ACC: Merck anacetrapib reveal bodes neutral at best for DalCor’s dalcetrapib

Pfizer, Roche, Lilly and finally, Merck. One by one, they ended their CETP inhibitor programs, giving up the ghost on a once-vaunted class of cholesterol-targeting drugs thought to be a potential game-changer for heart disease. In spite of the mass exodus, little DalCor Pharmaceuticals emerged in 2015, with the Roche castoff dalcetrapib and a goal to succeed where the heavy hitters of Big Pharma had failed. 

DalCor was founded on the premise that even though dalcetrapib hadn’t worked in a broad population of 15,000 patients, it had reduced cardiovascular events, such as heart attack and stroke, in patients with a particular form of the adenylate cyclase type 9 (ADCY9) gene. Specifically, patients with an AA polymorphism at a specific spot on that gene saw a 39% decline in cardiovascular events, while patients with other polymorphisms either had no effect, or experienced an increase in events.

The company’s raison d’être is to test a precision medicine approach to CETP inhibition—it is now elbows deep in a trial testing dalcetrapib in more than 6,000 patients. 

At the annual meeting of the American College of Cardiology this week, a new analysis of data for Merck’s CETP drug anacetrapib cast a shadow on DalCor’s hypothesis. The analysis, of the phase 3 REVEAL study of anacetrapib, found “no meaningful differences between characteristics between genotypes”—that is, the drug didn’t work better for people with the genetic variant that DalCor is interested in. The findings echo an analysis presented at last year’s ACC meeting that found genotype didn’t affect the efficacy of Eli Lilly’s CETP drug evacetrapib. 

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However, the results for anacetrapib should not be extrapolated to DalCor’s dalcetrapib, as the two drugs inhibit CETP in different ways and that anacetrapib had been tested in a lower-risk patient population, said DalCor CEO Fouzia Laghrissi-Thode. The REVEAL study enrolled 30,000 patients—about 19,000 of whom had ADCY9 genotype data—who had stable disease, whereas DalCor is studying dalcetrapib in a higher-risk group. 

DalCor’s dream situation would have been a confirmed link between the AA polymorphism and drug efficacy, but the Merck data don’t necessarily spell doom for the biotech. It might mean that CETP inhibition may not have much of an effect in stable patients and could be more effective in sicker patients. DalCor’s Dal-Gene study, as well as Roche’s original dalcetrapib trial, recruited patients who had experienced acute coronary syndrome in the three months before enrollment. 

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“I wouldn’t say [the new analysis] is discouraging,” Laghrissi-Thode said. “I would put it this way: if Merck had confirmed the gene, it would be an upside for what we are doing because it means the gene is relevant for the class, that the gene is relevant for a broad population.” With the data as they are, DalCor is in the same position that it was before the data reveal. 

“Our own data show that genetic testing is clearly relevant for dalcetrapib and the post-acute coronary syndrome population,” she added.

DalCor is going full-steam ahead, with a futility analysis planned for the fourth quarter this year. If all goes well, the company expects the study to read out in late 2020 or early 2021. 

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The anacetrapib presentation may not have done any favors for DalCor, but it could drum up interest in DalCor’s precision medicine approach in cardiovascular medicine. The REVEAL Collaborative Group at the University of Oxford, which carried out the analysis and presented the data, is looking at other genes that might be relevant to anacetrapib. 

“I was pleased to see other groups seeing interest in a pharmacogenomic approach in cardiovascular disease ... It’s good news for us if they are fortunate enough to identify other genes that could be relevant to anacetrapib or other products they have in hand,” Laghrissi-Thode said.