Nov. 5 (Bloomberg) -- Roche Holding AG’s abandoned heart drug dalcetrapib, designed to raise levels of good cholesterol, also boosted blood pressure and inflammation, researchers said.
Dalcetrapib marks the second failure in what was expected to be a new blockbuster class of heart medicines known as CETP inhibitors. The Basel, Switzerland-based drugmaker halted development of the drug in May, saying an early look at study results found the medicine wasn’t helping patients. Pfizer Inc. dropped its pill torcetrapib in December 2006 after studies showed it raised blood pressure and boosted death rates.
The findings presented today at the American Heart Association meeting in Los Angeles showed dalcetrapib had unexpected side effects that may have contributed to its downfall. While it didn’t increase hypertension in the same manner or amount as torcetrapib and there weren’t more deaths, it’s possible the medicines could have damaged blood vessels, the researchers said. That may have implications for Merck & Co. and Eli Lilly & Co., who are developing similar compounds.
“It was a surprise that the blood pressure effect was evident,” since earlier studies didn’t find any increase, said Gregory Schwartz, chief of cardiology at the U.S. Department of Veterans Affairs Medical Center in Denver, in an interview. “That’s why it’s so important to do large trials, to detect small but important safety effects.”
Neither Merck’s anacetrapib nor Lilly’s evacetrapib have shown any signs of boosting blood pressure, Schwartz said. That could change in larger trials. Both medicines also raise levels of good cholesterol much more than dalcetrapib and slash bad cholesterol that chokes the arteries. The improvement in bad cholesterol levels may propel the drugs to market, he said.
Officials at Whitehouse Station, New Jersey-based Merck and Indianapolis-based Lilly said the difference in potency makes comparisons between dalcetrapib and their compounds irrelevant. The drugs are designed to inhibit a molecule known as CETP, which results in higher levels of good HDL cholesterol that is known to ferry fatty lipids out of the arteries. Still, the amount and type of good cholesterol varies between drugs.
“We haven’t changed our confidence in the molecule,” said Yale Mitchel, associate vice president of cardiovascular research at Merck. “We believe the epidemiology and other evidence support CETP as a mechanism that provides a benefit.”
In the Roche study known as dal-Outcomes, dalcetrapib raised good cholesterol called HDL by 30 percent and had no effect on bad cholesterol. The trial of 15,871 patients found 8.3 percent of those getting the drug died, suffered another heart attack, stroke or were hospitalized for chest pain, compared with 8 percent of those on a placebo.
“What you have here is a weak inhibitor of CETP,” said Jeffrey Reismeyer, Lilly’s senior medical director for evacetrapib. “You need more inhibition than you can get with dalcetrapib,” he said. The benefit of raising good cholesterol with powerful CETP inhibitors “is still an important question and one that hasn’t been answered. This study doesn’t reflect on our development or even Merck’s.”
Merck’s anacetrapib raises good HDL cholesterol by 140 percent and cuts bad LDL cholesterol by 40 percent, Mitchel said. Lilly’s evacetrapib increases good cholesterol by about 130 percent and cuts bad cholesterol by 36 percent in studies.
“Based on what we now know with dalcetrapib and how far along we are with anacetrapib, the idea of having a deleterious effect is very unlikely,” Mitchel said.
The final studies of anacetrapib are well under way, with more than 20,000 of the 30,000 patients enrolled, he said. Merck expects to report results in 2016, he said. Lilly began its 11,000 patient final study of evacetrapib last month and said it may be completed by the end of 2015.
There are other reasons dalcetrapib may not have worked, said Schwartz, who is also a professor of medicine at the University of Colorado in Denver. Even in the patients who had the biggest HDL boost, there was no apparent decrease in heart risk, he said. About 1,600 patients had their HDL levels rise well into the 70s, though that didn’t cut their risk.
Patients had recently had a heart attack or were hospitalized for chest pain, and were already getting aggressive medical care. For them, raising HDL may not provide additional benefits. In addition, the good cholesterol that was created may not have functioned properly, he said, or the way dalcetrapib raises good cholesterol may not be beneficial.
“HDL is a very complicated particle and has a very complicated function,” Schwartz said, pointing out that several recent trials found raising levels didn’t bring heart benefits. “We’ll have to see if the HDL that was formed had good function.”
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