Today AstraZeneca and Ionis reported that Wainua (eplontersen) missed the primary endpoint of CARDIO-TTRansform, the largest ATTR cardiomyopathy trial ever run. The easy read is that TTR silencing failed in the heart. Look closer.

CARDIO-TTRansform was designed against a placebo arm that has since changed. Stabilisers, first tafamidis and then acoramidis, became standard of care, and most patients in the trial were on one. The trial did not test whether silencing works. It tested whether a silencer adds benefit on top of a stabiliser. In the full population the answer was no, even though a prespecified monotherapy subgroup reached nominal significance.

We mapped every TTR-directed asset with a cardiomyopathy program. There are 18, across six mechanism classes. Two were built to answer the add-on question. One is Wainua, which has now answered it. The other is Intellia and Regeneron's one-shot CRISPR edit, reading out in 2027. Every therapy that has won in ATTR-CM did it as the stabiliser or through a mixed design that held up with and without one, the way vutrisiran did in HELIOS-B.

The bar has moved. Lowering TTR is table stakes. The prize goes to whoever can beat a stabiliser-treated patient who already feels well.