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Jump to Key Points MUNICH — Eplontersen, a drug already approved for polyneuropathy caused by transthyretin (TTR) amyloid deposits, does not protect against cardiovascular events or death associated with TTR-mediated amyloid cardiomyopathy (ATTR-CM), according to a phase 3 trial.
With up to 140 weeks of follow-up, the rate of the primary endpoint of cardiovascular mortality or events was 11% lower in the eplontersen than in the placebo group (rate ratio [RR], 0.89), but the difference was nonsignificant (P = .28), said principal investigator Mathew S. Maurer, MD, director of the Cardiac Amyloidosis Program at Columbia University in New York City.
The failure to show clinical benefit was seen despite a 60% reduction in trough serum TTR levels at the first analysis. This reduction at week 13 persisted over time with a slight climb in TTR levels with placebo, producing a mean placebo-corrected percent change for eplontersen of 77.2% from baseline at week 140.
The results of the CARDIO-TTRansform trial were presented at the European Society of Cardiology (ESC) Congress 2026 and simultaneously published in The New England Journal of Medicine.
- Eplontersen failed to reduce CV death/events in ATTR-CM; RR 0.89, P=.28.
- TTR trough levels ↓ 60% at week 13; placebo-corrected ↓ 77.2% by week 140.
- 1432 ATTR-CM patients randomized; 29.4% vs 32.2% reached primary endpoint.
- No significant benefit for MI, HF hospitalization, stroke/TIA, or urgent HF visits.
- Subgroups: benefit signal in no baseline TTR stabilizer and NAC stage 1 disease.
By the Numbers
In the trial, 1432 patients with ATTR-CM were randomized to eplontersen, an antisense oligonucleotide that targets TTR mRNA, or placebo at 130 centers in 20 countries. Adults were eligible for enrollment if they had an interventricular septum thickness ≥ 12 mm, a history of heart failure with a New York Heart Association class of III or less, and an N-terminal pro-B-type natriuretic peptide ≥ 600 pg/mL.
In the experimental group, a subcutaneous 45-mg dose of eplontersen was administered every 4 weeks.
By the end of the study, 29.4% of the 715 patients in the eplontersen group and 32.2% of the 717 patients in the placebo group had died of a cardiovascular cause or had one predefined cardiovascular event. Those events included myocardial infarction, hospitalization for heart failure, stroke, transient ischemic attack, or an urgent emergency room visit for heart failure that required administration of diuretics.
There were no significant between-group differences for any of the individual components of the composite endpoint. There was a nominal advantage for eplontersen for the endpoint of death by any cause, with a 95% confidence interval below 1.0 (HR, 0.78; 95% CI, 0.60-0.99).
No Benefit Seen on Top of TTR Stabilizers
When the 43% of patients who were not taking a TTR stabilizer at baseline were compared to the 57% who were, significant reductions in cardiovascular events were observed, but there was “no additional clinical benefit of eplontersen therapy” overall, which included a substantial uptake of TTR stabilizers over the course of the study.
Rates of adverse events — whether total events, serious events, or events leading to discontinuation — were similar. For adverse events leading to discontinuation, the rate was lower with eplontersen (6.4% vs 7.4%).
The failure of CARDIO-TTRansform to meet its primary endpoint might be considered particularly disappointing because of the study's many strengths, said Gianfranco Sinagra, MD, chief of the cardiothoracovascular department, University Hospital Trieste, Italy.
“CARDIO-TTRansform is the largest trial to date in ATTR-CM, and it included a population with a broader spectrum of disease severity than we have seen before,” said Sinagra, pointing out that there was no upper limit for NTProBNP and that almost 20% of patients had NYHA class III heart failure.
He appreciated the ambitious effort to maintain a focus on cardiovascular endpoints, but did express interest in the apparent all-cause mortality benefit.
“As ATTR-CM amyloidosis is a systemic disease, this finding suggests that there may be clinically relevant effects beyond the cardiovascular system,” he said.
He also cautioned that failure to meet the primary endpoint does not mean lack of efficacy of any kind. In addition to the benefit among those who were not taking a TTR stabilizer at baseline (RR, 0.71; P = .017), those who entered the trial with National Amyloidosis Centre (NAC) stage 1 disease — signifying the lowest risk of early mortality — also achieved significant protection against the primary endpoint (RR, 0.63; P = .01).
Ultimately, CARDIO-TTRansform should not be considered a comparison between eplontersen monotherapy and a combination strategy, Sinagra said. He called for in-depth subgroup analyses to further explore this and other unanswered questions.
“We now know that more TTR targeting is not necessarily better, but we do not necessarily know what is the right treatment for the right patient at the right time,” Sinagra said.
Referring to the possibility of better outcomes with earlier treatment based on the signal of benefit in the NAC stage 1 patients, he suggested there might be an opportunity for treatment sequencing as the disease progresses.
“The next questions are which treatment should we use first and when, and is there still a place for combination therapy in selected patients?” Sinagra said.
Maurer has reported financial relationships with Alnylam, AstraZeneca, Bayer, BridgeBio, Ionis, Intellia, Novo Nordisk, and Pfizer. Sinagra has reported financial relationships with Alnylam, Amgen, AstraZeneca, Biotronik, Boston Scientific, Bristol-Myers Squibb, Menarini, Novartis, and Pfizer.
Ted Bosworth, a career medical writer based in New York City, has been covering advances in clinical medicine for several decades.
