Phase 3 Trial Collapses in Modern Standard-of-Care Setting

AstraZeneca (AZN) and Ionis Pharmaceuticals (IONS)’s Wainua·Wainzua (eplontersen) is a ligand-conjugated antisense oligonucleotide (LICA-ASO) that inhibits transthyretin (TTR) production. In the CARDIO-TTRansform Phase 3 trial involving 1,432 patients with ATTR cardiomyopathy (ATTR-CM) across 130 sites in 20 countries, 45mg was administered every four weeks, but the primary composite endpoint of cardiovascular death and recurrent cardiovascular events was not met through week 140. In the eplontersen group, 381 events occurred in 210 patients, compared to 392 events in 231 patients in the placebo group, with event rates of 29% and 32%, respectively, failing to demonstrate statistical superiority.

Core Failure: Limited Add-on Efficacy with Combination

At enrollment, 57% of patients in each group were already taking TTR stabilizers such as tafamidis, and an additional 24% initiated them during the trial, resulting in 81% overall exposure to stabilizers. No treatment effect was observed in patients receiving stabilizers, while a nominally significant reduction in events was seen in the prespecified subgroup not using baseline stabilizers. This highlights that the commercial bottleneck for gene silencers targeting TTR production lies in the limited incremental benefit when added on top of existing therapies such as Pfizer’s Vyndamax·Vyndaqel (tafamidis) or BridgeBio Pharma (BBIO)’s Attruby (acoramidis). The broad patient inclusion criteria and improved heart failure management during the trial period also narrowed the difference between treatment groups.

Competitive Landscape with Approved Products

Eplontersen was approved by the U.S. FDA for adult hereditary ATTR polyneuropathy (ATTRv-PN) on December 21, 2023, but this result significantly weakens its regulatory pathway for expansion into the ATTR-CM indication. The ATTR-CM market is already contested by Pfizer’s TTR stabilizer tafamidis, BridgeBio’s stabilizer acoramidis, and Alnylam Pharmaceuticals (ALNY)’s TTR-targeting siRNA Amvuttra (vutrisiran). Amvuttra, which received FDA approval on March 20, 2025, following success in the HELIOS-B Phase 3 trial, had a stabilizer use rate of 53%, lower than the 81% in the CARDIO-TTRansform trial. Thus, this result underscores that RNA therapy outcomes are more influenced by the proportion of combination-treated patients and the timing of treatment initiation rather than simple drug superiority.

Impact on Market and Pipeline

The global ATTR-CM patient population is estimated at approximately 300,000 to 500,000, and BridgeBio projects the ATTR treatment market revenue to reach around USD 9 billion in 2025 and USD 15–20 billion in the long-term peak market. Pfizer’s tafamidis franchise recorded USD 5.45 billion in 2024, and Amvuttra reached USD 1.9 billion in H1 2026, demonstrating the market’s commercial depth. Eplontersen’s setback strengthens the defensive position of the three already approved products and may pressure Alnylam’s next-generation Phase 3 candidate, nucresiran, which allows combination with stabilizers, to reconsider its trial design. TTR amyloid depleters in development by AstraZeneca, Novo Nordisk (NVO), and Attralus, which target existing amyloid deposits rather than new deposition, are emerging as a differentiating therapeutic axis.