Survival benefit observed with Birtamimab in Mayo Stage IV AL amyloidosis supports initiation of confirmatory AFFIRM-AL phase 3 study

Background Light chain (AL) amyloidosis is a rare and typically fatal disorder caused by misfolded AL protein, resulting in amyloid deposits in tissues that cause organ dysfunction and failure, most commonly in the heart and kidneys. Birtamimab is an investigational monoclonal antibody designed to indirectly promote phagocytic clearance of amyloid deposits. The phase 3 VITAL study was terminated based on a futility analysis of the composite primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization >90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (HR: 0.835, 95% CI: 0.5799, 1.2011; p=0.330). Post hoc analysis of ACM over 9 months revealed a pronounced survival benefit (HR: 0.413, 95% CI: 0.191, 0.895; p=0.025) in patients at high risk for early mortality (Mayo stage IV); proportions of surviving patients were 74% (birtamimab + SOC) and 49% (placebo + SOC). Across all birtamimab trials, no drug-related deaths, dose-limiting toxicities, or major risks were identified. Birtamimab + SOC will provide significant clinical benefit for Mayo stage IV patients with AL amyloidosis versus placebo + SOC (ie, concomitant chemotherapy with a first-line bortezomib-containing regimen). Methods The phase 3, double-blind, placebo-controlled AFFIRM-AL study will enroll up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis with cardiac involvement. Patients will be randomized 2:1 to receive either intravenous birtamimab + SOC or placebo + SOC. The primary efficacy endpoint of AFFIRM-AL is time to ACM. Safety endpoints include adverse events, clinical laboratory observations, and immunogenicity analyses. Results The phase 3 AFFIRM-AL study is designed to confirm this effect of birtamimab under a Special Protocol Assessment agreement with the US FDA. If the study is positive, it would confirm the >50% relative risk reduction for ACM in Mayo stage IV disease observed over 9 months with birtamimab in VITAL. Conclusions Birtamimab is the only investigational therapeutic in which a survival benefit has been observed in a post hoc analysis of patients with AL amyloidosis with cardiac involvement. AFFIRM-AL is initiating mid-2021.