Merck & Co recently decided not to apply for regulatory approval of anacetrapib, one of the last-standing drugs from the doomed cholesteryl ester transfer protein (CETP) class of cholesterol-lowering therapies.

CETP transfers cholesterol from high-density lipoprotein C (HDL-C) particles, more widely known as ‘good cholesterol’, to the atherogenic low and very low-density lipoprotein (LDL and VLDL) particles, sometimes referred to as ‘bad cholesterol’. The rationale for inhibiting CETP is that it would result in increased levels of good versus bad cholesterol.

Despite the promising mechanism of action, the CETP class has long been associated with high-profile failures in clinical studies due to safety and efficacy issues.

CETP inhibitors: a reputation for failure

Key opinion leaders (KOLs) interviewed by GlobalData have been voicing their concerns for quite some time about the efficacy of this whole drug class and expressed doubt about the benefit of targeting HDL-C.

Pfizer’s torcetrapib was the main contributor to the negative attitude towards CETP inhibitors. A Phase III study of torcetrapib was stopped early due to an increase in cardiovascular events and all-cause mortality in the treatment group. Roche’s dalcetrapib and Eli Lilly’s evacetrapib have also been discontinued due to the lack of efficacy as there was no reduction in cardiovascular events.

Even if it had been approved, Merck’s anacetrapib would have struggled to penetrate the well-established cholesterol-lowering market, as it would have had to compete for patient share in a space that is almost entirely dominated by the generic statins. In addition, with the recent launches of two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, Amgen’s Repatha and Sanofi’s Praluent, which have demonstrated superior efficacy and are well-tolerated, anacetrapib would have faced fierce competition from all angles.

Therefore, given the overall bad reputation of CETP inhibitors and the hard-to-penetrate cholesterol-lowering space, Merck’s decision to withdraw from this race was a smart move and unsurprising to many.