P56 SURVIVAL BENEFIT OF BIRTAMIMAB IN MAYO STAGE IV AL AMYLOIDOSIS IN THE PHASE 3 VITAL STUDY WAS CONSISTENT ACROSS ALL KEY BASELINE VARIABLES (2023)

Introduction: Amyloid light chain (AL) amyloidosis – a progressive disorder caused by misfolded light chains (LCs) that aggregate and deposit in vital organs – is associated with high mortality, poor quality of life, and increased healthcare costs, particularly in newly diagnosed patients (pts) with advanced disease (Mayo 2012 Stage IV, median overall survival [OS] <6 months [mos]). Birtamimab is an investigational humanized monoclonal antibody that directly binds a conserved epitope on κ and λ LCs and is designed to neutralize circulating soluble and deplete deposited insoluble amyloid by promoting phagocytic clearance. In 2018, the Phase 3 VITAL study – a multicenter, global, randomized, double-blind, placebo (PBO)-controlled study (NCT02312206) conducted in newly diagnosed, treatment-naïve pts with AL amyloidosis and cardiac involvement – was terminated per a futility analysis of the primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization ≥91 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over PBO + SOC (0.826 [95% confidence interval (CI): 0.574,1.189]). Post hoc analysis of ACM over 9 mos revealed a significant survival benefit (HR=0.413 [95% CI: 0.191,0.895]) in pts at high risk for early death (ie Mayo 2012 Stage IV). Here we report the results of ACM sensitivity analyses in the subgroup of pts with Mayo 2012 Stage IV AL amyloidosis, adjusting for key baseline variables. Methods: For ACM, the HR and 90% two-sided CIs were estimated from the semi-parametric Cox Regression model stratified by randomization strata (ie Mayo Stage I/II vs III/IV, renal stage I vs II/III, and 6-minute walk test [6MWT] distance). Separately, key baseline variables were added to the Cox Regression model to evaluate the impact on OS benefit. All adjudicated deaths before 9 mos were included in the analysis. Pts who had no events were censored at 9 mos. Results: Of the 260 pts enrolled in the VITAL study, 77 (29.6%) were characterized as Mayo 2012 Stage IV at baseline, 38 randomized to birtamimab + SOC, and 39 to PBO + SOC. Pts had a median age of 64 years and were primarily white (93.5%) and male (68.8%). Baseline demographic and clinical characteristics were generally balanced between Mayo Stage IV pt treatment groups. After adjusting for key baseline demographic, clinical, and laboratory variables, the HRs with each of the baseline variables added separately to the Cox Regression model ranged from 0.336 to 0.465, with all the upper bounds of the 90% CIs <1 (Figure). Consistent with previous studies, birtamimab was generally well tolerated in Mayo Stage IV pts. Conclusions: Birtamimab is the only investigational therapeutic that has shown a significant survival benefit in Mayo Stage IV AL amyloidosis pts. The survival benefit of birtamimab was consistent across all key baseline variables, including demographic factors (age, sex, race, ethnicity), clinical characteristics (age at diagnosis, duration since diagnosis, NYHA class, 6MWT distance), and laboratory parameters (NT-proBNP, dFLC, FLC, troponin-T), reinforcing the strength of the survival data in Mayo Stage IV pts. The AFFIRM-AL study (NCT04973137), designed to confirm the VITAL study results in Mayo Stage IV AL amyloidosis pts, is currently being conducted under a Special Protocol Assessment agreement with the US FDA with α=0.10 for the primary endpoint of ACM. This study is active and enrolling.