Pooled on treatment lipid lowering efficacy of the CETP inhibitor obicetrapib in phase III trials

Background and Aim Obicetrapib is a potent, selective CETP inhibitor in development for patients with HeFH or ASCVD. Prior phase III studies have consistently shown that obicetrapib, alone or with ezetimibe, lowers LDL-C, non-HDL-C and ApoB while markedly raising HDL-C. To understand the magnitude of these effects in patients who remained pharmacologically exposed throughout the trials, we performed a pooled on-treatment analysis. This approach minimizes adherence-related variability and isolates true drug-mediated changes in LDL-C, non-HDL-C and ApoB across the three Phase III programs. Objective This analysis quantified the on-treatment lipid-lowering effectiveness of obicetrapib and the obicetrapib–ezetimibe fixed-dose combination by evaluating a pooled PK-confirmed on-treatment population across three phase III trials conducted on top of maximum-tolerated lipid-lowering therapy in patients with ASCVD or HeFH. Methods Baseline characteristics and Day 84 responses from 3,088 patients in BROOKLYN, BROADWAY, and TANDEM were pooled, limited to those with PK-confirmed on-treatment status and complete Day 1 and Day 84 labs. Lipids were directly measured except LDL-C, which used the Martin–Hopkins equation. Outcomes are reported as least-squares mean percent change versus placebo, aligned with each trial’s primary endpoint methods. LDL-C goal attainment was assessed at <70 mg/dL and <55 mg/dL per the 2022 ACC Expert Consensus Pathway Results 83% of ITT patients (N=2,551) were included in the pooled on-treatment dataset. Baseline LDL-C (102.2 mg/dL), HDL-C (49.6 mg/dL), non-HDL-C (126.6 mg/dL), and TG (139.4 mg/dL) in the obicetrapib arm were similar to placebo (p>0.05). Monotherapy produced a -36.4% LDL-C reduction versus placebo, with 67% and 48.5% achieving LDL-C <70 mg/dL and <55 mg/dL (placebo: 21.6% and 6.7%) [FIGURE 1]. HDL-C increased by +141%. Non-HDL-C, ApoB, and TG were reduced by -31.9%, -21.2%, and -10.3%. With obicetrapib + ezetimibe, on-treatment ApoB decreased by -32.6% and non-HDL-C by -51.1%. LDL-C decreased by -55.8%, with 79.8% and 72.7% achieving <70 mg/dL and <55 mg/dL (placebo: 20.4% and 7.1%) [FIGURE 2]. Conclusions Both obicetrapib and the obicetrapib–ezetimibe fixed-dose combination on-treatment populations showed substantial LDL-C reduction, with 3 out of 4 patients reaching a LDL-C goal of <55 mg/dL and 4 out of 5 patients achieving a LDL-C goal of <70 mg/dL with the obicetrapib + ezetimibe fixed dose combination.