Sunday, May 6, 2012

Dalcetrapib (CETP inhibitor) fails in Phase 3 study

The DSMB has recommended discontinuation of Phase 3 study (DAL-OUTCOME) on Dalcetrapib (CETP inhibitor) due to lack of clinical efficacy, when compared to intensive statin treatment. This failure of DAL-OUTCOME study when viewed in conjunction with the AIM-HIGH trial, poses questions on the benefit of HDL control over intensive LDL control.   Dalcetrapib was developed by Japan Tobaco and  was outlicensed to Roche. Torii Pharma, a subsidiary of Japan Tobaco was expected to sell Dalcetrapib in Japan.  There are two other CETP inhibitor in late stage development Anacetrapib (MRK) and Evacetrapib (LLY).  Although the profile of Anacetrapib and Evacetrapib is very much different from Dalcetrapib, but two successive failures (Torcetrapib and Dalcetrapib) certainly poses a question on the mechanism. The observed data on Anacetrapib has also not been very encouraging so far, as there was an imbalance in mortality events in the two arms.
Trial design of anacetrapib Phase III trial- REVEAL study is different from DAL-OUTCOME in terms of targeted patient populations.  Patients with recent ACS was an inclusion criteria in DAL-OUTCOME, while in the REVEAL trial, the same is an exclusion criteria, hence in terms of read out from Dalcetrapib failure, we do not see any implications for Anacetrapib.

Although Anacetrapib, is much more potent  and impacts both LDL and HDL unlike Dalcetrapib, but it may be still difficult to say, whether a more potent clinical profile would really translate into clinical benefit.  In the DEFINE trial, Anacetrapib did reduce CV events (MI/Stroke/UA/Revascularization) but was also associated with numerically higher incidence of CV death (0.5% versus 0.1%) and all cause death (1.4% vs. 1%) at 76 weeks, which makes us cautious. 

Predicting the outcome is always difficult, but a138% rise in HDL is very unnatural and makes us suspicious.

The profile of evacetrapib is very similar to Anacetrapib. 

Tredaptive (modified Niacin), is also being explored in an outcome study (HPS-2 THRIVE), and the results are expected in 1H 2013. HPS-2 THRIVE being the largest and adequately powered study, and DSMB has already given a go-ahead to the trial and the fact that Niacin is a proven drug with LDL lowering benefits in addition to HDL raising benefits, the odds  favor of a successful outcome for Tredaptive.  HPS-2 THRIVE aims at less intensive LDL control as DAL-OUTCOME.