Drug Lowers a Heart-Damaging Protein, but Patients Do No Better in a Large Trial

A phase III trial of the gene-silencing drug eplontersen in patients whose hearts are stiffened by protein deposits did not meet its primary endpoint, the European Society of Cardiology reported on Aug. 28 from its annual congress in Munich.

The double-blind trial, CARDIO-TTRansform, enrolled 1,432 patients at 130 centers in 20 countries, all with wild-type or hereditary transthyretin amyloid cardiomyopathy, a disease in which the misfolded protein transthyretin builds up in heart muscle, according to the ESC release. Participants were randomized to eplontersen 45 mg or placebo by injection under the skin every four weeks, on top of standard care. Mean age was 72, and 9.4% were women.

The primary endpoint combined cardiovascular death and recurrent cardiovascular events. The release reports 381 such events among 210 patients on eplontersen and 392 events among 231 patients on placebo, a rate ratio of 0.89 (95% confidence interval 0.73 to 1.09, p=0.277). That is no significant difference over follow-up lasting up to 140 weeks.

Eplontersen did lower its molecular target. Circulating serum transthyretin was suppressed, the ESC said, consistent with the expected effect of silencing the gene, as measured through week 140.

A prespecified subgroup analysis found that the effect differed by whether patients were already taking a stabilizer, a drug that keeps transthyretin from misfolding rather than lowering how much of it is made. Among patients not on a stabilizer, fewer primary endpoint events occurred with eplontersen, a result the release reports as reaching only nominal statistical significance, which makes it exploratory rather than settled. Among the 57% who were on one at baseline, no additional benefit was seen.

Eplontersen is already approved for hereditary transthyretin amyloid polyneuropathy, a nerve disease caused by the same protein. Presenter Mathew Maurer of Columbia University Irving Medical Center said the trial "did not demonstrate a significant reduction in the primary endpoint in the overall population."

The trial was funded by AstraZeneca and Ionis, per the ESC release.