ATTR-CM is a progressive disease caused by the accumulation of misfolded transthyretin (TTR) protein in the heart. Eplontersen, an RNA-targeted therapy approved for hereditary transthyretin-mediated amyloidosis with polyneuropathy, works by suppressing hepatic production of TTR. Investigators sought to determine whether deeper reductions in circulating TTR levels could improve outcomes for patients already receiving modern medical management.

The global trial enrolled 1,432 patients across 130 centers in 20 countries. Participants, whose average age was 76 years and who were predominantly male, were randomly assigned to receive monthly subcutaneous eplontersen 45 mg or placebo for up to 140 weeks.

A key feature of the study population was the extensive use of current ATTR-CM therapies. More than half of participants were already receiving a TTR stabilizer at enrollment, and approximately one-quarter began stabilizer therapy during the study. Standard heart failure treatments, including mineralocorticoid receptor antagonists and SGLT2 inhibitors, were also commonly used.

The primary outcome combined cardiovascular death and recurrent cardiovascular events. During follow-up, 381 primary endpoint events occurred among patients receiving eplontersen compared with 392 events in the placebo group. Although the numerical trend favored eplontersen, the difference did not reach statistical significance, indicating no overall cardiovascular benefit when the drug was added to existing care.

Separate analyses of the primary endpoint components showed similar findings. Cardiovascular mortality was recorded in 74 patients treated with eplontersen and 70 patients receiving placebo, while cardiovascular clinical events occurred in 307 and 322 patients, respectively.

Despite the neutral primary result, several subgroup findings generated interest. Patients who were not using a TTR stabilizer at baseline experienced fewer primary endpoint events with eplontersen than with placebo, suggesting potential benefit when the therapy is used as monotherapy. Likewise, patients with earlier-stage disease, classified as National Amyloidosis Center stage I, appeared to derive greater benefit than those with more advanced ATTR-CM.

Treatment produced the expected biological effect, reducing serum TTR concentrations by nearly 70% over 140 weeks. Investigators also reported that eplontersen helped preserve functional capacity and health-related quality of life compared with placebo.

Safety results were consistent with prior experience. Serious adverse events occurred at similar rates in both treatment groups, and no new safety concerns emerged during the study.

Researchers noted that the management of ATTR-CM and heart failure evolved substantially during the course of the trial. Widespread use of TTR stabilizers and the increasing adoption of other evidence-based therapies may have reduced the opportunity to demonstrate added benefit from TTR-lowering treatment. Differences in disease stage and background treatment patterns may also have influenced outcomes.

The findings raise questions about the value of combining TTR silencers and stabilizers in ATTR-CM. While both therapeutic approaches have demonstrated effectiveness individually, the trial did not show that pairing eplontersen with a stabilizer translates into additional reductions in morbidity or mortality. The results suggest that the incremental benefit of combination therapy may be less substantial than previously anticipated.

Investigators cautioned that the study population consisted largely of White male patients, potentially limiting generalizability. In addition, tafamidis was by far the most commonly used stabilizer, meaning the results cannot be extrapolated to combinations involving newer agents such as acoramidis.

Overall, CARDIO-TTRansform demonstrated that eplontersen effectively lowers TTR levels and may help maintain function and quality of life, but it did not significantly improve cardiovascular outcomes when added to contemporary standard therapy for ATTR-CM. Further research may help identify patient groups, particularly those with early-stage disease or those not receiving stabilizers, who could benefit most from TTR-silencing strategies.