Ionis Pharmaceuticals (IONS) shares cratered roughly 20% in pre-market trading after the company and partner AstraZeneca announced that eplontersen failed to hit the primary endpoint in the Phase 3 CARDIO-TTRansform study. The stock had closed Wednesday at $84.46, then tumbled to $67.25 in early action, extending a year-to-date decline of almost 12% despite still being up about 99% over the past year.
The trial enrolled 1,432 adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) across 130 sites in 20 countries. Participants received either eplontersen 45 mg or placebo via subcutaneous injection every four weeks. The main goal was a composite of cardiovascular death and recurrent cardiovascular clinical events through Week 140, but eplontersen did not deliver a statistically significant benefit in the overall population.
A crucial factor was widespread stabilizer use. At baseline, 57% of patients were already on a stabilizer drug, and another 24% started one during the study. In this setting, eplontersen showed no treatment effect. However, a subgroup of patients not taking stabilizers saw a nominally significant 29% reduction in the combined risk of cardiovascular death and repeat events (hazard ratio 0.71). The drug also produced large, sustained reductions in transthyretin protein levels and met several secondary and imaging endpoints, with a favorable safety profile consistent with prior data.
Analysts reacted skeptically. Stifel’s Paul Matteis wrote that “trying to approach regulators here on these data would seem like a stretch.” Neither Ionis nor AstraZeneca indicated plans to seek approval or run another trial. CEO Brett Monia attributed the miss to an evolving treatment landscape where stabilizers are now standard care. The companies plan to present full results at the European Society of Cardiology Congress in August 2026.
For Ionis, the failure removes expected profit-sharing, royalties, and milestone payments from eplontersen in ATTR-CM. AstraZeneca’s U.S.-listed shares fell about 9% on the disappointment. Meanwhile, rival drugmakers Alnylam Pharmaceuticals and BridgeBio surged double digits, as Alnylam’s Amvuttra remains the sole RNA-silencing therapy in the space. Pfizer’s market-leading Vyndamax—with over $6 billion in annual sales—also benefits from reduced competition.
