The transthyretin amyloidosis (ATTR) drug development field experienced significant disruption in July when AstraZeneca and Ionis Pharmaceuticals’ antisense drug Wainua failed to demonstrate a cardiovascular benefit in a Phase 3 trial for transthyretin amyloid cardiomyopathy (ATTR-CM), according to an Aug. 3 announcement. The result has created uncertainty for other developers with similar therapies while providing opportunities for those exploring alternative approaches.
Wainua, already approved for treating transthyretin amyloid polyneuropathy (ATTR-PN), was expected to expand its reach into the larger ATTR-CM market. Faisal Khurshid, managing director of biotechnology equity research at Jefferies, said in an email that "the same biology manifests very differently depending on where the amyloid is causing the most damage." He added, “A drug can be mechanistically rational across ATTR but still show very different clinical results depending on the organ involved, baseline disease stage, endpoint sensitivity, and background therapy.”
Following Wainua’s setback, several companies are advancing their own candidates. AstraZeneca continues development of cliramitug—an investigational antibody targeting cardiac amyloid clumps—with a Phase 3 placebo-controlled DepleTTR-CM trial underway and nearly 1,200 patients enrolled. Novo Nordisk is also moving forward with coramitug after acquiring Prothena Corp.’s ATTR business; its CLEOPATTRA Phase 3 study is recruiting patients following promising reductions in NT-proBNP levels observed during Phase 2 testing.
Alnylam’s RNA interference therapy nucresiran remains under investigation despite questions raised by Wainua’s failure about whether such silencers can provide sufficient benefit in ATTR-CM patients already receiving stabilizer therapy. Alnylam aims to launch nucresiran for ATTR-PN by 2028 and for ATTR-CM by 2030 while continuing studies on Amvuttra—a product approved first for hereditary ATTR-PN and later for ATTR-CM.
Intellia Therapeutics is taking a gene therapy approach with nexiguran ziclumeran (nex-z). While early data showed sustained reduction of serum transthyretin levels after one-time infusion, safety concerns led to temporary FDA holds due to elevated liver enzymes requiring protocol adjustments and stricter monitoring before trials resumed.
BridgeBio has seen potential benefits from reduced competition following Wainua’s failure. Its oral stabilizer acoramidis (Attruby) was approved in 2024 for ATTR-CM and recently demonstrated reduced cardiovascular hospitalizations compared with Pfizer’s Vyndaqel/Vyndamax during follow-on analysis of its Phase 3 trial. BridgeBio continues studying Attruby as both treatment and prevention among asymptomatic carriers of pathogenic mutations.
