AstraZeneca and Ionis Pharmaceuticals’ data drop divulging more details from its highly watched Phase 3 transthyretin silencer trial “further confuses the picture” for Wainua when combined with the standard of care for ATTR-CM, analysts say.
AstraZeneca and Ionis Pharmaceuticals’ antisense oligonucleotide Wainua has failed a Phase 3 trial of patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) more spectacularly than analysts previously understood based on the data drop earlier this summer.
The previously released findings had already sent shockwaves through the industry, given that analysts had predicted a high approval likelihood for the indication. But the companies did not provide specific figures behind the fail at the time.
Now, data presented at the annual European Society of Cardiology meeting on the TTR silencer has confirmed the flop, reporting a hazard ratio of 1.14—"clearly worse than expected,” Stifel analysts wrote to investors on Friday.
AstraZeneca and Ionis’ presentation reviewed an analysis of patients taking Wainua (eplontersen) and standard of care treatment (Pfizer’s tafamidis/Vyndamax).
While minimal benefit was “largely expected,” Stifel wrote, the hazard ratio represented “an incremental surprise.” The reported hazard ratio of 1.14 means patients had a 14% higher rate of cardiovascular mortality and recurrent clinical events versus the comparator arm.
The Wainua trial, CARDIO-TTRansform, did demonstrate a “very respectable benefit” when used as a monotherapy, however, according to Stifel. Specifically, there was a 29% improvement in cardiovascular events for patients receiving Wainua by itself. This suggests potential safety signals for Wainua combined with an antisense oligonucleotide–stabilizer, Oppenheimer analysts wrote in a Friday note.
Both analyst firms questioned the difference in outcomes for CARDIO-TTransform and HELIOS-B, the Phase 3 study of Alnylam’s Amvuttra (vutrisiran), an RNAi silencer approved to treat ATTR-CM, as well as hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).
TTR knockdown was about 10% less in CARDIO-TTRansform versus HELIOS-B. Meanwhile, Wainua’s placebo-adjusted impact on a six-meter walk test at 30 months was “far less robust” than Amvuttra monotherapy, indicating that the Alnylam asset “provides a greater benefit on functional outcomes,” Oppenheimer said.
While the Wainua arm had a similar 6.4% rate of treatment discontinuations due to adverse events as compared to placebo, that’s more than double Amvuttra’s 3% AE-related discontinuation rate seen in HELIOS-B.
Stifel said the full readout “makes it hard” for the analyst to see a path toward approval for Ionis and AstraZeneca. The analysts don’t think the Wainua data will bleed through to commercially impact Alnylam’s Amvuttra market performance but said the company could still make multiple pivots for its late-stage next-generation RNAi therapeutic nucresiran, which is currently being assessed in a Phase 3 AATR study called TRITON-CM.
“The fact that the CARDIO-TTransform data are so negative for the combo (they are unequivocal) could further embolden ALNY to make changes sooner, which would be good for the stock since this is what investors want,” Stifel wrote. The analyst said Alnylam could direct further enrollment toward monotherapy and make results from that group the primary outcome. The current assumption is that most of the patients already recruited are on background tafamidis, according to Oppenheimer.
The new data suggest that oral stabilizers from BridgeBio and Pfizer remain the preferred first-line option for ATTR-CM, Jefferies said Friday. BridgeBio followed Pfizer’s tafamidis to market, receiving an FDA nod for Attruby (acoramidis) in 2024.
