results have been released, and Merck is poised to advance toward regulatory approval.

First study: CORALreef HeFH

In 303 HeFH patients on statins, once‑daily oral enlicitide achieved 58.2% LDL‑C reduction at 24 weeks, vs. a 2.6% increase in the placebo arm. At 52 weeks, the reduction remained stable at 55.3%.

Second study: CORALreef Lipids

Among 2,909 patients with established cardiovascular disease or high risk, enlicitide reduced LDL‑C by 57.1% at 24 weeks, a 55.8% difference vs. placebo. At 52 weeks, the reduction held at 52.4%, with mean LDL‑C falling to 45.7 mg/dL (~1.18 mmol/L)—potent and durable.

Critically, enlicitide also significantly lowered non‑HDL‑C and apolipoprotein B, key cardiovascular risk markers.

Behind these “three straight wins” is Merck’s distinctive technological approach.

Enlicitide is a macrocyclic peptide identified and optimized via mRNA display. This platform offers unique advantages against historically “undruggable” targets relying on protein–protein interactions and intrinsically disordered proteins.

Merck’s breakthrough has electrified the entire industry.

Cardiovascular disease is the world’s leading cause of death, and the lipid‑lowering market continues expanding. According to MENET, in the first three quarters of 2025, sales of lipid regulators across China’s three major terminal markets exceeded ¥20 billion, up 15.7% year‑over‑year.

Novartis has reaped major rewards. In November 2019, it acquired The Medicine Company for $9.7 billion to gain the PCSK9 siRNA therapy inclisiran (Leqvio), approved by the FDA two years later.

Leqvio uses RNA interference to suppress PCSK9 synthesis at the genetic level. Its greatest advantage is dosing convenience: an initial injection, a second at three months, then only twice yearly. In 2025, Leqvio achieved global sales of $1.198 billion, up 57%—becoming the first blockbuster siRNA drug for a chronic disease.

Pioneers Regeneron and Amgen continue pursuing differentiation, seeking to expand PCSK9 mAbs from statin adjunctive therapy to broader primary prevention.

Yet Novartis shows no sign of yielding. In July 2025, the FDA approved a label update allowing Leqvio to be used as first‑line monotherapy with diet and exercise, no longer requiring mandatory statin combination—further extending its lead.

Active dealmaking reflects MNCs’ battle for the sector.

In June 2025, Eli Lilly acquired gene‑editing firm Verve Therapeutics for $1.35 billion. Early data showed Verve’s one‑time PCSK9 gene‑editing therapy sustained ~60% LDL‑C reduction two years after dosing.

Prior to acquiring Verve, Lilly paid Beam Therapeutics $200 million upfront plus $50 million equity for an option to jointly develop base‑editing cardiovascular programs.

Dr. Steve Nissen of the Cleveland Clinic commented: “Gene therapy changes everything.” For young patients with familial hypercholesterolemia, a single DNA edit could eliminate lifelong medication—a transformative vision for lipid care.

Oral formats remain highly attractive.

Beyond Merck, AstraZeneca has also bet heavily on oral PCSK9 inhibitors. Phase IIb data in 2025 showed AZD0780 reduced LDL‑C by 50.7% in patients with inadequate statin response. Analysts forecast peak annual sales could exceed $5 billion with positive late‑stage data.

In the monoclonal antibody sector, domestic PCSK9 inhibitors have already broken through.

Innovent’s *tirzepatide (correction: tolcisipan),** Akeso’s inucizumab, Junshi’s ongericimab, and Hengrui’s recasicimab have been approved, breaking the MNC monopoly in China.

Although mAbs still require injection every 2–4 weeks, competitive pricing and national medical insurance coverage are improving accessibility.

CSPC Pharmaceutical’s SYH2053 is the first domestic PCSK9 siRNA to enter Phase III. A GalNAc‑conjugated siRNA targeting adult primary hypercholesterolemia or mixed dyslipidemia, patient recruitment has recently launched.

If successful, SYH2053 could become the first approved domestic PCSK9 siRNA, competing head‑to‑head with Novartis’ Leqvio.

In oral small‑molecule PCSK9 inhibitors, domestic players are also present.

Early R&D is far more challenging than for mAbs or siRNA, which follow standardized development. Small molecules require extensive screening and rational design to achieve strong binding, safety, and stability.

Cviae Pharmaceuticals has taken a critical step.

Its CVI‑LM001—the first domestic oral PCSK9 small molecule to enter the clinic—achieved a 26.3% LDL‑C reduction from baseline after 28 days of 300 mg daily dosing in Phase I.

Some companies are pursuing even more promising dual targets and novel mechanisms.

In February 2026, Betta Pharmaceuticals’ BEBT‑701 received NMPA IND approval for mild‑to‑moderate hypertension with elevated LDL‑C.

Built on Betta’s proprietary GalNAc dual oligonucleotide conjugation platform, it simultaneously targets AGT (angiotensinogen) and PCSK9, enabling synergistic blood pressure and lipid control. If successful, BEBT‑701 would be the world’s first AGT/PCSK9 dual‑target siRNA.

In the same month, Frontier Biotech entered an exclusive license agreement with Austria’s AFFiRiS for AT04, a PCSK9 active immunotherapy, in Greater China.

Unlike conventional passive antibody therapies, AT04 acts as a vaccine that induces the body to produce its own anti‑PCSK9 antibodies, potentially enabling less frequent dosing and more manageable costs.

Merck has lifted expectations for oral PCSK9 inhibitors to new heights with enlicitide’s latest data.

Yet among China’s fast followers, the race is far from decided.

From mAbs, siRNA, to oral small molecules; from single targets to multi‑pathway inhibition, Chinese innovative pharma companies are using diverse technical routes to answer the same question haunting MNCs:

How to make lipid‑lowering therapy more effective, convenient, and accessible?

In an increasingly crowded market, commercialization capability will be decisive.

Even leading siRNA drugs, moving from rare diseases to common indications, compete not only with expensive innovative therapies but also with mature small molecules.

Merck expects to file enlicitide for approval as early as mid‑2026, with potential launch by year‑end.

Domestic PCSK9 siRNAs are advancing into Phase III, and oral small molecules continue progressing, with a harvest period expected in the coming years.