BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.

The only catch? It didn’t seem to work by raising HDL.

Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.

Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.

“As a clinician, this was an interesting and important result,” said Dr. Landray, professor of medicine and epidemiology at the University of Oxford (England).

“This is a drug that would have a role clinically, along the lines of ezetimibe,” said Louise Bowman, MD, a clinical epidemiologist and clinical trialist at Oxford who served with Dr. Landray as coprincipal investigator on the study.

Even at a time when proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are now routinely available to produce profound reductions in LDL cholesterol, a drug like anacetrapib that produces a more modest reduction can have a clinically useful role, she said. Having anacetrapib available as another option for safely lowering LDL cholesterol “could be complementary” to the lipid-lowering drug classes already in use, Dr. Bowman stressed in a video interview.

“This was a very well treated population on an intensive statin dosage, but when we added the new drug on top of that we saw a clear additional benefit.”

Despite this now proven potential to make a clinical impact, executives at Merck, the company developing anacetrapib, and a cosponsor of this trial, have not yet decided how to follow up on the results. A statement released by the company just before Dr. Landray’s report said: “Merck continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the [Food and Drug Administration] and other regulatory agencies.”

The results also provided a striking lesson that proving a new drug’s value can require running a very large trial for several years.

“Why was this trial positive” when the earlier trials with torcetrapib, dalcetrapib, and evacetrapib were not? “One reason is that our trial had twice as many patients and twice as many events with much longer follow-up,” Dr. Landray said.

Concurrently with his report, the results appeared in an article published online (N Engl J Med. 2017 Aug 29. doi: 10.1056/NEJMoa1706444).

The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial enrolled 30,449 patients at 431 centers in North America, Europe, and China. The average age of the patients was 67 years. Patients had to have established arterial disease: 88% had coronary artery disease, 22% had cerebrovascular disease, and 8% had peripheral artery disease (numbers total more than 100% because some patients had documented disease in more than one arterial bed). The average level of LDL cholesterol was 61 mg/dL, HDL cholesterol was 40 mg/dL, and non-HDL cholesterol averaged 92 mg/dL. During anacetrapib treatment HDL levels roughly doubled, while levels of non-HDL cholesterol fell by an average of 18%.

After a median treatment time of 4.1 years, the study’s primary endpoint – the combined rate of coronary death, nonfatal MI, or need for coronary revascularization – occurred in 10.8% of the patient on anacetrapib and in 11.8% of those in the placebo-control group, a 9% relative risk reduction that was consistent across all prespecified subgroups of patients in the study.

This level of benefit compared with the degree of non-HDL cholesterol lowering observed was strikingly consistent with the relationships between achieved lipid reductions and the clinical results seen in all the published studies with statins and with ezetimibe.

“Anacetrapib lowers LDL and raises HDL, so we knew it would be difficult to disentangle” which effects led to the clinical benefits seen, said Dr. Bowman. But the magnitude of the non-HDL lowering effect relative to the observed benefit “lined up very nicely” with the effects in the statin and ezetimibe trials. On the other hand, “if you double HDL cholesterol you’d expect to see a substantial contribution from that, and we did not, so if the HDL-lowering has an effect it’s probably small,” she said, cautioning that right now this is just an unproven inference. “Our findings are consistent with an LDL effect.”

REVEAL’s other major finding was anacetrapib’s good safety and tolerance profile, with 85% of patients randomized to receive anacetrapib continuing to take the drug through the end of the study. Treatment with the drug linked with a small but statistically significant 0.6% drop in the incidence of diabetes compared with placebo patients, and a small but statistically significant 0.84% increase in new onset stage 3 chronic kidney disease but with no increase in serious adverse events associated with kidney failure. The drug’s use showed no suggestion of a link with cancer, liver disease, muscle effects, cognitive effects, infections, or other serious or nonserious adverse effects. Patients on anacetrapib had on average a systolic blood pressure that was 0.7 mm Hg higher than that of patients on placebo and a diastolic blood pressure that averaged 0.3 mm Hg higher compared with the placebo group. The rate of hypertension-associated serious adverse events was low and virtually identical in the two study groups.

REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.

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mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

VIDEO: Anacetrapib doubles HDL, but patients gain from its modest LDL cut