AstraZeneca and Ionis' Wainua Misses Primary Goal in Phase 3 ATTR-CM Heart Trial

The Phase 3 CARDIO-TTRansform trial of Wainua (eplontersen) in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) did not meet its primary efficacy endpoint, AstraZeneca announced on July 9. The drug is developed jointly by AstraZeneca and Ionis Pharmaceuticals.

The primary endpoint was a composite of cardiovascular death and recurrent cardiovascular clinical events up to 140 weeks, compared with placebo. In a patient population treated with current standard of care, most of whom were taking a stabiliser drug, adding Wainua "did not provide a statistically significant benefit" on that composite, the company said. Wainua was generally well tolerated, with a safety profile consistent with previous results, according to AstraZeneca. The results are company-reported topline data; the companies did not release effect sizes or p-values.

Subgroups and stabiliser use

In a prespecified subgroup analysis of patients who received Wainua as monotherapy, fewer primary composite events were observed than with placebo, and the result was nominally significant, AstraZeneca said. In patients who were already on stabiliser therapy at the start of the trial, no treatment effect was observed.

Stabiliser use was substantial on both sides of the trial: 57% of patients in each arm were receiving a stabiliser at baseline, and a further 24% in each arm started one during the study, according to the release. HCPLive reported that this background use complicates attributing any additional benefit to gene silencing, and that the subgroup findings were reported without effect sizes or p-values.

"Although the trial did not meet its primary objective, we believe the results support greater scientific understanding of treatment approaches for the hundreds of thousands of patients worldwide suffering from this progressive and often fatal condition," said Sharon Barr, executive vice president of BioPharmaceuticals R&D at AstraZeneca.

The trial and the drug

CARDIO-TTRansform is a global, randomised, double-blind, placebo-controlled Phase 3 trial in adults with wild-type or hereditary ATTR-CM. It enrolled 1,432 participants at 130 sites in 20 countries, who were randomised 1:1 to eplontersen 45 mg or placebo by subcutaneous injection every four weeks. AstraZeneca describes it as the largest enrolled ATTR-CM trial to date. Secondary endpoints include the six-minute walk test, the Kansas City Cardiomyopathy Questionnaire score, all-cause mortality and cardiovascular mortality.

ATTR-CM occurs when misfolded transthyretin (TTR) protein builds up as amyloid fibrils in the heart, making it harder to pump blood. AstraZeneca estimates that 300,000 to 500,000 people worldwide live with the condition.

Wainua is a once-monthly RNA-targeted silencer designed to reduce production of TTR in the liver. It is approved for the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults in more than 20 countries, including in the EU under the name Wainzua, the company said. AstraZeneca and Ionis co-develop and co-commercialise the drug in the US; AstraZeneca holds rights elsewhere.

What comes next

AstraZeneca and Ionis said they will analyse the full data set and present the results at the European Society of Cardiology Congress in August 2026. HCPLive noted that the size of the treatment effect in the overall population, the subgroup results by stabiliser use and complete safety data remain to be disclosed.