Evaluation of Obicetrapib on Major Adverse Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients on Maximal Lipid-Modifying Therapy

The primary objective of this study is to evaluate the effect of **obicetrapib** on the risk of major adverse cardiovascular events (MACE) in participants with atherosclerotic cardiovascular disease (ASCVD) who are not adequately controlled despite maximally tolerated lipid-modifying therapies. This includes assessing the incidence of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, or non-elective coronary revascularization. The clinical relevance of this objective lies in its potential to provide evidence for the efficacy of obicetrapib in reducing the risk of significant cardiovascular events in a population with high unmet medical needs.

Secondary objectives include: - Evaluating the incidence of cardiovascular death, non-fatal MI, or non-fatal stroke. - Assessing all-cause mortality, non-fatal MI, non-fatal stroke, or non-elective coronary revascularization. - Determining the total number of cardiovascular events. - Investigating any individual component of the primary composite endpoint. - Measuring all-cause mortality.

The clinical trial involves a total of **4972 participants** who are being evaluated for the effect of obicetrapib on the risk of major adverse cardiovascular events (MACE) in individuals with **atherosclerotic heart and blood vessel disease**. The study population includes both male and female subjects aged 18 years and older. Participants have a history of atherosclerotic cardiovascular disease (ASCVD) and are on maximally tolerated lipid-modifying therapy, which may include statins, ezetimibe, bempedoic acid, or PCSK9-targeted therapy, alongside a lipid-lowering diet and other lifestyle modifications. The trial population was selected based on specific inclusion criteria, such as having a fasting serum LDL-C level within defined ranges and an estimated glomerular filtration rate of at least 30 mL/min/1.73 m². The study also considers relevant lifestyle factors, including adherence to a lipid-lowering diet and other lifestyle modifications. Both male and female participants are included, and the trial does not exclude vulnerable populations.

The clinical trial is designed to evaluate the effect of **obicetrapib**, a selective Cholesteryl Ester Transfer Protein (CETP) inhibitor, on the risk of major adverse cardiovascular events (MACE) in participants with atherosclerotic cardiovascular disease (ASCVD) who are not adequately controlled despite maximally tolerated lipid-modifying therapies. This is a randomized, double-blind, placebo-controlled Phase 3 study. Participants will be randomly assigned to receive either 10 mg of obicetrapib or a matching placebo, administered orally in capsule form. The trial is expected to last until December 31, 2025, with an estimated recruitment start date of February 1, 2022.

The study will include several key visits: an initial screening visit, follow-up visits, and an end-of-study (EOS) visit. During the **screening** visit, eligibility will be assessed based on criteria such as age, history of ASCVD, and current lipid-modifying therapy. Participants must have a fasting serum LDL-C level within specified ranges and meet other protocol-defined criteria. Follow-up visits will occur at regular intervals to monitor the participants' health, adherence to the study medication, and any adverse events. The primary endpoint is the time from randomization to the first confirmed occurrence of any component of the composite endpoint, including cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, or non-elective coronary revascularization. Secondary endpoints include various composite measures of cardiovascular outcomes and total event analysis.

Participant involvement is expected to last up to 48 months, depending on the timing of recruitment and randomization. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial aims to provide valuable insights into the efficacy of obicetrapib in reducing cardiovascular risk in a high-risk population.

The clinical trial involves the administration of **Obicetrapib**, a small molecule and selective **Cholesteryl Ester Transfer Protein (CETP) inhibitor**. Obicetrapib is provided in the form of a capsule, with a maximum daily dose of 10 mg. The route of administration is oral. The treatment period for participants is up to 48 weeks. Obicetrapib is chemically synthesized and is not formulated for pediatric use. The pharmaceutical product is manufactured by NewAmsterdam Pharma B.V. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen.

The study also includes a placebo control, which is designed to match the appearance of the active Obicetrapib tablets. The placebo is a 6 mm diameter, white, film-coated, round, biconvex tablet with no identifying markings. It contains the same qualitative excipient blend as the active tablets, with microcrystalline cellulose replacing the Obicetrapib drug substance. The placebo is administered orally, following the same dosing schedule as the active treatment, to maintain the double-blind nature of the trial. Participant compliance with the placebo regimen is similarly monitored to ensure the integrity of the study results.

The efficacy of **Obicetrapib** in the clinical trial will be assessed by evaluating its impact on the risk of major adverse cardiovascular events (MACE) in participants with atherosclerotic cardiovascular disease (ASCVD) who are not adequately controlled despite maximally tolerated lipid-modifying therapies. The primary endpoint for efficacy evaluation is the time from randomization to the first confirmed occurrence of any component of the composite endpoint, which includes cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal stroke, or non-elective coronary revascularization.

Secondary endpoints include the time from randomization until the first confirmed occurrence of a composite of CV death, non-fatal MI, or non-fatal stroke; the time from randomization until the first confirmed occurrence of a composite of all-cause mortality, non-fatal MI, non-fatal stroke, or non-elective coronary revascularization; a total event analysis defined as the number of CV death events and first and subsequent/recurrent events of non-fatal MIs, non-fatal strokes, and non-elective coronary revascularization from randomization until the end of study (EOS) visit; the time from randomization until the first confirmed occurrence of non-fatal MI; and the time from randomization until the first confirmed occurrence of non-elective coronary revascularization.