Merck’s magic touch extends to high-risk heart drug

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The success of the Reveal trial might go down as the clinical surprise of 2017. Merck & Co’s anacetrapib, the last CETP inhibitor left standing, has significantly reduced major coronary events in a huge outcomes study, confounding widely held pessimism.

The news initially sent the company’s stock higher this morning, but a notably cautious statement quickly restrained excitement. The fact that Merck has not committed to file for approval hints at a result that might not be clinically relevant, whatever the statistics are saying.

Full data are being held back for the ESC meeting at the end of August, so firm conclusions are impossible to draw at this stage – the company only said that the primary endpoint was met. However, headlining a press release with “provides update” is rarely a signal of good news.

And Merck has little reason to overstate its opportunity here; after the failure of three previous agents in this class hopes were low, while the huge success of Keytruda has relegated much else in its portfolio to a footnote.

Salvaging a signal

Developing the only successful CETP inhibitor would still be a coup, though. Lilly, Roche and Pfizer all invested heavily in their own agents, and their collective failure was costly, as well as dealing a heavy blow to the HDL hypothesis.

Little faith remains in the clinical benefits of this mechanism, and if anacetrapib starts to look more like a statin – in that it works by lowering LDL – Merck will have to consider that its rivals on the market are largely generic.

Anacetrapib, like Lilly’s evacetrapib, aggressively lowers LDL while hiking HDL. However Merck opted to run a much longer and larger outcomes study than Lilly, a bold strategic decision that ultimately might have paid off.

The ups and downs of the CETP inhibitors 
Project Company CVOT study Enrolment Outcome  LDL lowering  HDL raising  Trial ID
Torcetrapib Pfizer Illuminate 15,067 Stopped in 2006 for safety -25% +70% NCT00134264
Dalcetrapib Roche Dal-Outcomes 15,865 Stopped in 2012 for futility minimal +35% NCT00658515
Evacetrapib Lilly Accelerate 12,092 Stopped in 2015 for futility -37% +130% NCT01687998
Anacetrapib  Merck  Define* 1,600 Completed  -40% +138% NCT00685776
Anacetrapib Merck  Reveal  30,624 Ongoing  ? ? NCT01252953
Dalcetrapib Dalcor Dal-Gene 5,000 Ongoing  ? ? NCT02525939
*Not an outcomes study.

The Reveal study recruited more than 30,000 patients with circulatory problems who were already on statins, and followed them to measure major coronary events. For the primary endpoint these included coronary death, myocardial infarction or a coronary revascularisation procedure; secondary endpoints included stroke (Event – Merck awaits news on free win with high risk heart drug, January 19, 2017).

Merck’s reticence could be caused by safety concerns, although the group stressed that anacetrapib’s profile was consistent with previous studies, including accumulation of anacetrapb in adipose tissue. Still, this has long been a worry, and regulators will be wary of the issue – Leerink analysts believe that the project needs to show a very robust impact on key cardiovascular events like death to justify filing.

Also closely watched will be blood pressure, a signal that has raised concerns across this class. However it seems more likely that modest efficacy is causing the company’s caution.

The trial was 88% powered to show a 15% relative risk reduction. However, Umer Raffat of Evercore ISI points out that, because Reveal was such a large trial, statistical significance could have been met at a much lower threshold; the compound’s clinical relevance would certainly be questioned should this fall into single digits.

Merck will also be considering the wider cardiovascular space when deciding whether to launch – as well as a generic statin class the latest entrants, the PCSK9s, have come under huge payer pressure. But barring a real long-term safety concern it surely has little to lose here – and a limited clinical benefit has not historically prevented the pharmaceutical industry from having a go.

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @ByAmyBrown on Twitter

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