Safety and Efficacy of Obicetrapib in Patients at High Cardiovascular Risk

Authors, Journal, Affiliations, Type, DOI

• Stephen J. Nicholls, Adam J. Nelson, Marc Ditmarsch, John J.P. Kastelein, Christie M. Ballantyne, Kausik K. Ray, Ann Marie Navar, Steven E. Nissen, et al. for the BROADWAY Investigators
• New England Journal of Medicine, 2025; 393(1):51–61
• Victorian Heart Institute, Monash University (lead); NewAmsterdam Pharma (sponsor); multinational academic steering committee
• Phase 3 multinational randomised, placebo-controlled superiority trial (BROADWAY; NCT05142722)
• DOI: 10.1056/NEJMoa2415820

Overview

BROADWAY was a multinational, randomised, placebo-controlled trial evaluating obicetrapib — a highly selective, hydrophilic CETP inhibitor — added to maximum tolerated lipid-lowering therapy in 2,530 patients with established ASCVD or heterozygous FH. The primary endpoint, LDL-C percent change at day 84, showed a −32.6 percentage-point between-group difference (P<0.001), with obicetrapib reducing LDL-C by 29.9% from a mean baseline of 98 mg/dL. The drug also lowered Lp(a) by 33.5%, ApoB by 18.9%, and non-HDL-C by 29.4%, while dramatically raising HDL-C by 136.3% — consistent with its CETP mechanism. Safety was comparable to placebo with no adverse metabolic, hepatic, or renal signals, though the trial was not powered to demonstrate CV outcome benefit; that is being evaluated in the ongoing BROOKLYN outcomes trial.

Keywords

Obicetrapib, CETP inhibitor, LDL cholesterol, lipoprotein(a), apolipoprotein B, heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease, lipid-lowering therapy, PCSK9, statin

Key Takeaways

Background and Rationale

• Despite high-intensity statin therapy, most high-risk patients fail to reach guideline LDL-C targets (<55 mg/dL); combination therapy uptake remains low
• Obicetrapib's hydrophilicity allows selective CETP tunnel binding, avoiding off-target effects (e.g., aldosterone pathway) that caused torcetrapib's failure
• Phase 2 data (TULIP, Nature Med 2022, J Clin Lipidol 2023) established ~50% LDL-C reduction when combined with high-intensity statin + ezetimibe; BROADWAY tests obicetrapib alone on top of background therapy

Methods

• Population: Adults ≥18 y with established ASCVD (89%) or heterozygous FH (17%); 38% had diabetes; on maximum tolerated statin (91%; 70% high-intensity), ± ezetimibe (27%), ± PCSK9 inhibitor (4%)
• LDL-C eligibility: ≥100 mg/dL (no risk enhancers) or 55–100 mg/dL + ≥1 additional CV risk factor
• Randomisation: 2:1 obicetrapib 10 mg OD vs placebo for 365 days; n=2,530 (1,686 obicetrapib / 844 placebo)
• Sites: 188 sites in China, Europe, Japan, and the United States (Dec 2021–Aug 2023)
• Primary endpoint: Percent change in LDL-C from baseline to day 84 (by preparative ultracentrifugation; Friedewald/Martin-Hopkins as exploratory)
• Double-blind design with sponsor participation in data collection; independent academic statistician; MedPace CRO

Primary Endpoint Results

• Obicetrapib: LDL-C −29.9% (95% CI −32.1 to −27.8)
• Placebo: LDL-C +2.7% (95% CI −0.4 to +5.8)
• Between-group difference: −32.6 percentage points (95% CI −35.8 to −29.5; P<0.001)
• Absolute LDL-C at day 84: 62.8 mg/dL (obicetrapib) vs 92.3 mg/dL (placebo)

Target Attainment at Day 84

Other Lipid Effects at Day 84

Effect Over Time (LDL-C)

• Day 30: −36.6 pp (largest reduction)
• Day 84 (primary): −32.6 pp
• Day 180: −32.7 pp
• Day 270: −30.2 pp
• Day 365: −24.0 pp (modest attenuation; partially explained by 11.5% premature discontinuation)

Safety

• Any adverse event: 59.7% (obicetrapib) vs 60.8% (placebo) — no significant difference
• Liver enzyme abnormalities: 0.6% vs 0.9%
• Muscle enzyme abnormalities: 0.3% vs 0.4%
• New-onset diabetes or worsening glycaemic control: 35.1% vs 40.0% (numerically favoured obicetrapib)
• Worsening kidney function: 6.8% vs 8.3%
• No blood pressure or aldosterone changes (24h ABPM in 229 patients: no difference)
• Exploratory CV events (death from CHD, nonfatal MI, stroke, or revascularisation): 4.2% vs 5.2% (HR 0.79; 95% CI 0.54–1.15) — not powered

Limitations of the Document

• 365-day lipid endpoint only: No CV outcomes data; trial not powered or designed for hard endpoints
• Attenuating LDL-C effect at Day 365: Reduction fell from −36.6 pp (Day 30) to −24.0 pp (Day 365), partly due to 11.5% premature discontinuation; true pharmacological durability is uncertain
• Industry sponsorship: NewAmsterdam Pharma funded and participated in design and data collection; potential influence despite academic committee oversight
• Limited demographic diversity: Predominantly European/Asian populations; 34% women; limited Black/Hispanic representation — may not reflect real-world high-risk populations
• Low PCSK9 inhibitor use (4%): Current practice increasingly combines statins + ezetimibe + PCSK9i; incremental benefit of adding obicetrapib on top of triple therapy not well characterised
• No patient with hoFH: Enrolled only HeFH and ASCVD; hoFH patients may respond differently
• Lp(a)-specific enrolled population: Patients were not selected for elevated Lp(a); Lp(a) subgroup effect on those with high baseline Lp(a) not reported

Key Concepts Mentioned

• concepts/CETP-Inhibitors — mechanism class; history of failed predecessors; obicetrapib as next-generation hydrophilic agent
• concepts/Dyslipidemia-Management — BROADWAY adds obicetrapib as an emerging oral nonstatin LDL-C–lowering agent
• concepts/Familial-Hypercholesterolemia — 17% of BROADWAY population; obicetrapib as oral add-on option in HeFH
• concepts/Lipoprotein-a — obicetrapib lowers Lp(a) by 33.5%, unlike statins which may raise it

Key Entities Mentioned

• entities/Acute-Coronary-Syndrome — ASCVD population context for secondary prevention
• NewAmsterdam Pharma — sponsor

Wiki Pages Updated

• Created wiki/sources/obicetrapib-broadway-nejm-2025.md
• Created wiki/concepts/CETP-Inhibitors.md
• Updated wiki/concepts/Dyslipidemia-Management.md — added obicetrapib to nonstatin agents table and emerging oral agents section
• Updated wiki/concepts/Familial-Hypercholesterolemia.md — added obicetrapib as emerging HeFH oral add-on
• Updated wiki/concepts/Lipoprotein-a.md — added CETP inhibitor Lp(a) lowering data
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md