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News
A major phase 3 trial found that eplontersen — already approved for TTR amyloid polyneuropathy — did not significantly reduce cardiovascular deaths or events in patients with TTR amyloid cardiomyopathy (ATTR-CM). This was despite a dramatic 77% reduction in circulating TTR levels. The CARDIO-TTRansform results, presented at ESC 2026 and published in the NEJM, suggest that lowering TTR alone may not be enough when patients are already on stabilizer therapy.
The CARDIO-TTRansform trial — the largest study ever conducted in ATTR-CM — delivered a sobering result: eplontersen, a once-monthly RNA-silencing drug that dramatically reduces TTR production, failed to significantly cut cardiovascular deaths or recurrent CV events compared to placebo. The trial enrolled 1,432 patients across 130 sites in 20 countries, with up to 140 weeks of follow-up. Despite a striking 77% placebo-corrected reduction in serum TTR levels, the primary composite endpoint showed only an 11% relative risk reduction (RR 0.89; P = .28) — falling well short of statistical significance.
A key factor? Background therapy. At baseline, 57% of patients in both groups were already on TTR stabilizers (mostly tafamidis), and another 24% started one during the trial. When eplontersen was analyzed in patients not on a stabilizer at baseline, it did show a significant benefit (RR 0.71; P = .017). Similarly, patients with early-stage (NAC stage I) disease saw meaningful protection (RR 0.63; P = .01).
Key Takeaways:
Why it matters: These results reframe the treatment landscape for ATTR-CM. More TTR suppression isn't automatically better — identifying the right drug, for the right patient, at the right disease stage is now the central question going forward.
