Ionis Pharmaceuticals' Wainua Fails Late-Stage Heart Disease Trial

What happened

Ionis Pharmaceuticals and partner AstraZeneca announced that Wainua (eplontersen) failed to meet its primary endpoint in the CARDIO-TTRansform Phase 3 trial. The study tested whether adding the once-monthly injection to standard care could reduce cardiovascular deaths and recurrent heart events in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) over 140 weeks. ATTR-CM is a progressive and potentially fatal disease where misfolded transthyretin proteins accumulate in the heart muscle, affecting an estimated 300,000 to 500,000 patients globally. The trial enrolled patients with 57% already receiving a TTR stabilizer at baseline, and another 24% starting stabilizer therapy during the study. While the overall study population showed no statistically significant benefit, a prespecified subgroup analysis of patients receiving Wainua as monotherapy demonstrated a nominally significant result. The companies said Wainua was well tolerated with a favorable safety profile consistent with previous trials. Complete results will be presented at the European Society of Cardiology Congress in August. Wainua remains approved for treating hereditary transthyretin-mediated polyneuropathy (ATTRv-PN), a nerve disorder caused by the same protein deposits.

Why it matters

This trial failure represents a significant setback for Ionis, as ATTR-CM offered a substantially larger commercial opportunity than the drug's existing polyneuropathy indication. Analysts had estimated Wainua could reach peak sales between $4.1 billion and over $5 billion, with the broader ATTR-CM therapy market expected to reach $18 billion by 2030. The miss removes a major growth driver from Ionis's pipeline and raises questions about the company's ability to expand Wainua beyond its current tens-of-thousands patient base into the much larger cardiomyopathy market. For investors, the failure highlights the risk in combination therapy approaches, as the high proportion of patients already using stabilizers (81% at any point in the trial) may have blunted Wainua's effect. While the nominally positive monotherapy results offer a potential regulatory path, management acknowledged there is lower unmet need in that setting. Ionis stated it will discuss regulatory options with authorities but recognized the challenges. The setback also affects AstraZeneca, though analysts noted it is unlikely to derail the company's $80 billion revenue target for 2030, as the drug represented only one piece of its broader cardiovascular strategy.

Bigger picture

The failed trial reshapes the competitive landscape for ATTR-CM treatments, a market that has become increasingly crowded as improved diagnostics reveal the disease to be more prevalent than previously believed. Pfizer's Vyndaqel and Vyndamax stabilizers remain the standard of care, while BridgeBio's next-generation stabilizer Attruby won FDA approval in late 2024 and generated $362.4 million in U.S. revenue in its first full year. Alnylam Pharmaceuticals added ATTR-CM to the label of its gene-silencing drug Amvuttra in early 2025, completing a similar Phase 3 trial assessed over 156 weeks with lower stabilizer usage rates than the Wainua study. Following the announcement, shares of Alnylam and BridgeBio rose while Ionis fell sharply, reflecting investor view that the failure strengthens competitors' positions and could support better pricing for existing ATTR therapies. The outcome also raises broader questions about combination therapy strategies in this indication, as analysts noted it suggests there may be no benefit to adding silencers on top of stabilizers, potentially increasing payer pushback on such approaches. AstraZeneca retains another ATTR-CM opportunity with cliramitug, a monoclonal antibody designed to deplete TTR deposits, with Phase 3 results expected in mid-2027.

What to watch

Investors should monitor whether Ionis and AstraZeneca pursue regulatory approval based on the nominally significant monotherapy subgroup results, though management acknowledged this represents a smaller commercial opportunity. The companies will present detailed trial data at the European Society of Cardiology Congress in August, which may provide further insight into why the study failed in the broader population and whether specific patient characteristics influenced outcomes. Watch for any guidance on potential combination development with AstraZeneca's cliramitug depleter antibody, though management indicated more work is needed for such an approach. For the broader ATTR-CM market, monitor uptake trends for recently approved competitors Attruby and Amvuttra, as this failure may accelerate their market penetration. Finally, track AstraZeneca's mid-2027 Phase 3 readout for cliramitug, as questions remain about optimal patient selection and whether depleters should be used in combination or sequentially with other therapies.