TRIAL FAIL

Ionis and AstraZeneca's eplontersen misses primary endpoint in ATTR-CM trial

CARDIO-TTRansform did not beat placebo on CV death and recurrent events in 1,432 patients, though a monotherapy subgroup and TTR reduction data complicate the read.

By AppliedXLJuly 9, 2026Trial NCT04136171

Executive Summary

Eplontersen did not separate from placebo on the primary composite outcome of cardiovascular death and recurrent cardiac events in a large, global Phase 3 trial in ATTR cardiomyopathy, closing out a readout the sponsor had guided to since late 2024.
The sponsor is emphasizing a favorable signal in a subgroup of patients not on background stabilizer therapy and pointing to secondary biomarker and imaging measures, but those are not the primary result and were highlighted after a miss on the trial's registered endpoint.
The trial tested whether adding an RNA-targeted TTR silencer to a treatment landscape now dominated by oral stabilizers produces a mortality and morbidity benefit, and the negative primary result suggests that in patients already stabilized, the added benefit was not detectable at this endpoint.
The full data set arrives at a major cardiology conference within weeks, which will determine whether the subgroup and biomarker findings are sufficient to support any regulatory follow-through, distinct from the primary efficacy claim that failed.

The result

Ionis Pharmaceuticals, Inc. and AstraZeneca disclosed on July 9, 2026 that CARDIO-TTRansform, a Phase 3 trial of eplontersen in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), did not meet its primary efficacy endpoint: the composite of cardiovascular mortality and recurrent CV clinical events through Week 140, measured against placebo. The trial enrolled 1,432 of a planned 1,438 patients and ran across ten countries including the United States, Japan, Germany, and Brazil. Chief executive Brett Monia called the miss disappointing while pointing to what he described as evolving standard of care, since a majority of patients in each arm were already on an oral TTR stabilizer at baseline and a further 24% in each arm started one during the trial. Update+1

The subgroup signal

In a prespecified subgroup of patients treated with eplontersen alone, without a background stabilizer, the companies reported a nominally hazard ratio of 0.71 on the same composite outcome versus placebo. Among patients who were already on a stabilizer at baseline, no treatment effect was observed. The companies also reported large and sustained reductions in serum TTR, consistent with the drug's silencer mechanism, and said multiple secondary, imaging, and biomarker measures favored eplontersen over placebo in the overall population. None of those are the trial's registered primary measure, and the disclosure itself carries the hallmarks of post-hoc emphasis and subgroup-only framing rather than a primary-endpoint win. Update

Safety and next data

Eplontersen was described as well tolerated, with a safety profile consistent with prior results in the drug's approved polyneuropathy indication. Ionis and AstraZeneca said the full data set will be presented at the European Society of Cardiology Congress in August 2026, which is the disclosure that will show whether the subgroup and biomarker findings hold up under fuller scrutiny. Eplontersen is already FDA-approved as WAINUA for hereditary ATTR polyneuropathy, administered subcutaneously, so this trial was testing a label expansion into cardiomyopathy against a bar of adding benefit on top of, not instead of, oral stabilizer therapy. Update

The competitive field

The ATTR-cardiomyopathy field is mechanistically diverse, not sparse: direct comparators sharing the TTR target include Alnylam's patisiran and vutrisiran and BridgeBio/Bayer's oral stabilizer acoramidis, alongside Intellia's CRISPR-based NTLA-2001, all in Phase 3 or later development for the same or an adjacent TTR-amyloidosis indication. Pfizer's tafamidis, an oral stabilizer, already established the modern standard of care that CARDIO-TTRansform's patients were layered on top of, which is the same standard the primary analysis failed to beat. That context narrows what a positive result would have needed to show: a benefit incremental to stabilization, not merely a repeat of the TTR-lowering effect the drug had already demonstrated in polyneuropathy.

Protocol history

The trial's primary completion date moved from January 2024 to June 2025 and then to April 1, 2026 over the study's life, and enrollment grew from a planned 750 to a final 1,438 as the design was adjusted. Those changes predate this readout and reflect a trial that grew and extended rather than one that shrank going into its result. The July 9, 2026 disclosure of a missed primary endpoint arrived within the sponsor's own guided H2-2026 window, repeated consistently across six guidance updates since November 2024. NCT04136171

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