An RNA therapy from partners Ionis Pharmaceuticals and AstraZeneca failed a pivotal study as a treatment for a type of cardiomyopathy that can progress to heart failure, dashing hopes of blockbuster sales in a growing indication that’s becoming more competitive with the emergence of new therapies, including genetic medicines.
Eplontersen, brand name Wainua, was tested as a treatment for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). On Thursday, Ionis and AstraZeneca announced this drug did not meet the Phase 3 study’s main goal, a composite of cardiovascular measures during the trial. Specific details of those measures were not disclosed, but the companies said adding Wainua on top of the standard of care did not lead to a statistically significant benefit.
ATTR-CM develops when misfolded versions of transthyretin (TTR), a liver-produced protein, build up around the heart. While these abnormal proteins can stem from genetic mutations, normal versions of the protein can also cause deposits that lead to the cardiovascular problems associated with the disease.
Ionis, a specialist in antisense oligonucleotide (ASO) therapies, discovered and developed Wainua. The drug is a ligand-conjugated ASO designed to bind to and degrade messenger RNA for TTR, both mutated and normal versions of the protein. By “silencing” the production of TTR, this approach is intended to reduce levels of this protein in the blood as well as the protein deposits in tissues. The once-monthly injection initially won FDA approval in 2023 as a treatment for polyneuropathy caused by ATTR. Estimates place this patient population in the tens of thousands.
ATTR-CM is more prevalent, estimated to total between 300,000 and 500,000 patients worldwide. That larger market opportunity makes the Phase 3 test of Wainua in the heart indication particularly important to Ionis and AstraZeneca as well as their investors. Analysts at William Blair had estimated the drug could reach $4.1 billion in total peak U.S. sales.
The blockbuster Pfizer drugs Vyndaqel, and its successor, Vyndamax, are the standard of care for ATTR-CM. These small molecules work by binding to and stabilizing TTR, preventing the protein from misfolding and depositing in bodily tissue. BridgeBio’s next-generation TTR stabilizer, Attruby, won FDA approval in late 2024. In early 2025, Alnylam Pharmaceuticals added ATTR-CM to the label of Amvuttra, a drug that was initially approved for ATTR polyneuropathy in 2022. This drug, administered by injection every three months, takes a slightly different approach to silencing TTR by using small-interfering RNA to degrade the mRNA for the problem protein.
In the placebo-controlled Phase 3 test of Wainua, the main goal was measuring cardiovascular events over the course of the 140-week trial. Ionis and AstraZeneca said the study drug did not meet the main goal at this time point. The pivotal test of Alnylam’s drug was also time-driven, but assessed over 156 weeks. Ionis hosted an analyst call on Thursday to answer some questions about the trial. Analysts from William Blair participated and wrote in a research note that management said no benefit was shown for Wainua overall, and the company does not believe a longer study would have led to a different outcome.
The trial failure might be due to higher use of stabilizers in the Wainua trial, Leerink Partners analyst Andrew Berens said in a research note. Ionis and AstraZeneca said 57% of participants in each arm received a stabilizer at baseline; 24% of participants in each arm started a stabilizer during the trial. That means that at any point in the trial, 81% of participants were receiving a stabilizer. While the Alnylam drug’s trial also included patients treated with stabilizers, the rates were not nearly as high. Higher usage of stabilizers in the Wainua trial may have blunted the magnitude of effect of the study drug, Berens said.
While Wainua missed the Phase 3 study’s main goal, the companies said a prespecified subgroup analysis of patients who received the study drug as a monotherapy showed a “nominally significant” result. Ionis and AstraZeneca said Wainua was well tolerated and showed a favorable safety consistent with previous trial results. The companies added that they will continue to analyze the data set and results will be shared at the European Society of Cardiology Congress in Munich next month.
AstraZeneca has another ATTR-CM opportunity with cliramitug, a monoclonal antibody designed to deplete TTR deposits. A Phase 3 study is expected to be complete in mid-2027. Physicians have told Leerink that they are excited about the depleter mechanism, but questions remain on the patients best suited to show efficacy with such a drug. Berens said there are also questions about whether the drug should be used in a combination approach or as part of a sequence of treatments.
AstraZeneca management told Berens the company will discuss with regulators the potential for seeking regulatory approval for Wainua based on the nominally statistically significant results in the monotherapy group. But they also recognize there’s a lower unmet need in this setting. Another possibility is developing a combination of Wainua and cliramitug, but more work is needed for such a pairing. Management also told Berens there are both positive and negative implications for the Wainua trial failure.
“While it removes a potential competitor for [Alnylam’s] Amvuttra, it also reignites the debate comparing silencers vs. stabilizers, suggests there could be no benefit to a combination approach, and could increase payer push-back on combination therapies,” Berens wrote.
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