The late-stage miss is “surprising,” Stifel analysts said, given that Wainua’s mechanism of silencing transthyretin protein expression has previously proven effective.
AstraZeneca and Ionis Pharmaceuticals’ antisense therapeutic Wainua failed to show significant cardiovascular benefit in a Phase 3 study of patients with transthyretin-mediated amyloid cardiomyopathy.
The companies didn’t provide specific data in their news release Thursday morning, revealing only that Wainua, when added to standard of care, “did not meet the primary efficacy endpoint,” which was a composite of cardiovascular (CV) mortality and recurrent CV clinical events vs. placebo after up to 140 weeks of follow-up.
The failure is “surprising,” Stifel analysts told investors in a Thursday note. “The study here was expected to work since we know TTR [transthyretin] silencers are effective,” the firm added. H.C. Wainwright, in a June 25 note, ascribed a “75% probability of approval” for Wainua in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).
Wainua in ATTR-CM was “a key valuation driver” for Ionis, Stifel noted Thursday, adding that the disappointing outcome is “obviously a negative” for the biotech. Ionis is down 20% in premarket U.S. trading, while AstraZeneca took a 9% hit on the British stock exchange.
The partners will conduct a full analysis of the results and present their findings at an upcoming medical congress next month.
Wainua was first approved in December 2023 for the treatment of polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (hATTR-PN). The drug was originally discovered and developed by Ionis and came to AstraZeneca in December 2021 when the pharma dropped $200 million upfront for the right to jointly advance and commercialize the product. This deal also included a $485 million payment upon regulatory approvals and up to $2.9 billion in sales-related milestones, plus royalties.
The companies ran CARDIO-TTRansform to assess the therapeutic value of Wainua in patients with ATTR-CM. The trial enrolled more than 1,400 patients who were already receiving available standard of care, and who were then randomly assigned to receive add-on Wainua or placebo.
AstraZeneca and Ionis on Thursday made no mention of their regulatory strategy going forward for Wainua in ATTR-CM. However, Stifel in its note said that “trying to approach regulators here on these data would seem like a stretch.”
CARDIO-TTRansform’s disappointing result comes after BridgeBio last week released posthoc data suggesting that its transthyretin stabilizer Attruby preserved kidney function in patients with ATTR-CM—a benefit that analysts say could set it apart from other therapies in this space. BridgeBio is up nearly 10% in pre-market trading Thursday.
The kidney benefit “adds differentiation” to Attruby, Jefferies said in a July 2 note, adding that the magnitude of renal improvements even “looks competitive to kidney-targeted therapies.
“Cardiorenal protective effects seem distinct from other therapies,” Jefferies added, pointing to Pfizer’s Vyndaqel/Vyndamax. “Ultimately, slowing down kidney progression could improve hospitalization/mortality outcomes.”
Meanwhile, the failure of Ionis and AstraZeneca’s trial is “absolutely the most complicated possible outcome” for another key competitor, Alnylam, which markets Amvuttra for ATTR-CM, Stifel wrote.
On the one hand, “not having [Wainua] launch in TTR-CM in 2027 should represent a significant tailwind for vutrisiran relative to expectations,” the analysts wrote. However, Alnylam has another asset, nucresiran, in Phase 3 trials for the disease. The general expectation is that patients in Alnylam’s trial will be on background therapy, as was the case for AstraZeneca and Ionis’ trial, which Stifel said it had been watching for “to affirm this combo synergy.”
Alnylam shares were up nearly 18% in premarket trading on Thursday.
