Birtamimab in AL Amyloidosis: A Comprehensive Analysis of a Promising Amyloid Depleter from Post-Hoc Signal to Confirmatory Trial Failure

Executive Summary

Birtamimab (formerly NEOD001) is an investigational humanized IgG1 monoclonal antibody developed by Prothena Corporation for the treatment of light chain (AL) amyloidosis. The therapeutic was designed based on a compelling scientific rationale: to directly target and clear pathological amyloid deposits from vital organs, a mechanism complementary to standard-of-care therapies that only halt the production of new amyloidogenic proteins. This approach held particular promise for patients with advanced, Mayo Stage IV disease, for whom existing organ damage is the primary driver of a grim prognosis.

Birtamimab’s clinical development was a dramatic and ultimately cautionary tale. The initial Phase 3 VITAL trial was terminated early in 2018 for futility, as it failed to demonstrate a benefit in the broad population of AL amyloidosis patients. However, a subsequent post-hoc analysis of a small subgroup of Mayo Stage IV patients within VITAL revealed a striking and statistically significant survival benefit, prompting Prothena to resurrect the program in 2021. This led to the design of the confirmatory Phase 3 AFFIRM-AL trial, which focused exclusively on this high-risk patient population and was conducted under a Special Protocol Assessment with the U.S. Food and Drug Administration (FDA).

In May 2025, the AFFIRM-AL trial definitively failed, meeting neither its primary endpoint of improving all-cause mortality nor any of its secondary endpoints. The hazard ratio for mortality was near unity, indicating a complete lack of efficacy. In contrast to its efficacy failure, Birtamimab consistently demonstrated a favorable safety and tolerability profile across all clinical trials, with adverse event rates comparable to placebo.