Merck & Co. Inc. took cardiovascular disease (CVD) experts – and, perhaps, some of its own decision-makers – by surprise last month when it disclosed that the REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid modification) outcomes study of its cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, met its primary endpoint by reducing major coronary events (defined as the composite of coronary death, myocardial infarction and coronary revascularization) compared to placebo in patients at risk for cardiac events who were already receiving a regimen to lower low-density lipoprotein, or LDL.

Details about the findings remain under wraps, and analysts have questions about the drug's safety. Merck said only that the safety profile of anacetrapib in the early phase III analysis was generally consistent with that demonstrated in previous studies of the drug, including accumulation of anacetrapib in adipose tissue, as previously reported.

A Merck spokeswoman told BioWorld Insight that the company had nothing to add before detailed results of REVEAL are presented at the European Society of Cardiology meeting on Aug. 29. And Merck hasn't tipped its hand on a filing strategy, acknowledging that it is reviewing trial results with external experts before determining whether to file new drug applications with the FDA and other regulatory agencies.

Still, the efficacy win, no matter how small, led many who had written off CETP inhibitors to rethink whether the drug class could, indeed, offer additive value to statins for patients who don't need quite the heavy lifting of a PCSK9 inhibitor.

Most assets in the class fell short in the clinic

In a similarity to PCSK9s, CETP inhibitors were envisioned as add-on therapies for patients unable to achieve cholesterol reduction goals on statin therapy alone and to treat individuals who didn't respond to statins. CETP facilitates the transfer of cholesteryl ester from high-density lipoprotein cholesterol (HDL-C) to low and very low-density lipoprotein, and of triglycerides in the reverse direction. Inhibition of that process results in higher HDL, or "good" cholesterol levels while reducing LDL, or "bad" cholesterol levels.

But as indicated in the chart below, based on data from Cortellis Competitive Intelligence, Merck, of Kenilworth, N.J., became the first to see phase III success in a CETP inhibitor following a long list of failures in the field. Dalcor Pharmaceuticals Inc., a 2015 startup based in San Mateo, Calif., is close behind with dalcetrapib, an asset abandoned both by Japan Tobacco Inc. and Roche AG during late-stage development after it failed to show efficacy in the treatment of dyslipidemia in patients with coronary heart disease.

Dalcor has taken a precision medicine approach to advance dalcetrapib, and its randomized, double-blind, placebo-controlled 5,000-patient phase III Dal-GenE trial, which is six months ahead of schedule and on budget, is expected to be fully enrolled by the end of the first quarter of 2018, according to Robert McNeil, the Sanderling Ventures founder who co-founded the company and serves as its CEO. The event-driven primary outcome measure is time to a composite of major cardiovascular adverse events (MACE) that include death, myocardial infarction and stroke. Dal-GenE also includes a half-dozen secondary endpoints, all driven by the occurrence of 434 adjudicated events. (See BioWorld Today, March 8, 2017.)

Three assets in the CETP class have advanced to phase II, but their future prospects aren't clear. Amgen Inc., following its 2015 acquisition of Dezima Pharma BV, was developing the oral CETP inhibitor obicetrapib (AMG-899, DEZ-001, TA-8995), under license from Mitsubishi Tanabe, to treat dyslipidemia. But in an SEC filing earlier this year, Amgen reported that development of the drug was being delayed pending the outcome of trials for competing drugs in the class. Tellingly, Dezima had been seeking to out-license the drug prior to the Amgen deal. (See BioWorld Today, Sept. 17, 2015.)

In 2014, Dr. Reddy's Laboratories Ltd., of Hyderabad, India, completed a phase II study testing DRL-17822, its CETP inhibitor, in 176 individuals with abnormal cholesterol levels, but the asset stalled at that stage. And Chong Kun Dang Pharmaceutical Corp., of South Korea, just this year moved CKD-519, administered with HMG-CoA reductase inhibitors, into a small phase II to treat lipid metabolism disorders after testing the drug in a handful of phase I experiments.

As indicated by the list of candidates that have been discontinued or suspended, most assets in the class fell short, including CETi-1, which Celldex Therapeutics Inc. gained in its acquisition of Avant Immunotherapeutics Inc.; Bayer AG's BAY-60-5521 and BAY-38-1315; Pfizer Inc.'s torcetrapib, which had safety issues that also torpedoed back-up compound CP-800569; and DS-1442, which was dropped by Daiichi Sankyo Co. Ltd. during a pipeline reprioritization.

The field was holding out hope for Eli Lilly and Co.'s evacetrapib (formerly LY-2484595) until its phase III flop in 2015 seemed to doom the class. Indianapolis-based Lilly abruptly halted the ACCELERATE study in high-risk atherosclerotic CVD for lack of efficacy following an interim look by the independent data monitoring committee. The move to scrap evacetrapib, then one of just seven Lilly assets in phase III studies, sent the company's shares (NYSE:LLY) tumbling as much as 10 percent at the time. (See BioWorld Today, Oct. 13, 2015.)

ACCELERATE had fully enrolled 12,095 patients across 540 sites in 37 countries, with patients receiving once-daily evacetrapib 130 mg or placebo along with standard-of-care treatment for high-risk vascular disease. The primary outcome measure was time to first occurrence of any component of the composite events of CVD death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. Secondary endpoints included mean percentage change from baseline to three months in LDL-C and HDL-C levels as well as time to first occurrence of the composite endpoint of a mixture of measures that included all-cause mortality, MI, stroke, coronary revascularization or hospitalization for unstable angina.

Six months earlier, Lilly had reported that the study academic executive committee recommended extending the trial by approximately six months, based on emerging science in the CVD field. That recommendation was not based on study data since the academic committee and company remained blinded at the time to efficacy results, so analysts surmised that the interim analysis was conducted without incident, which proved not to be the case.

Lilly subsequently drew down the phase III ACCENTUATE study of evacetrapib in patients with high cholesterol and two phase III studies of the compound in Japan, with and without atorvastatin, in patients with primary hypercholesterolemia.

'Likely that Merck got a signal' from subset of patients

Given the dismal track record of CETP inhibitors, analysts were astonished when anacetrapib hit its efficacy endpoints.

"Following failures by other in this class, expectations had been low for anacetrapib to work, so we believe this should be viewed positively," Credit Suisse analyst Vamil Divan wrote last month about Merck's REVEAL. That said, the drug's downside still could outweigh its benefits, he said, recalling Merck's previous disclosure that low concentrations of anacetrapib were detectable in plasma in some patients up to four years following their last treatment dose.

"We have previously discussed this issue with several cardiologists with mixed feedback," Divan continued. "Some feel that as long as the overall outcomes study is positive (especially a study as large as the 30,000-patient REVEAL study) that is sufficient for them to be comfortable using the drug broadly in their patients. Others have expressed caution on the potential long-term safety issues of this accumulation and, given multiple other oral and injectable therapies being available for treating hyperlipidemia, feel it would take a long time for them to incorporate anacetrapib into their practice in any meaningful way. These discussions were obviously before we had the actual results from REVEAL so it will be interesting to see how perspectives evolve once the full data are presented publicly."

Leerink Partners LLC's Seamus Fernandez was of the same mind, describing the primary endpoint hit as a "surprise" but citing caution on the opportunity for the drug.

In addition to concern about the accumulation of anacetrapib in adipose tissue that has dogged the drug's development, "the primary endpoint in REVEAL included urgent revascularizations but not stroke, a somewhat unusual approach to the typical MACE endpoint," Fernandez pointed out. Too, "the 30,000-patient trial, while providing a definitive test of the CETP hypothesis using anacetrapib, also has the potential to deliver a statistically positive outcome with a small effect size. We estimate this could be a relative risk reduction well below 10 percent, which we would argue is not clinically significant unless the benefit was driven almost entirely by CV death."

For his part, Dalcor's McNeil wasn't the least surprised at the outcome of REVEAL, which, he contended, validates his company's thesis.

"It is highly likely that Merck got a signal from a portion of their patients," McNeil said, "but that activity is not so robust that it can overcome the toxicity associated with the fact that the drug does reside in the tissue for a very long period of time."

Merck – which accepted all comers, on a genetic basis, into REVEAL – has said that high-sensitivity C-reactive protein, or HSCRP, was a factor in the anacetrapib findings, according to McNeil, who ascribed the drug's downside to the known effect of CETP inhibitors on a certain portion of the genetic population. Dalcor's drug, dalcetrapib, behaves the same way, he said, but in individuals with a different genotype, HSCRP is reduced, producing a marked clinical benefit.

'This is not just lipid metabolism'

Dalcor's very existence is based on that premise. In 2013, Jean-Claude Tardif, director of the Research Center at the Montreal Heart Institute, professor of medicine at the University of Montreal and the Canada research chair in personalized medicine, published data suggesting that certain genotypes were more likely than others to show a direct benefit from dalcetrapib in reducing the risk of CVD.

With colleague Marie-Pierre Dubé, Tardif showed a significant association between the effects of dalcetrapib in altering CV events and the allelic polymorphism at the rs1967309 location in the adenylate cyclase type 9 (ADCY9) gene. Using data from dal-Outcomes – the randomized, double-blind phase III study conducted by Roche that enrolled more than 15,000 patients who were already taking statins to control cholesterol – the researchers showed that patients with an AA polymorphism had a 39 percent decline in CV events compared to placebo while those with the GG variant were associated with a 27 percent increase and those with AG had a neutral effect.

The retrospective analysis of Roche's data was conducted in 5,749 patients and corroborated in a subsequent prospective analysis of 386 patients from Roche's phase IIb dal-Plaque study, which measured change in carotid intima-media thickness (cIMT). As hypothesized, patients with an AA allele showed regression in cIMT while patients with GG progressed.

On the basis of those findings, McNeil and Fred Middleton, a Sanderling managing director and Genentech Inc. co-founder, licensed the oral CETP inhibitor from Roche and founded Dalcor. The company closed a $50 million series A in 2015 and has drawn down about half of a $100 million B round completed last year, according to SEC filings. (See BioWorld Today, April 20, 2016.)

"The length of time of maintaining your observation is very important in this equation, because it says if you go long enough you get a signal, even in the general population," McNeil told BioWorld Insight. Based on the Merck findings, "even skeptics have picked up on that."

Dalcetrapib, meanwhile, has been shown to reduce atherosclerosis as much as statins do against placebo, and on top of statins – the first drug in three decades to show that additive effect, he maintained. Additional work that the company expects to submit for peer review shows "a deep implication between what's going on with ADCY9 and the biology of a CETP inhibitor," McNeil said. "This is not just lipid metabolism. This is more than that. And that's the great discovery which is going on today at Dalcor."

The Dal-GenE trial is recruiting patients on the basis of a companion diagnostic test that Dalcor developed in partnership with Roche.

Whether the ultimate fate of Merck's anacetrapib provides momentum for CETP assets in the pipeline and a dozen more in discovery, according to Cortellis, remains to be seen. But McNeil is confident that, with or without Merck, dalcetrapib is leading the way into precision medicine in CVD. If Dalcor's theory is borne out by the data, the development program for dalcetrapib could provide a new template to advance CVD candidates. Understanding of the genetic nuances of individuals with CVD could offer a path not only to advance CETP inhibitors as preventive treatment for responders but also to develop drugs for those with the AG variant, who saw little improvement, and the GG variant, who may actually be harmed by drugs in the CETP inhibitor class.

"We're pretty sure that the direction of genetically defined populations makes a huge difference in these studies, and we think that's what we're seeing in Merck's results from the REVEAL trial," McNeil said, noting that the findings from REVEAL mirror Roche's earlier experience with dalcetrapib in dal-Outcomes.

"Only one variable is changing in our study, and that is whether patients are genetically defined for CETP," he added. "If they are, this is Herceptin all over again."