Ionis Pharmaceuticals and AstraZeneca have encountered a significant setback in their development of eplontersen, a novel RNA therapy, after the drug failed to meet its primary endpoint in a crucial Phase 3 trial aimed at treating transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). This outcome diminishes prospects for successful sales in an increasingly competitive market, particularly with the rise of new therapies including genetic treatments.<\/p>\n
Eplontersen, marketed as Wainua, was evaluated as a treatment for ATTR-CM, a condition characterized by the accumulation of misfolded transthyretin (TTR) proteins around the heart. On Thursday, both companies announced that Wainua did not achieve its main cardiovascular outcome measures during the trial. While specific details of these measures were not disclosed, the companies confirmed that the addition of Wainua to standard care resulted in no statistically significant benefit.<\/p>\n
ATTR-CM arises from the pathological deposition of TTR proteins, which can be influenced by genetic mutations or can occur from normal versions of the protein. Ionis, a leader in antisense oligonucleotide (ASO) therapies, developed Wainua as a targeted treatment aiming to bind and degrade both mutated and normal TTR mRNA. By suppressing TTR production, the therapy seeks to reduce TTR levels in the bloodstream and mitigate protein deposits in tissues.<\/p>\n
The drug received FDA approval in 2023 for the treatment of hereditary transthyretin-mediated polyneuropathy (hATTR-PN), a condition affecting tens of thousands of patients. In contrast, the broader ATTR-CM is estimated to impact between 300,000 and 500,000 individuals worldwide, highlighting the market potential that the Phase 3 trial represented for both Ionis and AstraZeneca, with analysts projecting possible U.S. sales of $4.1 billion.<\/p>\n
The current standard of care for ATTR-CM includes Pfizer’s Vyndaqel and its successor Vyndamax, both of which stabilize TTR by preventing misfolding and deposition in bodily tissues. Additionally, BridgeBio has recently received FDA approval for a next-generation TTR stabilizer, Attruby, while Alnylam Pharmaceuticals has amended the label of Amvuttra, previously approved for hATTR-PN, to include ATTR-CM treatment.<\/p>\n
The Phase 3 trial for Wainua was a placebo-controlled study designed over 140 weeks to measure cardiovascular events. Both companies noted that the drug did not meet its primary objective by this stage. Alnylam’s pivotal trial for a competing product had a longer assessment period of 156 weeks. Following the announcement, Ionis convened a call with analysts, stating no overall benefit for Wainua was observed, and they did not anticipate a longer study period would yield different results.<\/p>\n
Analysts have suggested that an increased use of stabilizers among trial participants may have influenced the results. Data indicated that 57% of participants in both trial arms were already taking a stabilizer at the outset, and 24% began taking one during the trial. This suggests that at any point, 81% of participants were on a stabilizer, potentially masking the effect of Wainua. In comparison, Alnylam’s trial involved a significantly lower proportion of stabilizer use among patients.<\/p>\n
Despite failing to meet the primary endpoint, analysis of predefined subgroups receiving Wainua monotherapy indicated a “nominally significant” result. The companies affirmed that Wainua was well tolerated and exhibited a safety profile consistent with prior trial results. Further data analysis is underway, with findings expected to be presented at the upcoming European Society of Cardiology congress in Munich next month.<\/p>\n
AstraZeneca and Ionis began collaborating on Wainua in 2021, with the two companies sharing marketing duties in the U.S., while AstraZeneca oversees commercialization in other global markets. AstraZeneca is also pursuing a second candidate for ATTR-CM, cliramitug, a monoclonal antibody aimed at depleting TTR deposits, with a Phase 3 study expected to conclude by mid-2027. Physicians have expressed interest in the depleting mechanism, although questions remain regarding which patient populations might best demonstrate efficacy.<\/p>\n
Management at AstraZeneca has indicated they may discuss potential regulatory approval for Wainua based on the nominally significant subgroup results, acknowledging the reduced unmet need in this context. Another option could involve assessing a combination of Wainua and cliramitug, though further exploration is necessary to validate such an approach. The broader implications of the failed trial include both competitive and regulatory considerations, as highlighted by analyst Andrew Berens, who noted that it not only diminishes a competitor for Alnylam’s Amvuttra but also reignites discussions about the relative merits of silencing versus stabilizing therapies.<\/p>\n
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