CETP Inhibitor Obicetrapib Moves Forward in EMA Review, With Dual Cardiovascular and Neurology Impact

Michael Davidson, MD

The European Medicines Agency (EMA) has validated NewAmsterdam Pharma’s marketing authorization application (MAA) for investigational obicetrapib and its fixed-dose combination with ezetimibe as potential treatments for patients with hypercholesterolemia, including both heterozygous familial (HeFH) and non-familial or mixed dyslipidemia. Obicetrapib, an oral CETP inhibitor, continues to advance as a candidate for both cardiovascular and neurodegenerative indications.¹

The MAAs, submitted by NewAmsterdam’s partner, A. Menarini International Licensing S.A. “Menarini,” was based on data from 3 pivotal phase 3 trials: BROOKLYN (NCT05425745), TANDEM (NCT06005597), and BROADWAY (NCT05142722). Across these studies, investigators reported low-density lipoprotein cholesterol (LDL-C) lowering of 35% to 40% with obicetrapib vs placebo as a monotherapy and LDL-C lowering of 50% vs placebo when used in combination with ezetimibe.

Over the coming months, the EMA will continue to review the data to determine whether obicetrapib is deserving of approval. Regarding the accepted application, Michael Davidson, MD, chief executive officer at NewAmsterdam, said in a statement.¹ "This marks a significant step forward in our mission to deliver a novel, first in class therapeutic option to add to statin therapy to further reduce LDL-C for millions of patients not reaching their LDL-C goals."

BROADWAY, the most large-scale of the three studies, comprised 2530 adults with established atherosclerotic cardiovascular disease (ASCVD) and/or HeFH, whose LDL-C was not adequately controlled despite being on maximally tolerated lipid-lowering therapy. The trial ultimately met its primary end point, as the obicetrapib 10 mg group had a least-square (LS) mean LDL-C reduction of 33% (P <.0001) compared with placebo at day 84.

Reported earlier this year, a prespecified biomarker analysis from a substudy (n = 1727) of BROADWAY showed that obicetrapib has an ability to lower phosphorylated tau (p-tau) 217, a notable biomarker associated in Alzheimer disease (AD) pathology. The data, released in June and further presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31 in Toronto, Canada, further supported the therapeutic potential of the agent to treat both cardiovascular and neurodegenerative disorders.^2,3

The substudy comprised 1727 patients with ASCVD and/or HeFH, including a subgroup who were apolipoprotein e3/4 or 4/4 carriers (n = 367). In the latest data presented at AAIC 2025, obicetrapib-treated patients had a 1.1% increase in median plasma p-tau217 whereas those on placebo climbed at more rapid rates of 4.8% (P = .01). In addition, investigators observed lowering of p-tau217/Aß42:Aß40 ratio (obicetrapib: 2.7%; placebo: 6.5%; P = .006).

Despite the fact that baseline p-tau217 levels were higher in APOE e4 carriers compared with noncarriers (0.47 pg/mL vs 0.39 pg/mL; P <.0001), the treated group still continued to show greater benefit than placebo. All told, obicetrapib led to stabilization of p-tau217 levels (0% increase vs. 5.7%; P = .03) and limiting increases in the p-tau217/Aβ42:Aβ40 ratio (2.1% vs. 10.2%; P = .005).

Additional data from the original BROADWAY study showed benefits from obicetrapib on secondary end points such as ApoB, Lp(a), ApoA1, HDL-C, non-HDL-C, total cholesterol, and triglycerides at day 84, as well as LDL-C levels at days 180 and 365. After 1 year of treatment, investigators recorded a 21% reduction in the composite of coronary heart disease death, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization.⁴

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TANDEM, a trial of 407 patients with established ASCVD or multiple risk factors for ASCVD and/or HeFH, whose LDL-C is not adequately tolerated, tested obicetrapib as part of a FDC tablet with ezetimibe, a non-statin oral LDL-lowering therapy. All told, the FDC achieved a nearly 49% greater reduction in LDL-C vs placebo, and was also superior to ezetimibe (–27.9%) and obicetrapib monotherapy (–16.8%).⁵

The final trial, BROOKLYN, tested obicetrapib as a monotherapy in 354 patients with HeFH. Similar to the other studies, it met its primary end point, with treated patients showing a LS mean LDL-C reduction of 36% (P <.0001) compared with placebo at day 84. Notably, 51% of treated patients achieved LDL-C levels <70 mg/dL, a key guideline-recommended threshold for high-risk populations. The therapy was well tolerated, with fewer discontinuations (7.6% vs 14.4% with placebo) and no observed increases in blood pressure, liver enzymes, or renal dysfunction.

"Cardiovascular disease is the leading cause of death globally, taking an estimated 17.9 million lives each year. Despite the widespread availability of lipid lowering therapies, CVD-related deaths have risen, and patients remain above LDL-C targets, failing to achieve guidelines recommended LDL-C target goals. Patients and their doctors need additional options," Elcin Barker Ergun, chief executive officer at Menarini, said in a statement.¹

He added, "Obicetrapib, if approved, could provide an effective and safe oral option for patients with hypercholesterolemia. We look forward to working with the EMA to potentially bring this new treatment to patients in need."

REFERENCES
1. NewAmsterdam Announces Acceptance of Marketing Authorization Applications for Review by European Medicine Agency for Obicetrapib. News release. NewAmsterdam Pharma. August 18, 2025. Accessed August 19, 2025. https://www.globenewswire.com/news-release/2025/08/18/3134956/0/en/NewAmsterdam-Announces-Acceptance-of-Marketing-Authorization-Applications-for-Review-by-European-Medicine-Agency-for-Obicetrapib.html
2. NewAmsterdam Pharma Announces Positive Topline Alzheimer’s Disease Data from BROADWAY Clinical Trial. News Release. NewAmsterdam Pharma. Published June 9, 2025. Accessed August 19, 2025. https://ir.newamsterdampharma.com/news-releases/news-release-details/newamsterdam-pharma-announces-positive-topline-alzheimers
3. Davidson M, Szarek M, Nicholls S, et al. Effects of Obicetrapib, a Potent Oral CETP Inhibitor, on Alzheimer's Disease Biomarkers in 1727 Patients with cardiovascular disease. Presented at: 2025 Alzheimer’s Association International Conference; July 27-31; Toronto, Canada. Abstract 108443.
4. Nicholls SJ, Nelson AJ, Ditmarsch M, et al. Safety and Efficacy of Obicetrapib in Patients at High Cardiovascular Risk. NEJM. 2025;393:51-61. doi:10.1056/NEJMoa2415820
5. Sarraju A, Brennan D, Hayden K, et al. Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2025;405:10491:1757-1768. doi:10.1016/S0140-6736(25)00721-4
6. NewAmsterdam Pharma Announces Positive Topline Data from Pivotal Phase 3 BROOKLYN Clinical Trial Evaluating Obicetrapib in Patients with Heterozygous Familial Hypercholesterolemia. News release. NewAmsterdam Pharma. July 29, 2025. Accessed August 19, 2025. https://ir.newamsterdampharma.com/news-releases/news-release-details/newamsterdam-pharma-announces-positive-topline-data-pivotal