The Failure of Torcetrapib -- The Search for the Reason Why

Linda Brookes, MSc


February 14, 2008

In This Article

Progress in Cholesteryl Ester Transfer Protein Inhibition

As Dr. Rader and others observed, it is still possible that a CETP inhibitor without the off-target effects of torcetrapib could be viable as a therapy for cardiovascular disease. The effects of torcetrapib are molecule-specific and are not related to the mechanism of CETP inhibition; other CETP inhibitors, including anacetrapib, do not raise blood pressure in CETP-expressing species, including humans, according to a number of reports.

First clinical data on anacetrapib were revealed in September 2007 at the European Society of Cardiology Congress[14,15] and phase IIb study results with anacetrapib were presented in October at the XVI International Symposium on Drugs Affecting Lipid Metabolism (DALM),[16] both showing that anacetrapib significantly reduced LDL-C and increased HDL-C as monotherapy and in combination with atorvastatin 20 mg compared to placebo in patients with dyslipidemia (primary hypercholesterolemia or mixed hyperlipidemia). In the double-blind, randomized, placebo-controlled trial reported at DALM, 10 regimens were evaluated in 589 patients over 8 weeks. Anacetrapib monotherapy at doses of 10 mg, 40 mg, 150 mg, and 300 mg reduced LDL-C levels by 16%, 27%, 40%, and 39%, and increased HDL-C levels by 44%, 86%, 139%, and 133%, respectively, compared with placebo (2% and 4%, respectively) in a dose-dependent manner. Anacetrapib coadministered with atorvastatin, across all doses studied, also produced significant incremental reductions in LDL-C and increases in HDL-C compared with atorvastatin alone. The comparative lipid results in the study were statistically significant (P <.001 vs placebo for all doses).

Reductions in apo B and Lp(a) (lipoprotein a) and increases in apo A-1 and apo E were seen that were consistent with the respective LDL-C and HDL-C changes in the study. Anacetrapib was not associated with a mean increase in blood pressure in any treatment arm. The incidence rates of individual adverse events were similar across the placebo, atorvastatin, and active treatment groups (≤5.5%). There were sparse and non-dose-related incidences of clinically important elevations in ALT, AST, and CPK. There were no treatment-related serious adverse events or deaths. Treatment-related discontinuations were ≤5% and no patients discontinued due to serious treatment-related adverse events.

The first clinical trial data with anacetrapib from 2 phase I trials investigating lipoproteins changes in patients with dyslipidemia and on 24-hour ambulatory blood pressure in healthy individuals was recently published in The Lancet.[17] In an invited commentary accompanying publication of these data,[18] Patrick Duriez, PhD (INSERM U545, Lille and University of Law and Health, Lille, France) suggested that "an important proof of absence of toxic effects with anacetrapib on blood pressure regulation would involve having data on aldosterone production and the expression of genes coding for mineralocorticoid biosynthesis in the adrenal glands." He noted that although the decrease in LDL-C and the large increase in HDL-C induced by anacetrapib would in theory decrease cardiovascular risk, "there is no proof that decreasing the activity of CETP reduces cardiovascular risk, although there are several potential mechanisms by which HDLs protect against the development of vascular disease." The short-term safety of anacetrapib needs to be confirmed in the longer term, said Dr. Duriez, "but the data opens new perspectives in the study of the effect of CETP inhibition on atherogenesis and cardiovascular risk, and may resuscitate the hope that CETP inhibitors could be an important new class of drugs that normalize lipidemia."

Merck has said that before starting an outcomes study with anacetrapib, a sequenced phase III program will be carried out to obtain additional clinical experience with the drug.[19] The company intends to evaluate the effects of anacetrapib on blood pressure, electrolytes, and aldosterone with longer patient exposures. A cardiovascular outcomes study could begin as early as 2009, the company said.

Another CETP inhibitor in development, R1658 (Hoffmann-LaRoche), may enter phase III clinical trials in 2008 following encouraging data from phase II studies and positive discussions with the health authorities.[20] R1658 has a different chemical structure from either torcetrapib or anacetrapib, and in preclinical and clinical studies has reportedly not shown any blood pressure effect.[21,22,23] In phase II, treatment with 900 mg for 4 weeks led to a 37% decrease in CETP activity (P <.0001 vs placebo), a 34% increase in HDL-C (P <.0001), and a 7% decrease in LDL-C (P = .017). Levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. Increases were seen in HDL2, HDL3, and apo A-1 and were noted to be in line with the increase in HDL-C. There were no blood pressure changes and no other toxicities associated with the drug, but minor gastrointestinal side effects were reported (P = .06).

Roche licensed R1658 from Japan Tobacco in 2004; Roche has worldwide rights except Japan, where in the compound is in Phase I trials as JTT-705.