Drug development is a perilous and unpredictable business. Just ask Pfizer CEO Jeffrey B. Kindler: In 2006, he announced that the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib “will be one of the most important compounds of our generation.” Mere days later, all development of the drug was abruptly halted when an interim analysis of the ILLUMINATE trial suggested that it conferred a 25% increase in cardiovascular deaths and a 60% increase in all-cause mortality compared to placebo. The $800 million development effort in tocetrapib was finished, and Pfizer’s market value fell by $21 billion overnight.
When the bell tolled for torcetrapib, did a death knell sound for all CETP inhibitors? Based on their recent work, Dr Christopher Cannon, of Brigham and Women’s Hospital in Boston, and his TIMI Study Group colleagues think not. Simultaneously published in NEJM and presented at the American Heart Association Scientific Sessions, they report on the DEFINE trial, a double-blind, placebo controlled, Phase 2 safety study of Merck’s CETP inhibitor anacetrapib. Patients enrolled in the study had to have coronary heart disease (CHD) or CHD equivalent, and had to be on treatment with a statin to current guideline recommendations. 1623 such patients were randomized to anacetrapib 100mg or placebo for 18 months.
On the primary efficacy endpoint at 24 weeks, there was a 40% decrease from baseline in low-density lipoprotein-cholesterol (LDL-C). The mean serum LDL-C was an impressive 45mg/dL (1.16mM) in the active treatment group. High-density lipoprotein-cholesterol (HDL-C) was strikingly increased by 138% to a mean of 101mg/dL (2.61mM).
What about safety endpoints? There were no differences in the proportion of patients with “adverse experiences” and no changes in mean blood pressure, serum electrolytes, or serum aldosterone levels compared to baseline. There was no difference in the pre-specified adjudicated cardiovascular endpoint (cardiovascular death, myocardial infarction, unstable angina, or stroke) between the anacetrapib and placebo-treated groups at 18 months (2.0% v 2.6%, p=0.40). The pre-specified Bayesian analysis of the events estimated a 94% predictive probability of excluding a torcetrapib-like 25% increase in cardiovascular events.
So what’s next for anacetrapib? “With reasonable confidence, DEFINE excludes a very large increase in cardiovascular events with anacetrapib,” says cardiologist and NEJM executive editor Dr. Gregory Curfman, “As such, it gives a cautious green light to larger and longer trials. Critical questions about anacetrapib remain unanswered: Will the dramatic changes in LDL-C and HDL-C result in improvements in clinical outcome? What are the long-term consequences of lowering LDL-C to such extremely low levels? Will anacetrapib continue to appear safe in larger, longer trials?”
Investigators are already moving ahead with the “larger and longer” trials, which are expected to take several years to complete. Stay tuned: Although things are certainly looking brighter for CETP inhibitors than they did after ILLUMINATE, the world of drug development is the perilous and unpredictable. Who knows what might happen?
 Barter PJ et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007 Nov 22;357(21):2109-22.
 Cutler D.M. The Demise of the Blockbuster? N Engl J Med 2007; 356:1292 – 1293