Both Merck & Co. Inc. and Eli Lilly & Co. vow to continue work on their CETP inhibitors for cholesterol, despite the latest blow to the class – Roche’s decision to stop all studies of its competing compound dalcetrapib, due to lack of efficacy.

Of the three, Roche’s drug was furthest along in development. The company plans to terminate all studies in the dal-HEART program, including two outcomes trials and four other studies. The decision, announced on May 7, came after an independent safety monitoring board advised the Swiss pharma company to stop one of the outcomes studies of 15,6000 patients, called dal-OUTCOMES, due to lack of “clinically meaningful” efficacy.

No safety signals were reported, an important differentiation after the high-profile blow up in 2006 of Pfizer Inc.’s Phase III study of its first-in-class CETP inhibitor torcetrapib Also see "Pfizer’s Lipitor Extension Shot Down By Failure Of Torcetrapib Silver Bullet" - Pink Sheet, 11 December, 2006.. That drug increased cardiovascular events despite raising HDL in the ILLUMINATE trial, results that killed off the compound and led Pfizer, which at the time was the biggest player in the dyslipidemia market, to back out of further development of the class. But it did not deter some other Big Pharmas from pressing on with their development programs, claiming the safety problems were off-target effects particular to the molecule and not a class effect.

Cholesterylester transfer protein (CETP) is a plasma protein involved in the transport of cholesteryl esters and triglycerides between lipoproteins. To some, the class has represented the next frontier in dyslipidemia development following statins, which are now largely generic and which mainly tackle LDL Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 April, 2012.. In clinical trials, lower levels of “good” cholesterol or HDL have been associated with greater heart disease risk, even when LDL, or bad cholesterol, is under control. CETP inhibitors have demonstrated the ability to change the ratio of HDL to LDL cholesterol, boosting HDL, “good cholesterol,” and for some of the candidates, also substantially lowering LDL. But what’s been unclear is whether altering these levels with drugs improves outcomes.

Analysts speculate that Eli Lilly may pull the plug on Phase III ready evacetrapib, but the company vows that it is committed to development.

It’s hard to over-estimate the impact of the dalcetrapib failure. Reflecting its high hopes for the drug, its first entrant into major cardiovascular disease, Roche was in the midst of an ambitious program, which Bernstein analyst Tim Anderson estimated the company was on track to ultimately spend $1 billion.

Meanwhile, Merck says it remains committed to its own CETP inhibitor anacetrapib, which in the Phase III DEFINE study demonstrated dramatic HDL increases combined with impressive LDL-lowering, and is currently being tested in an even larger outcomes study called REVEAL with 30,000 patients Also see "Merck’s Anacetrapib Debut Many Years Away, Despite Robust Phase III Data" - Pink Sheet, 22 November, 2010.. Merck said it expects the events-driven REVEAL trial will conclude in 2015, though the completion date is listed as January 2017 on the clinicaltrials.gov website.

“Lowering cardiovascular risk beyond that which is achieved with intensive statin treatment is a very challenging goal,” says Roche, announcing the failure of dalcetrapib.

Eli Lilly said in a statement that it is continuing development of evacetrapib, which has shown positive results in Phase II, suggesting a similar profile to anacetrapib; Lilly says it plans to embark on a Phase III later in 2012 ([A#29111118001]). Akros Pharma and Dr. Reddy's Laboratories Ltd. also have candidates in Phase II.

Following the failure of torcetrapib, a few companies had continued to place heavy bets on the CETP inhibitors to further reduce risk for patients who have already had a coronary event, the so-called secondary prevention market.

However, entrants from the start faced high hurdles because their compounds would have to be compared to statins. The evidence base behind statins is very strong, including outcomes studies documenting up to a 50% reduction in mortality benefit. New drugs in development, therefore, by and large are tested on top of statins and other available therapies, and those targeting all but the smallest populations need to prove their value in large expensive outcomes studies, like dal-OUTCOMES and REVEAL.

“Lowering cardiovascular risk beyond that which is achieved with intensive statin treatment is a very challenging goal,” Roche said in a statement announcing the termination of the program.

The hypothesis that raising HDL improves outcomes had already been arguably damaged by the negative outcome of the AIM-HIGH outcomes study of Abbott Laboratories Inc.’s Niaspan (long-acting niacin) on top of simvastatin or simvastatin and ezetimibe (Merck & Co. Inc.’s Zetia). Niacin boosts HDL, albeit more modestly than CETP inhibitors.

The AIM-HIGH studyof about 3,300 patients with a history of cardiovascular disease and with well-controlled low-density lipoprotein (LDL) was sponsored by the National Heart, Lung and Blood Institute. In November 2011, it was terminated 18 months early in light of a small unexplained increase in strokes and no evidence of a benefit for cardiovascular risk reduction Also see "More Disheartening News For Abbott Cholesterol Franchise: Niaspan/Statin Study Halted Due To Lack Of Added Benefit" - Pink Sheet, 26 May, 2011..

However that trial was small and many experts claimed it was highly flawed. The same cannot be said for dal-OUTCOMES.

“The statin effect has been an issue for drug developers for some time and this latest development for dalcetrapib demonstrates how difficult it is to show even a marginal improvement over the current standards of care,” commented Donny Wong, therapeutic area director for metabolic disorders at Decision Resources.

Will Lilly Rethink Evacetrapib?

The companies in the space and some Wall Street analysts point to important differences between the candidates in development. They work differently on HDL, for example, an important distinction because HDL particles are very heterogenous in terms of size, shape, density and function.

The differences in the effects on various lipids are noteworthy, pointed out Credit Suisse analyst Catherine Arnold in a May 7 note, including much more dramatic elevation in HDL of from 80% to 140% for anacetrapib and evacetrapib, versus 30% for dalcetrapib. Furthermore, she noted, anacetrapib has demonstrated reduction in LDL of from 40% to 52%, compared to almost no effect for dalcetrapib.

Subtle differences between how Roche’s drug affects HDL may be more important than believed, but the outcome of the trial still casts a “cautious light on the class as a whole,” Arnold concluded.

Bernstein’s Anderson questioned whether LDL-lowering alone could “carry anacetrapib over the finish line.”

But in terms of LDL-lowering, any new dyslipidemia drug would likely face stiff competition from statins, including atorvastatin and AstraZeneca PLC’s Crestor (rosuvastatin), which is set to go generic in 2016.

Another study run by Merck could soon help shed light on how adding medications to statin therapy affects outcomes Also see "Merck Looks Beyond First-In-Class Only As It Seeks To Bolster R&D Productivity" - Pink Sheet, 1 December, 2011.. The HPS2-THRIVE outcomes study tests Tredaptive (long-acting niacin and laropiprant). With 25,000 patients, HPS2-THRIVE is much bigger than AIM-HIGH and there was pre-randomization of LDL. The study is powered at 95% to detect a 15% reduction in events and will wrap up in late 2012.

“Merck is committed to the development of medicines to advance the treatment of cardiovascular disease and Merck remains confident in our ongoing development programs for both TREDAPTIVE and anacetrapib,” the company said in a statement.

As for Lilly’s evacetrapib, analysts speculate that the company might reconsider its plans to progress to Phase III. The molecule will probably only move into Phase III if it can forge a risk and profit sharing agreement with another large pharma for this opportunity, surmised Deutsche Bank analyst Barbara Ryan in a May 7 note.

In a May 7 statement reiterating commitment to proceed to Phase III, Eli Lilly noted the differences in LDL-lowering and HDL increases between its evacetrapib and Roche’s dalcetrapib.

“There is a growing body of knowledge that raising good cholesterol as well as lowering bad cholesterol may play a beneficial role in treating cardiovascular disease, which remains the leading cause of death globally. Lilly is committed to identifying potential new medicines, such as evacetrapib, to address significant medical needs,” Lilly said in a statement.

Merck, Lilly Vow To Press On With CETP, Despite Dalcetrapib Disaster

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