Clinical Development of Obicetrapib (TA-8995)
Overview
Obicetrapib is a novel, selective cholesteryl ester transfer protein (CETP) inhibitor that potently decreases low-density lipoprotein-cholesterol (LDL-C) as well as increases high-density lipoprotein-cholesterol (HDL-C) and the number of ApoA1-containing lipoproteins.
In July 2021, we reported positive results from a Phase 2 study of oral obicetrapib demonstrating more than 50% LDL-lowering as an adjunct to high-intensity statins showing an oral dose of obicetrapib could potentially address the substantial unmet need for patients whose LDL-C levels and cardiovascular risk remain too high despite being treated. Additionally, clinical data from the study showed the genetic mechanism of CETP as an LDL-lowering mechanism, supporting NewAmsterdam’s strategy for developing obicetrapib in metabolic diseases and other major diseases of high unmet need. As of July 2022, NewAmsterdam has initiated all three of its planned Phase 3 trials: BROADWAY, BROOKLYN, and PREVAIL.
Randomized Study of Obicetrapib as an Adjunct to Statin Therapy (ROSE)
ROSE (NCT04753606) was designed as a placebo-controlled, double-blind, randomized, Phase 2 dose-finding study to evaluate the efficacy, safety, and tolerability of obicetrapib as an adjunct to high-intensity statin therapy. A total of 120 patients were randomized to placebo, 5-mg obicetrapib, or 10-mg obicetrapib for an 8-week treatment period. The primary end point was met for both doses. In the 10-mg dose group, obicetrapib lowered median LDL by 51% (primary endpoint least squares mean LDL-C decreased 44%, P < .0001; Shapiro-Wilk Normality Test, P = .0001, median LDL-C decreased by 51%). Following the treatment period, patients continued for a 4-week safety follow up and a 15-week PK follow up. Overall, obicetrapib was well tolerated compared to placebo.
Top-line results of the ROSE study show the effects of CETP inhibition on LDL-C reduction and HDL-C increase attributed to orally administered obicetrapib. Results included reduction of median LDL-C levels by greater than 50% (primary endpoint LS mean LDL-C decreased 44%, P < .0001; Shapiro-Wilk Normality Test, P = .0001, median LDL-C decreased by 51%). Notably, median baseline LDL-C for participants in the study was 52 mg/dL at day 56 of the study, compared with median LDL-C 94 mg/dL at baseline.
Randomized Study to Evaluate the Effect of Obicetrapib in Addition to Maximum Tolerated Lipid-Modifying Therapies (BROADWAY)
BROADWAY (NCT05142722) is a placebo-controlled, double-blind, randomized study to evaluate the effect of obicetrapib in addition to maximally tolerated lipid-lowering therapy in patients with established atherosclerotic cardiovascular disease who require additional lowering of low‑density lipoprotein cholesterol (LDL-C). A total of 2,400 patients will be randomized to placebo or 10 mg obicetrapib dosed as a once-daily oral treatment for a 52-week treatment period. The primary objective of the BROADWAY trial is to evaluate the effect of obicetrapib on LDL-C levels after 12 weeks of treatment. Secondary endpoints include the evaluation of obicetrapib on lipoprotein(a), apolipoprotein B, non-HDL-C, HDL-C, total cholesterol, triglycerides, MACE (major adverse cardiovascular effects such as cardiovascular death, myocardial infarction, stroke, or non-elective coronary revascularization), and safety. Initial data is expected to be reported in 2024.
Evaluate the Effect of Obicetrapib in Patients With Hypercholesterolemia in Addition to Maximum Tolerated Lipid-Modifying Therapies (BROOKLYN)
BROOKLYN (NCT05425745) is a placebo-controlled, double-blind, randomized, Phase 3 trial to evaluate the effect of obicetrapib on LDL-C levels in patients with heterozygous familial hypercholesterolemia (HeFH) as an adjunct to maximally tolerated lipid-lowering therapy. Approximately 300 patients on maximally tolerated lipid-modifying therapies with a history of HeFH, an inherited genetic disorder that causes high cholesterol levels, and who have a baseline LDL-C of at least 70 mg/dL will be randomized to placebo or 10 mg of obicetrapib dosed as a once-daily oral treatment for a 52-week treatment period. Additional measures will be recorded throughout the study to evaluate the effect of obicetrapib on fasting lipoprotein(a), apolipoprotein B, non-HDL-C, HDL-C and safety. Initial data is expected to be reported in 2024.
Cardiovascular Outcome Study to Evaluate the Effect of Obicetrapib in Patients With Cardiovascular Disease (PREVAIL)
PREVAIL (NCT05202509) is a placebo-controlled, double-blind, randomized study in patients with a history of atherosclerotic cardiovascular disease who do not have adequate control of their LDL-C despite being on maximally tolerated lipid-modifying therapies. The primary objective of the PREVAIL trial is to evaluate the effect of obicetrapib on the risk of major adverse cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or non-elective coronary revascularization. Secondary endpoints include the evaluation of obicetrapib to lower LDL-C and prevent new cases of type 2 diabetes and long-term safety. A total of 9,000 patients will be randomized to placebo or 10 mg of obicetrapib dosed as a once-daily oral treatment. Initial data is expected to be reported in 2026.