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Another CETP inhibitor failure

Highly awaited results from the Phase III study with evacetrapib which was stopped in October 2015 on the recommendation of the independent Data Monitoring Committee after preliminary data suggested the study would not meet its primary endpoint of a reduction in major cardiovascular events were presented recently at the American College of Cardiology’s 65th Annual Scientific Session. The original article you can find here.

Results clearly showed that despite significant decrease of “bad” cholesterol- LDL (i.e LDL- low density lipoprotein) and increase of “good” cholesterol- HDL (high density lipoprotein), the rate of cardiovascular events was not reduced.

It means that cardiovascular deaths, heart attacks, strokes and others occurred at the same rate in people who has lowered “bad” cholesterol as compared to placebo treated people with no cholesterol lowering

High cholesterol is thought to be a risk factor for heart and vascular failures and changing a lipoprotein profile is thought to modify this risk. Diet recommendations as well as drug treatments by statins, PCSK9 inhibitors, selective cholesterol absorption inhibitors, bile acids-binding drugs and other lipid lowering therapies are ways how to lower LDL currently in clinic. In case of statins, large population studies showed an effect on cardiovascular diseases rate. A new group of cholesterol-lowering drugs targeting the PCSK9 molecule (among them two approved and marketed monoclonal antibodies) is awaiting outcome studies on modification of cardiovascular events soon, showing clearly significant cholesterol lowering in indications where statins were not effective or tolerated.

Evacetrapib belongs to a class of CETP inhibitors. CETP is a “cholesterylester transfer protein” which transfers cholesterol from HDL to VLDL (very low density lipoprotein) and LDL. Evacetrapib as a CETP inhibitor thus increases HDL and lowers LDL. The investigational name for this drug is LY2484595 and it has been in development at Eli Lilly and Company. The drug was tested in more than 12 000 people and most probably only such high participants number tested through sufficient time period could show a meaningful outcome.

This class of drugs has faced already a 3rd failure, all small molecules. The first failure, Torcetrapib, was in development at Pfizer and was stopped in 2006 after excessive deaths in the Phase III. Roche´s Dalcetrapib development discontinued in 2012 due to a lack of efficacy.

There are two candidates in active development at Merck and Amgen. Merck´s Anacetrapib is currently in 3 Phase II studies- NCT00685776 (a long-term study since 2008, running until 2017), NCT01252953 (REVEAL, running until 2017) and NCT01524289 for heterozygous familial hypercholesterolemia patients in combination with statins (results will be available in 2018). The drug previously also showed significant effect on cholesterol levels.

Another CETP inhibitor, originally developed by Dezima and Xention as TA-8995 and which is now in portfolio of Amgen as AMG 899 showed promising results on LDL decreasing and HDL increasing in the TULIP Phase II as announced in 2015 and it was claimed that it is the most potent CETP inhibitor in means of cholesterol lowering. There is no active clinical trial with AMG 899 or TA-8995 running according to www.clinicaltrials.gov.

Of course, now, everybody is watching whether it will be possible to see an effect on cardiovascular diseases rate with these two active CETP drugs.

Let´s have a look on other cholesterol-lowering drugs, PCSK9 inhibitors. Two monoclonal antibodies were approved and marketed in 2015, other drugs are in development at Pfizer, Lilly, AFFiRiS, Alnylam and others. These drugs are of other class than CETP inhibitors, lowering LDL and increasing HDL by other mechanisms. Several “outcome” trials are running with Pfizer´s bococizumab and Amgen´s and Sanofi´s/Regeneron´s marketed mAbs to bring an evidence that these drugs in parallel to modifying a lipoprotein profile can also reduce cardiovascular diseases rate. Pfizer recently announced positive results on one Phase III study with bococizumab which met its primary endpoints and led to a significant LDL decrease. The study is expected to be a part of potential regulatory filing.

It automatically comes to one´s mind: Why significant decrease of bad cholesterol and increase of good cholesterol induced so far by CETP inhibitors was not accompanied by any effect on prevention of cardiovascular mortality and morbidity? Can this happen also with other cholesterol-lowering drugs of the same class and of other classes? What mechanisms prevented a positive impact of cholesterol lowering on cardiovascular diseases incidence? Coming years will bring answers.

Scientists now speculate that new ways of cholesterol lowering are needed. In light of CETP inhibitors failures there could be however a lower appetite of drug developers to bring another drug to development without a strong evidence of its potential to affect the cardiovascular disease rate in parallel to cholesterol lowering. It will be also interesting to watch how PCSK9 inhibitors will perform in outcome studies and whether they will translate significant cholesterol lowering  into prevention of cardiovascular deaths and diseases. There is a hope for that.