Anacetrapib, a new CETP inhibitor, raises high-density lipoprotein (HDL) cholesterol without affecting blood pressure

HDL Forum Editor Professor Philip Barter discusses new data on anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor published by Rajesh Krishna and co-workers in The Lancet, December 2007.

Krishna R, Anderson MS, Bergman AJ et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 2007;370:1907-14.

Anacetrapib (MK-0859), is an oral selective CETP inhibitor which is currently in clinical development. These two studies are the first full published reports of Phase I studies with anacetrapib.

The first study evaluated the pharmacokinetics and pharmacodynamics of anacetrapib in 50 patients with dyslipidaemia, with levels of low-density lipoprotein (LDL) cholesterol ranging from 100 to 190 mg/dL. The patients completed a 2-4 week washout screening period (4 weeks for statins or other lipid-modifying treatment or 2 weeks if treatment-naïve) and a 2-week diet run-in period before randomisation to anacetrapib 10, 40, 150 or 300 mg administered once-daily for 4 weeks, or placebo. Blood samples were taken at selected time points for measurement of plasma concentrations of anacetrapib. In addition, serum lipids and lipoproteins, including HDL cholesterol, LDL cholesterol and apolipoproteins (apo) A-I, B and E were measured at baseline, before and after dosing (see slide 1).

Study 1: Pharmacokinetics and pharmacodynamics of anacetrapib

  • Randomised, double-blind, placebo-controlled study
  • 50 patients with dyslipidaemia, LDL cholesterol 100-190 mg/dL
  • Treated with anacetrapib 10, 40, 150 or 300 mg daily for 4 weeks
  • Plasma drug concentrations were measured at selected time points
  • Total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, apolipoproteins A-I, B and E measured at baseline, pre- and post-dose

Anacetrapib was well absorbed with peak plasma drug concentrations achieved at about 4 hours. There was evidence of dose-related increases in anacetrapib exposure between 10 mg and 300 mg doses. The effective half-life was about 18 hours and steady state was achieved after about 7 days of dosing.

The doses of anacetrapib had been selected to achieve increases in HDL cholesterol of about 20-30% at the 10 mg dose and about 90% at the 300 mg dose. However, at the 10 mg dose, there was a 41% increase in HDL cholesterol and a 24% increase in apoA-I. At the 300 mg dose, HDL cholesterol was increased by 129%, apoA-I was increased by 47% and LDL cholesterol decreased by 38% (see slide 2).

There were no meaningful changes in total cholesterol or triglycerides compared with placebo.

The second study was designed to investigate the effects of anacetrapib on 24-hour ambulatory blood pressure. Clinical trials with torcetrapib, another CETP inhibitor, had shown significant increases in blood pressure associated with treatment. The ILLUMINATE trial was terminated in December 2006 due to evidence of a statistically significant excess of deaths in patients treated with torcetrapib compared with placebo. Among patients taking torcetrapib, there was a significant mean increase in blood pressure which was associated with a reduction in serum potassium and an increase in serum sodium, bicarbonate and aldosterone. These data raised the possibility that torcetrapib might have activated the renin-angiotensin-aldosterone system (RAAS), and that this may have contributed to the observed clinical harm. Therefore, the aim of this second study was to investigate whether anacetrapib had similar blood pressure raising effects.

This study used a crossover design, in which 22 healthy subjects were initially randomised to 150 mg anacetrapib or placebo once daily for 10 days, and then after a washout period, crossed over to receive the alternative study treatment in a further 10-day period. 24-hour ambulatory blood pressure was monitored before and at the end of each 10-day study period (see slide 3).

24-hour profiles for systolic and diastolic blood pressure showed that anacetrapib had no significant effect on 24-hour blood pressure compared with placebo. The researchers concluded that, despite the small sample size, the apparent lack of increase in blood pressure with anacetrapib, consistent with preclinical investigations in monkeys, showed that anacetrapib did not share the blood-pressure raising effects of other CETP inhibitors.

In an accompanying editorial in The Lancet, Dr Patrick Duriez (INSERM, Lille, France) commented on these results.

Duriez P. CETP inhibition. The Lancet 2007;370:1882-3.

He noted that the short-term safety of anacetrapib (which needs to be confirmed in the longer-term) opens new perspectives in the study of the effect of CETP inhibition on atherogenesis and cardiovascular risk. These data may resuscitate the hope that CETP inhibitors could be an important new class of drugs that normalise lipidaemia. However, he highlighted the need for data on aldosterone production and the expression of genes coding for mineralocorticoid biosynthesis in the adrenal glands to confirm that anacetrapib truly lacks the same off-target effects as torcetrapib (see slide 4).

Conclusions

  • Anacetrapib has potent effects in raising HDL cholesterol and apoA-I and lowering LDL cholesterol, more so than other CETP inhibitors
  • Anacetrapib does not appear to affect blood pressure
  • Larger scale studies are needed to evaluate the clinical efficacy and safety of anacetrapib, and whether these lipid changes translate to a clinically meaningful effect on cardiovascular risk.

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