The termination of Roche’s dalcetrapib in a massive outcomes study raises more questions about not only the class of CETP inhibitors but also, once again, about the value of any therapy aimed at raising so-called “good” HDL cholesterol.

Roche announced on May 7 that it is terminating its entire dal-HEART program studying dalcetrapib, which includes two outcomes trials and four other trials. The decision came after an independent data safety and monitoring board advised discontinuing the dal-OUTCOMES study of dalcetrapib in about 15,600 patients who had had an acute coronary syndrome, not due to a safety problem, but to a lack of “clinically meaningful” efficacy Also see "Merck, Lilly Vow To Press On With CETP, Despite Dalcetrapib Disaster" - Pink Sheet, 7 May, 2012..

Whereas therapies that lower LDL cholesterol are backed by convincing evidence-based studies, the therapeutic effect of raising HDL or “good” cholesterol has much less supporting data, though epidemiological studies have strongly linked low HDL with greater cardiovascular risk.

Cholesterylester transfer protein (CETP) is an enzyme that helps redistribute cholesterol to LDL and very low density lipoprotein, in exchange for triglycerides. LDL and VLDL contain apolipoprotein B, which carries cholesterol to tissues.

HDL particles are involved in the removal of cholesterol from cells, in a process called reverse cholesterol transport; apolipoprotein-A1 (Apo-A1) is the major protein component of HDL. Aside from CETP inhibitors, other approaches in development for changing HDL include niacin receptor agonists, direct intravenous infusion of Apo-A1, oral up-regulators of endogenous Apo-A1, Apo-A1 mimetic peptides (which mimic Apo-A1 functionality), and drugs that boost reverse cholesterol transport.

One major plus of the CETP inhibition approach is that it can be achieved with oral medications, opening the door for targeting a large patient population at reasonable prices. To some, the class has represented the next frontier in dyslipidemia development following statins, which are now largely generic and which mainly tackle LDL.

CETP inhibition has been linked with elevation of HDL, as well as, for some of the candidates in the class, lowering of LDL, but important questions remain about what these changes mean in terms of cardiovascular outcomes.

Roche and some big pharmas have been keeping the faith in CETP despite the high-profile blow up in 2006 of Pfizer Inc.’s infamous first-in-class CETP inhibitor torcetrapib. The drug significantly increased HDL in the Phase III ILLUMINATE study, but instead of reducing cardiovascular events, was associated with an increase Also see "Pfizer’s Lipitor Extension Shot Down By Failure Of Torcetrapib Silver Bullet" - Pink Sheet, 11 December, 2006.. The companies pursuing development have argued that torcetrapib’s safety problems were due to identifiable off-target blood pressure effects particular to that molecule. And in one positive development for the class, the dal-OUTCOMES trial did not uncover any safety problems.

“Given the size of the dal-OUTCOMES study, it was generally expected that if the hypothesis of raising HDL cholesterol through CETP inhibition held any water, it would have been borne out to some degree,” wrote Jefferies analyst Jeffrey Holford.

A large potential patient population has created a high-risk, high-reward scenario in dyslipidemia development Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 April, 2012..

The CETP inhibitors, like other new drugs in the field, have been aimed at patients who are on lipid-lowering therapy but are still more likely to have cardiovascular events. These patients may have already had an acute coronary syndrome or have a mix of other factors that increase risk, such as diabetes and obesity. Every year, an estimated 785,000 Americans have a new coronary attack and 470,000 have a recurrent attack. Research suggests that about 20% of those who have had an event will have another one within five years.

HDL Theories Damaged

The scientific and investment communities have been ambivalent about prospects for the class and also HDL-raising therapies generally. As ISI Group analyst Mark Schoenebaum pointed out in a May 7 note, the Street has assigned a low probability of success to CETP inhibitors, which include Merck & Co. Inc.’s Phase III anacetrapib and Eli Lilly & Co.’s Phase III-ready evacetrapib. Akros Pharma and Dr. Reddy's Laboratories Ltd. also have candidates in Phase II.

The hypothesis that raising HDL is beneficial was 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, and has been used as an adjunct to other cholesterol interventions. Released in May 2011, the AIM-HIGH studyof about 3,300 patients with a history of cardiovascular disease and with well-controlled LDL 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..

But the AIM-HIGH study was very small, and had a controversial design, so some clinicians view the results as inconclusive. Sales for Niaspan were $976 million in 2011, roughly flat year-over-year.

Prior to the release of AIM-HIGH, Abbott’s Trilipix (fenofibric acid), a follow-on to TriCor (fenofibrate), which was approved for reducing triglycerides and increasing HDL in combination with statins in high-risk patients, failed to show an overall cardiovascular benefit beyond statins in the National Institutes of Health-funded ACCORD study of type 2 diabetes patients. Results were released in April 2011 Also see "Trilipix Use In Diabetics Might Be Restricted After FDA Panel Review Of ACCORD Data" - Pink Sheet, 25 April, 2011.. Abbott reported sales of $1.37 billion for its Trilipix/TriCor franchise in 2011, again pretty much flat from the previous year.

The dal-OUTCOMES study of the most advanced CETP inhibitor in development was far larger and therefore could have more far-reaching negative implications, especially for drugs in the same class. Development is coming at high cost because of the need to conduct large, long outcomes studies. Merck’s ongoing events-driven REVEAL study tests anacetrapib in 30,000 patients at higher risk of events. While according to the clinicaltrials.gov website it officially finishes in 2017, the outcome could be known any time after 2015. Data will be reviewed every three months.

Epidemiological evidence does link lower levels of endogenous HDL with greater heart disease risk, even when LDL is under control. However, through human genetics studies, it’s becoming clearer that those with a genetic cause of low HDL are not necessarily at increased risk for CV disease and, conversely, those with genetic causes of high HDL are not necessarily at reduced risk, which “argues against a simplistic HDL hypothesis,” said Daniel Rader, associate director of the Institute of Translational Medicine and Therapeutics at the University of Pennsylvania.

“Different lines of evidence have brought the HDL hypothesis under a bit of a challenge,” Rader said.

The dal-OUTCOMES study had been viewed as a pure test of the value of HDL-raising because dalcetrapib mainly acts on HDL, with little effect on other lipids.

Contrasting CETP Inhibitors

In terms of gauging implications of the dal-OUTCOMES study, reactions were mixed. Some analysts were quick to point out the large differences in the lipid effects of various CETP inhibitors. Compared to torcetrapib, anacetrapib and evacetrapib, dalcetrapib binds to a different site, so its mechanism of action is fundamentally different. And compared to others in the class, it has different effects on lipid parameters. For example, dalcetrapib increased HDL by 31% from baseline and had minimal effects on LDL (see table).

In the Phase III DEFINE study, anacetrapib added to standard of care therapy demonstrated dramatic HDL increases of 138% combined with further LDL lowering of almost 40% Also see "Merck’s Anacetrapib Debut Many Years Away, Despite Robust Phase III Data" - Pink Sheet, 22 November, 2010.. On May 7, the day the dalcetrapib news was announced, Eli Lilly affirmed that it is continuing development of evacetrapib, which has shown positive results in Phase II, suggesting a similar profile to anacetrapib, with plans to embark on a Phase III later in 2012 ([A#29111118001]).

Robert Rosenson, director of cardiometabolic disorders at the Icahn School of Medicine in New York, said in his opinion, because of the differences in the binding sites of the drugs and the effect on lipids, the dal-OUTCOMES study does not resolve the question of whether raising HDL therapeutically will improve outcomes. Furthermore, Rosenson said that based on the large size of the REVEAL study and evidence from studies of statins, anacetrapib could show a benefit for risk reduction based on the additional LDL-lowering alone. A meta-analysis of 26 randomized clinical trials from the Cholesterol Treatment Trialists Collaboration published in The Lancet in November 2010 showed that every 1 mmol/L of LDL cholesterol reduction reduced risk by about one-fifth, irrespective of the baseline level. And a 2 to 3 mmol/L reduction would reduce risk by 40% to 50%. The size of reduction was directly proportionate to the level of absolute lowering of LDL, suggesting further benefit from more intensive statin therapy.

Similarly, Edward Saltzman, president and founder of the consultancy Defined Health, commented that if dalcetrapib had demonstrated the same effects on HDL and LDL as the others in the class, the implications for other CETP inhibitors would be more clear-cut. Studies are still needed to show whether anacetrapib and evacetrapib will be effective, Saltzman said.

Surrogate Markers Under Scrutiny

Whereas the dal-OUTCOMES study put to rest questions about safety of dalcetrapib, questions about efficacy, particularly whether CETP inhibitors are merely increasing the levels of non-functional HDL, persist. There are two camps, explained Saltzman. Those who believe in surrogate markers continue to be supportive of continuing work on anacetrapib and evacetrapib, while those who do not suspect that the HDL increase may not be functional and are pessimistic.

The CETP inhibitors have been targeted broadly at the secondary prevention market, but experts note the complexities of HDL, in contrast with the apparent simplicity of manipulation of LDL, which has been proven to reduce cardiovascular risk in numerous studies. Richard Pasternak, an industry consultant and former cardiovascular medicine exec at Merck, noted that research suggests some people are more dependent than others on CETP inhibition for reverse cholesterol transport. With Roche’s expertise in diagnostics and genetics, it would be interesting to see if it is possible to identify subgroups of patients who would benefit from treatment and run a new study in a more targeted population, he said.

Roche said it is analyzing the data from dal-OUTCOMES and will present its findings at future medical meetings.

Details are not available, but Roche’s announcement to terminate the whole program suggests that there are unlikely to be any encouraging signals coming from any patient subgroups, Jefferies analyst Jeffrey Holford wrote in a May 7 note. “However it may be a little early to write off the other CETP inhibitors just yet, given that they provide significantly greater levels of HDL-raising than dalcetrapib,” the analyst concluded.

Mori Krantz, director of cardiovascular risk reduction at the University of Colorado Health Sciences Center, a CETP skeptic, commented that the therapeutic graveyard is full of agents that altered intermediate markers of cardiac risk, including, for example, thiazoledinedones for glucose lowering.

“HDL cholesterol metabolism is far more complex, so future therapies need to be targeted to HDL functionality and cholesterol efflux, not just the HDL level itself,” Krantz said.

Trial May Take Toll On Small Developers

Looking ahead, with many outcomes studies of other drugs ongoing and other therapies in earlier stages of development and in need of funding to progress, the dal-OUTCOMES study results underscore the challenges of demonstrating risk reduction in trials of drugs aimed at diseases that are already treated with a full range of evidence-based therapies as current standard of care.

“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, of Decision Resources.

“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.

There is still residual risk for cardiovascular events despite available drugs and, in theory at least, a need for HDL-raising therapies. When it comes to HDL, thought leaders have been saying for some time now that it’s not the level of HDL that matters, but the mechanism by which it is increased. Nevertheless, the studies so far have not panned out and LDL continues to be the best proxy for improved outcomes, Wong said.

At least in the short term, getting funding to do the necessary outcomes studies will be a “hard sell.”

“The many biotech companies looking into HDL-raising MOAs are definitely in a pickle,” Wong said. “The larger companies will be reluctant to invest in HDL-raising therapies after these recent failures and the smaller ones cannot afford to conduct the necessary clinical trials needed to prove that their MOAs can lower CV risk beyond [what can be] achieved with a statin.”

Resverlogix Corp. is among the companies testing alternative approaches, with its reverse cholesterol transport-enhancing small-molecule therapy RVX-208 in Phase II. The therapy is designed to stimulate endogenous ApoA-1, thereby increasing HDL and reverse cholesterol transport. This, the company argues, is the opposite from the way CETP inhibitors work, which is by reducing the degradation of HDL. The HDL raised by the Resverlogix drug is functional, whereas the HDL raised by CETP inhibitors is “old and inefficient” when it comes to removal of atherosclerotic plaque, in effect “passed its prime,” explains a white paper on the company website.

The Resverlogix candidate did, however, miss a primary efficacy endpoint in a Phase II study presented at the American Heart Association 2010 annual meeting, where the results looked especially disappointing next to the show-stopping findings for Merck’s anacetrapib in the DEFINE study Also see "Debut Of Merck's Anacetrapib Debut Many Years Away, Despite Robust Phase III Data" - Pink Sheet, 17 November, 2010.

The company concluded that the design in the failed study was not appropriate and then launched two new Phase II studies, including a safety trial and an efficacy study that will assess benefits for plaque regression.

Resverlogix CEO Don McCaffrey pointed out that its drug decreases C-reactive protein, a marker of inflammation, whereas CETP inhibitors have not demonstrated reduction in CRP. Pending good results in the Phase II trials, McCaffrey said he believes the company will be able to get funding and/or partnership for an outcomes study in 8,000 acute coronary syndrome patients.

Dalcetrapib Failure Raises Yet More Questions On Value Of Tinkering With HDL Cholesterol

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