Antisense therapeutic AstraZeneca and Ionis Pharmaceuticals drug Wainua did not demonstrate a significant cardiovascular advantage in a Phase 3 trial of patients with transthyretin-mediated amyloid cardiomyopathy.
The companies didn’t provide specific data in their news release, 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 note Thursday. That the study here would be expected to work, the firm added, because we do know that TTR silencers are effective. A June 25 note from H.C. Wainwright gave a “75% probability of approval” for Wainua in transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).
The disappointing result was “obviously a negative” for the biotech, Stifel said Thursday, and was “a key valuation driver” for Wainua in ATTR-CM. Ionis is down 20% in premarket U.S. trading, while AstraZeneca took a 9% hit on the British stock exchange.
The partners will do a complete review of the results and present the results at an upcoming medical congress next month.
Wainua is currently approved for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR-PN) associated with polyneuropathy, first approved in December 2023. 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 used CARDIO-TTRansform as an assessment tool to evaluate the therapeutic potential of Wainua in patients with ATTR-CM. More than 1,400 patients were available for standard of care and were then randomized to add on Wainua or placebo.
AstraZeneca and Ionis did not disclose plans for the next steps in the regulatory journey of Wainua in ATTR-CM. But, in its note, Stifel said that “approaching regulators here on these data would seem like a stretch.”
The poor outcome of CARDIO-TTRansform follows BridgeBio last week reporting posthoc data indicating kidney protection was maintained in patients with ATTR-CM treated with its transthyretin stabilizer Attruby—a feature that analysts noted may help BridgeBio stand out from other therapies in the area. BridgeBio is trading 10% higher in pre-market trading Thursday.
The kidney benefit “provides differentiation” to Attruby, Jefferies wrote in a July 2 note, and the amount of renal benefits “seems competitive to kidney-targeted therapies.”
Jefferies noted that the cardiorenal protection appears to be independent of other drugs, like Pfizer’s Vyndaqel/Vyndamax. Finally, slowing kidney progression would have beneficial implications for hospitalization/mortality outcomes.
For one of the other key players, Alnylam, which sells Amvuttra for ATTR-CM, the failure of the Ionis/AstraZeneca trial is “absolutely the most complicated possible outcome,” wrote Stifel.
The analysts, on the other hand, said that “not launching [Wainua] in TTR-CM in 2027 is likely to be a key positive surprise for vutrisiran.” But Alnylam has another product under trial, nucresiran, for the disease, in Phase 3. As was the case with AstraZeneca and Ionis, patients should be on background therapy during the trial, for which Stifel says he has been waiting to see “for the purposes of affirming this combo synergy.”
Ionis and AstraZeneca have encountered a major clinical setback after their investigational therapy for transthyretin amyloid cardiomyopathy (ATTR-CM) failed to meet the primary endpoints in a Phase 3 clinical trial. The outcome represents a significant challenge for Ionis as the company evaluates the study findings and considers the future direction of the development program.
Phase 3 Trial Falls Short
The Phase 3 study was designed to assess the safety and effectiveness of the investigational ATTR-CM treatment in patients living with the progressive heart condition. While the therapy showed promise during earlier stages of development, Ionis announced that the trial did not achieve its primary objectives.
The disappointing results highlight the complexity of developing innovative therapies for cardiovascular diseases.
Impact on Ionis and AstraZeneca
The unsuccessful trial is expected to influence the development strategy for both companies. For Ionis, the outcome may require additional analysis of clinical data to determine whether specific patient groups or alternative study designs could still demonstrate meaningful benefits.
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