Final phase 3 study of bempedoic acid met safety and tolerability endpoints
The Cholesterol Lowering via BEmpedoic Acid, an ACL-inhibiting Regimen (CLEAR) Wisdom Phase 3 clinical trial of bempedoic acid (Study 2 or 1002-047) demonstrated safety and tolerability of bempedoic acid compared to placebo in patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) during 52 weeks. These results complete the global phase 3 LDL-c lowering development program of bempedoic acid.
Bempedoic acid is a first-in-class, complementary, orally available, once-daily ATP Citrate Lyase (ACL) inhibitor that reduces cholesterol biosynthesis and lowers LDL-c by up-regulating the LDL receptor. The study included high CV risk patients taking maximally tolerated statins who required additional LDL-c lowering. The 52-week, global pivotal CLEAR Wisdom Phase 3 randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of bempedoic acid 180 mg/day versus placebo. The study was conducted at 93 sites in North America and Europe. A total of 779 patients were randomized 2:1 to receive bempedoic acid or placebo. The primary efficacy objective was to assess the 12-week LDL-c lowering efficacy of bempedoic acid versus placebo. Secondary objectives included evaluating the safety and tolerability of bempedoic acid versus placebo, the 24-week and 52-week LDL-c lowering efficacy of bempedoic acid versus placebo, and its effects on other risk markers after 12 weeks of treatment, including high-sensitivity C-reactive protein (hsCRP).
The study achieved its efficacy endpoints and other key measures at 12 weeks, including:
- On-treatment LDL-c lowering of an additional 18% (vs. placebo, p<0.001), and in the intent to treat analysis, LDL-c lowering of an additional 17% (p<0.001)
- Reduction of 19% in hsCRP
- Reduction in HbA1c of 0.21% vs. placebo in patients with diabetes
At 52 weeks, adjudicated major adverse cardiovascular events (MACE) in the bempedoic acid arm as compared to placebo were:
- 3-component MACE: 2.7% for bempedoic acid compared to 4.7% for placebo
- 4-component MACE: 5.7% for bempedoic acid compared to 7.8% for placebo
- 5-component MACE: 6.1% for bempedoic acid compared to 8.2% for placebo
In this study, bempedoic acid was observed to be safe and well-tolerated. The results showed no clinically relevant differences between the bempedoic acid and placebo treatment groups in the occurrence of:
- Adverse events (AEs) with 70% and 71%, respectively;
- Serious adverse events (SAEs) with 20% and 19%, respectively;
- Discontinuations due to AEs with 11% and 9%, respectively;
- Fatal adverse events with 1.1% and 0.8%, respectively. No fatal adverse events were determined to be related to study medication. CV deaths were balanced between the study arms (0.8% vs. 0.8%). The bempedoic acid arm included a case of gas poisoning and a case of sepsis as a complication of planned abdominal surgery. No fatal AEs due to neoplasms.
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