Full results from a large heart drug trial run by AstraZeneca and Ionis Pharmaceuticals have raised doubts about a class of medicines investors had valued at billions of dollars.
The trial tested eplontersen, sold as Wainua, in patients with transthyretin amyloidosis cardiomyopathy, a condition in which a protein made by the liver misfolds and accumulates in the heart muscle.
Those deposits stiffen the heart and eventually cause heart failure, and the disease is fatal if left untreated.
Two ways to attack the problem
Doctors already have drugs called stabilisers, made by Pfizer and BridgeBio, which hold the protein in its correct shape so it does not misfold in the first place.
The newer approach is the silencer, a medicine that uses RNA to switch off production of the protein at source, so less of it is made at all.
Eplontersen is a silencer, as is Alnylam Pharmaceuticals' Amvuttra, approved last year after a trial suggested patients taking it lived longer and spent less time in hospital.
The open question was whether adding a silencer on top of a stabiliser delivers extra benefit, or whether the two largely do the same job.
What the trial found
CARDIO-TTRansform enrolled more than 1,400 patients already on standard medication, half of whom received eplontersen and half a placebo, or dummy treatment.
After 140 weeks, 29% of those on the drug had suffered a serious cardiovascular event or died, against 32% on placebo.
That gap was too narrow to rule out chance, which in trial terms means the drug failed.
The findings were published in the New England Journal of Medicine and presented at a medical conference on Friday.
Why it may have failed
Investigators pointed to the patients recruited.
Some 81% of those in the AstraZeneca trial were already taking a stabiliser, against 53% in the earlier Alnylam study, leaving far less room for a second drug to add anything.
They also noted the trial admitted patients across the full range of disease severity, and that people whose deposits are already established may gain little from a drug that only slows new production.
Who pays the price
Alnylam shares fell as much as 5% on Friday and are down about 30% since the headline result emerged in July.
Amvuttra generated $1.9 billion in the first six months of 2026, or 86% of the company's revenue.
Michael Leuchten, an analyst at Jefferies, said the outcome suggested the added benefit of combining a silencer with a stabiliser was smaller than assumed, rather than the trial having been poorly designed.
Paul Matteis at Stifel said he could not see a route to approval for eplontersen in this condition.
AstraZeneca and Ionis shares slipped about 1% and 2% respectively.
The greater concern for Alnylam is nucresiran, its next-generation follow-up, whose ongoing trial also permits patients to take stabilisers.
