Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial

Literature - Ballantyne CM, Ditmarsch M, Kastelein JJP, et al. - J Clin Lipidol. 2023 May 31;S1933-2874(23)00186-1 [Online ahead of print]. doi: 10.1016/j.jacl.2023.05.098

Introduction and methods

Background

Among high-risk patients with ASCVD, use of high-intensity statin therapy is suboptimal and only few receive combination lipid-lowering therapy, resulting in frequent failure to achieve guideline-mandated LDL-c treatment goals [1-3]. Increasing evidence suggests that additional lipid-lowering agents, in combination with intensive statin therapy, are required to achieve low LDL-c levels [4,5].

Early studies have shown that obicetrapib, an oral, selective cholesteryl ester transfer protein (CETP ) inhibitor, reduced LDL-c levels by up to 50% and was well tolerated when administered to patients with dyslipidemia as monotherapy in combination with moderate- or high-intensity statins [6,7].

Aim of the study

The study aim was to evaluate the lipid-altering efficacy and safety of combination therapy with obicetrapib and ezetimibe in patients with suboptimally controlled LDL-c levels despite high-intensity statin therapy.

Methods

The ROSE2 trial (Study to Evaluate the Effect of Obicetrapib in Combination with Ezetimibe as an Adjunct to High Intensity Statin Therapy) was a multicenter, placebo-controlled, double-blind, phase 2 RCT conducted in the US. Patients with LDL-c >70 mg/dL and triglycerides (TG) <400 mg/dL on stable high-intensity statin therapy (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) were randomized to the combination of obicetrapib 10 mg plus ezetimibe 10 mg (n=40), obicetrapib 10 mg only (n=39), or placebo (n=40) for 12 weeks. Exclusion criteria were, among others, clinically manifest ASCVD.

Outcomes

The primary endpoint was the percent change (from baseline to week 12) in Friedewald-calculated LDL-c level for the obicetrapib plus ezetimibe combination treatment group compared with placebo. Secondary efficacy endpoints included percent changes (from baseline to week 12) in LDL-c level for obicetrapib monotherapy versus placebo and in apoB for obicetrapib plus ezetimibe combination versus placebo and obicetrapib monotherapy versus placebo groups.

Exploratory efficacy endpoints included percent changes (from baseline to week 12) in other lipids, lipoprotein particles, PCSK9, and the proportion of participants that achieved LDL-c<100, <70, and <55 mg/dL at the end of treatment for obicetrapib combination therapy and monotherapy groups compared with placebo.

Safety and tolerability were also assessed.

Main results

Efficacy

• The on-treatment analysis (n=97) showed that combination therapy with obicetrapib and ezetimibe reduced the median Friedewald-calculated DL-c level from baseline to week 12 (primary endpoint) by 63.4% compared with 6.35% for placebo (P<0.0001).
• In the obicetrapib monotherapy group, median Friedewald-calculated LDL-c level was decreased by 43.5% after 12 weeks (secondary efficacy endpoint; difference with placebo: P<0.0001).
• As for the other secondary efficacy endpoint, median apoB level was reduced by 2.05% in the placebo group, 24.2% in the obicetrapib monotherapy group (difference with placebo: P<0.0001), and 34.4% in the obicetrapib combination therapy group (difference with placebo: P<0.0001).
• In the obicetrapib combination therapy group, LDL-c levels of<100, <70, and <55 mg/dL were achieved by 100%, 93.5%, and 87.1% of the patients, respectively, compared with 66.7%, 16.7%, and 0.0%, respectively, in the placebo group (all P<0.05).
• From baseline to 12 weeks, both obicetrapib combination therapy and monotherapy also altered median levels of non-HDL-c, HDL-c, total and small LDL particles, and large HDL particles (all P<0.0001).
• Compared with placebo, there were no significant differences in percent changes in VLDL-c , TG, medium HDL particle, or PCSK9 level for either the obicetrapib combination therapy group or monotherapy group.

Safety

• Treatment-emergent adverse events were reported by 35 of the 119 patients (29.4%) in the safety population: 16 patients (40.0%) in the placebo group, 8 (20.5%) in the obicetrapib monotherapy group, and 11 (27.5%) in the obicetrapib combination therapy group.
• The most frequently reported adverse events were nausea, urinary tract infection, and headache, and most events were classified as mild or moderate in severity.
• In total, 5 patients discontinued the study due to adverse events: 2 (5.0%) in the placebo group, 2 (5.1%) in the obicetrapib monotherapy group, and 1 (2.5%) in the obicetrapib combination therapy group.

Conclusion

References

Find this article online at J Clin Lipidol.