ESC 2017 – Merck still won’t Reveal its hand

Merck & Co looks unlikely to file its CETP inhibitor anacetrapib with the FDA after reporting a lacklustre effect on cardiovascular events in the Reveal trial, full results of which were unveiled at the European Cardiology Society meeting today.

The study showed a significant 9% reduction in the risk of major coronary events with anacetrapib versus placebo, which was described as clinically meaningful by one of the lead investigators, Professor Martin Landray of the University of Oxford. However, Reveal had been powered to show a 15% improvement. 

There had already been a hint that the data were disappointing: Merck reported in June that the study had met its primary endpoint, but would not commit to moving forward with anacetrapib (Merck’s magic touch extends to high-risk heart drug, June 27, 2017). 

And this stance has not changed. The company told EP Vantage that it “continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the FDA and other regulatory agencies”.

Bernstein analysts wrote this morning that they believe it is unlikely that the company will submit anacetrapib for approval, a view widely held by the sell side community.

LDL, not HDL?

Commercial considerations must be one factor in Merck’s decision. PCSK9 inhibitors have failed to take the market by storm, and a 15% benefit on cardiovascular outcomes with Amgen’s Repatha was seen as a disappointment (ACC – No Repatha of glory, March 17, 2017). 

As anacetrapib has not even met this threshold, it would surely find it difficult to gain a foothold in the market.

Then there is the question of how Merck’s project achieved the effect seen in Reveal. At the trial midpoint, anacetrapib lowered LDL cholesterol by 18% and more than doubled HDL cholesterol levels, but it appeared that the cardiovascular benefit was driven by its impact on LDL, Professor Landray told ESC attendees.

“If there is an effect on HDL, I’d suggest it was probably small and probably a minor contributor to the benefits we see. But we can’t nail that question for certain,” he said during a press conference to discuss the Reveal results.

If he is correct this is yet another blow to the HDL hypothesis, and would put anacetrapib in direct competition with a slew of other LDL cholesterol-lowering drugs.


In spite of all this, Reveal, whose results were also published in the NEJM today, was technically a success. Anacetrapib was given to atherosclerotic vascular disease patients on top of intensive atorvastatin therapy, and the primary endpoint was the first major coronary event, a composite of death, myocardial infarction or coronary revascularisation.

While anacetrapib outperformed placebo on the composite endpoint, it did not manage to show a significant benefit on coronary death, which was 8% lower in the treatment versus the placebo group. Myocardial infarction was reduced by 13% with anacetrapib, a significant difference, while coronary revascularisation also fell significantly, by 10%.

Safety did not seem to be a problem, with no significant differences in serious adverse events between the treatment and placebo groups. There was a small increase in blood pressure, a side effect that scuppered Pfizer’s CETP inhibitor torcetrapib, but this did not appear to be as pronounced with anacetrapib.

However, Bernstein analysts were concerned about tissue accumulation of anacetrapib, due to its long half-life, even though there were no overt adverse clinical events.

Professor Landray seemed convinced that there could still be a place for Merck’s CETP inhibitor in the market, noting that it could be used in patients ineligible for other therapies including PCSK9 inhibitors. “Patients might be less keen on treatments that are injected, and payers might be less keen on treatments that are expensive,” he told the ESC.

However this is unlikely to be enough for Merck, even before considering potential nascent safety signals. 


One company, Dalcor, reckons it has found a way forward for CETP inhibitors with a personalised medicine approach. It licensed Roche’s failed project dalcetrapib and zoomed in on a subgroup of patients, those with the AA variant in the ADCY9 gene. This group, comprising 19% of heart disease patients, showed a benefit in a retrospective analysis of the pivotal Dal-Outcomes trial, which had failed in the overall population.

Dalcor has started a new study, Dal-Gene, in 5,000 subjects with this specific genotype. The trial has enrolled around 2,500 patients so far and should yield results in 2020, the company's chief medical officer, Donald Black, told EP Vantage

He believes that efficacy in this subgroup could be a class effect with the CETP inhibitors, but conceded that there was no direct evidence of this at present.

When asked if an analysis of AA genotype patients was being carried out in Reveal, Louise Bowman of the University of Oxford, the second lead investigator, replied: “We haven’t yet looked, but we do have plans to. I can’t give you an exact timeframe for that, but we’re doing it as quickly as we can because it’s a very interesting part of the story.”

Perhaps the results will have a bearing on whether Merck decides to take anacetrapib forward.

Project Study Trial ID
Anacetrapib Reveal NCT01252953
Dalcetrapib Dal-Gene NCT02525939

To contact the writer of this story email Madeleine Armstrong in Barcelona at [email protected] or follow @ByMadeleineA on Twitter

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