Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial

Author(s): Morie A. Gertz1; Adam D. Cohen2; Raymond L. Comenzo3; Efstathios Kastritis4; Heather J. Landau5; Edward N. Libby6,7; Michaela Liedtke8; Vaishali Sanchorawala9; Stefan Schönland10; Ashutosh Wechalekar11; Jeffrey A. Zonder12; Giovanni Palladini13,14; Jackie Walling15; Spencer Guthrie15; Christie Nie15; Carol Karp15; Yuying Jin15; Gene G. Kinney15; Giampaolo Merlini13,14
Source: Blood (2023) 142 (14): 1208–1218
Original Article
Professional photo of Maem Hussein, MD

Dr. Maen Hussein's Thoughts

Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. Per this study, it was effective in Mayo stage 4 amyloidosis. It is a rare disease, but at least now it has a possible option.

KEY POINTS

The VITAL study of birtamimab in all stages of newly diagnosed AL amyloidosis was discontinued early per futility analysis. Birtamimab improved post hoc ACM in patients with Mayo stage IV AL amyloidosis with cardiac involvement, who are at high risk of early death.

VISUAL ABSTRACT

ABSTRACT

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.

Author Affiliations

1Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN; 2Abramson Cancer Center, The Hospital of the University of Pennsylvania, Philadelphia, PA; 3Divison of Hematology and Oncology, Tufts Medical Center, Boston, MA; 4Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 5Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY; 6Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA; 7Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; 8Stanford Cancer Institute, Stanford, CA; 9Amyloidosis Center, Boston University School of Medicine, Boston, MA; 10Medical Department V, Amyloidosis Center, Universitätsklinikum Heidelberg, Heidelberg, Germany; 11Division of Medicine, National Amyloidosis Centre, University College of London, Royal Free Hospital, London, United Kingdom; 12Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI; 13Department of Molecular Medicine, University of Pavia, Pavia, Italy; 14Amyloidosis Research and Treatment Center, Fondazione IRCCS, Policlinico San Matteo, Pavia, Italy; 15Prothena Biosciences Inc, South San Francisco, CA

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