Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN.
Abramson Cancer Center, The Hospital of the University of Pennsylvania, Philadelphia, PA.
Blood. 2023 Oct 5;142(14):1208-1218. doi: 10.1182/blood.2022019406.
Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.
淀粉样轻链 (AL) 淀粉样变性是一种罕见的、通常致命的疾病，其特征是错误折叠的免疫球蛋白轻链 (LC) 的积累。Birtamimab 是一种研究性的人源化单克隆抗体，旨在中和有毒的 LC 聚集体，并通过巨噬细胞诱导的吞噬作用耗尽不可溶性器官沉积的淀粉样蛋白。VITAL 是一项评估 birtamimab+标准治疗 (SOC) 在 260 例新诊断、未经治疗的 AL 淀粉样变性患者中的疗效和安全性的 3 期随机、双盲、安慰剂对照临床试验。患者每 28 天接受 24mg/kg IV birtamimab+SOC 或安慰剂+SOC。主要复合终点是首次研究药物输注后全因死亡率 (ACM) 或中心裁决的心脏住院≥91 天的时间。在中期无效分析后提前终止试验；主要复合终点无显著差异（风险比 [HR]，0.826；95%置信区间 [CI]，0.574-1.189；对数秩 P=.303）。对 Mayo 分期 IV AL 淀粉样变性患者的事后分析显示，在 ACM 时间方面，birtamimab 有显著改善，9 个月时 HR 为 0.413（95%CI，0.191-0.895；对数秩 P=.021）。9 个月时，接受 birtamimab 治疗的 Mayo 分期 IV AL 淀粉样变性患者中 74%存活，而接受安慰剂的患者中 49%存活。总体而言，治疗出现的不良事件 (TEAE) 和严重 TEAEs 的发生率在治疗组之间通常相似。目前正在招募一项在 Mayo 分期 IV AL 淀粉样变性患者中进行的 birtamimab 的 3 期随机、双盲、安慰剂对照临床试验（AFFIRM-AL；NCT04973137）。VITAL 试验在 www.clinicaltrials.gov 上注册为 #NCT02312206。
