Efficacy, Safety, Tolerability, and Pharmacokinetic Profile of Evacetrapib Administered as Monotherapy or in Combination With Atorvastatin in Japanese Patients With Dyslipidemia

Teramoto T, Takeuchi M, Morisaki Y et al.
Am J Cardiol. 2014 Apr 2. pii: S0002-9149(14)00888-1. doi: 10.1016/j.amjcard.2014.03.045

Background

Pharmacological inhibition of cholesteryl ester transfer protein (CETP) leads to a substantial increase in HDL-c and decrease in LDL-c. The CETP-inhibitor torcetrapib led, however, to an increased risk of cardiovascular (CV) morbidity and mortality, and dalcetrapib did not differ from placebo with regard to reduction of CV events was seen. Torcetrapib was also associated with a significant increase in blood pressure (BP) and plasma sodium, bicarbonate and aldosterone levels, as well as a decrease in potassium levels [1].
Persistent effects on lipids and residual plasma levels of anacetrapib were observed 12 weeks after cessation of treatment in the DEFINE trial [2]. Evacetrapib also inhibits CETP activity in human plasma and transgenic mice with human CETP, without increases in aldosterone or BP [3].
Evacetrapib was well tolerated when administered for 14 days to healthy Japanese subjects in a phase 1 study, in doses ranging from 30 to 600 mg. Evacetrapib raised HDL-c and lowered LDL-c [4]. In a 12-week phase 2 study, evacetrapib raised HDL-c with up to 129% and lowered LDL-c with up to 36% in patients with dyslipidemia, while being well tolerated [5]. This randomized, double-blind study evaluated efficacy, safety, tolerability and pharmacokinetic profile of evacerapib monotherapy at doses up to 500 mg and evacetrapib 100 mg in combination with 10 mg atorvastatin against placebo in Japanese patients with hypercholesterolaemia or low HDL-c.

Main results

• Statistically significant dose-related increases in HDL-c and decreases in LDL-c were seen with evacetrapib treatment for 12 weeks. Relative changes in HDL-c between evacetrapib and placebo were 74%, 115% and 136% for 30 mg, 100 mg and 500 mg respectively. Relative decreases in LDL-c were 15%, 23% and 22% respectively.
• Combination therapy of evacetrapib and atorvastatin in comparison to atorvastatin alone gave similar changes in HDL-c and LDL-c to monotherapy with evacetrapib 100 mg.
• No significant changes were seen in fasting triglycerides with evacetrapib monotherapy or combination therapy as compared to the respective control therapies.
• CETP activity was lowered with evacetrapib monotherapy with 50% with 30 mg, up to 95% with 500 mg, as compared to placebo. Addition of evacetrapib 100 mg to atorvastatin lowered CETP activity with 68%.
  CETP mass had decreased after 12 weeks in the atorvastatin group (9%), but it increased in a dose-dependent manner (82-139% on average) on evacetrapib monotherapy.
• At the follow-up visit about 4 weeks after treatment cessation, HDL-c and LDL-c levels, and CETP activity and mass had returned to baseline in all active treatment groups, and most patients had evacetrapib concentrations below detection levels.
• No significant difference was seen in the incidence of treatment-emergent adverse events across treatment groups. No clinically relevant change in either systolic or diastolic blood pressure was seen during the study period in any of the treatment groups. Evacetrapib did not give any adverse effect on mineralocorticoid or glucocorticoid measures.

Conclusion

This study confirmed that evacetrapib is effective at increasing HDL-c and decreasing LDL-c in Japanese patients with either high LDL-c or low HDL-c. Dose-dependent effects on HDL-c and LDL-c were observed with evacetrapib as monotherapy and addition of evacetrapib to atorvastatin improved the response to atorvastatin, suggesting an additive and pharmacologically independent effect of evacetrapib. The low number of adverse effects seen with evacetrapib, and the lack of adverse effects on the mineralocorticoid or electrolyte measures supports the hypothesis that previously observed adverse effects with other CETP inhibitors are not related to the CETP mechanism.

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References

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