Wainua Phase 3 Setback Clouds TTR Silencers, Strengthening The Case For ATTR-CM Stabilizers

AstraZeneca and Ionis Pharmaceuticals’ Wainua has moved from a disappointing ATTR-CM readout to a more clearly negative one. Data presented at the annual European Society of Cardiology meeting showed a hazard ratio of 1.14 in Phase 3, adding numerical detail to the earlier failure and indicating a 14% higher rate of cardiovascular mortality and recurrent clinical events versus the comparator arm.

That matters because the summer disclosure had already surprised investors who had expected a relatively high probability of approval in transthyretin-mediated amyloid cardiomyopathy. The fuller dataset now sharpens the commercial implication: this was not simply a narrow miss in a competitive market, but a result that several firms read as a meaningful setback for this specific treatment approach in combination with current standard therapy.

The Data

The presentation covered patients in CARDIO-TTRansform who received Wainua, also known as eplontersen, plus standard of care treatment with Pfizer’s tafamidis/Vyndamax. Stifel wrote that only minimal benefit had been largely expected in that setting, but called the 1.14 hazard ratio an incremental surprise.

At the same time, the study did produce what Stifel described as a “very respectable benefit” for Wainua as a monotherapy. In that subgroup, patients receiving Wainua alone showed a 29% improvement in cardiovascular events.

That split between combination and monotherapy is driving much of the current debate. Oppenheimer said the data suggest potential safety signals for Wainua combined with an antisense oligonucleotide–stabilizer. The source also pointed to a weaker efficacy profile against Alnylam’s ATTR-CM program: TTR knockdown was about 10% less in CARDIO-TTRansform than in HELIOS-B, and Wainua’s placebo-adjusted effect on a six-meter walk test at 30 months was described as far less robust than Amvuttra monotherapy.

Safety also looks less favorable in that comparison. Wainua had a 6.4% rate of treatment discontinuations due to adverse events, similar to placebo, but more than double the 3% adverse-event discontinuation rate reported for Amvuttra in HELIOS-B.

The Commercial Picture

The immediate market read is that Wainua’s ATTR-CM opportunity has narrowed sharply. Stifel said the full readout makes it hard to see a path toward approval for Ionis and AstraZeneca in the indication.

The more important industry signal may be what the result says about treatment sequencing in ATTR-CM. Jefferies said the new data suggest oral stabilizers from BridgeBio and Pfizer remain the preferred first-line option. Pfizer’s tafamidis is already established in the market, and BridgeBio received an FDA nod for Attruby, also known as acoramidis, in 2024.

BioSpace reported that Stifel does not expect the Wainua failure to spill over into a commercial hit for Alnylam’s approved drug Amvuttra, also known as vutrisiran, in ATTR-CM. Instead, the pressure may fall more heavily on late-stage development strategy. Alnylam’s next-generation RNAi therapeutic nucresiran is being studied in the Phase 3 ATTR study TRITON-CM, and Stifel said the unequivocally negative combination data could embolden the company to change course sooner. One option raised by the analysts is to direct further enrollment toward monotherapy and make that cohort the primary outcome, while Oppenheimer noted that the current assumption is that most already enrolled patients are on background tafamidis.