Morie A Gertz, MD, MACP from the Division of Hematology, Department of Internal Medicine, Mayo Clinic speaks about the ASH 2021 Abstract – 2754 Birtamimab in Patients with Mayo Stage IV AL Amyloidosis: Rationale for Confirmatory Affirm-AL Phase 3 Study Design.
Link to Abstract:
https://ash.confex.com/ash/2021/webprogram/Paper146076.html
Background:
Light chain (AL) amyloidosis is a rare, deadly hematologic condition characterized by misfolded AL protein produced by plasma cells, culminating in amyloid deposits in tissues and organs, causing organ malfunction and failure. Birtamimab is an experimental monoclonal antibody that neutralizes circulating soluble amyloid and deposited insoluble amyloid, allowing amyloid deposits to be phagocytized and cleared. The global phase 3 VITAL study in newly diagnosed, treatment-naive patients was halted in 2018 due to 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 (0.835, 95 percent CI 0.5799, 1.2011; In a subgroup of patients at high risk for early mortality, a post hoc analysis of ACM over 9 months demonstrated a significant survival benefit (HR=0.413, 95 percent CI 0.191, 0.895; p=0.025; Figure) (Mayo stage IV). At 9 months, the percentage of surviving patients in the birtamimab + SOC and placebo + SOC groups were 74 percent and 49 percent, respectively. At 9 months, post hoc analyses of secondary endpoints in this subgroup confirmed the clinical and functional benefits of birtamimab + SOC, with clinically meaningful improvements in health-related quality of life (as measured by the 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance (both nominal p0.05). There were no drug-related deaths, dose-limiting toxicities, or severe hazards in any of the birtamimab clinical trials.
The goal of this study was to compare the efficacy and safety of birtamimab + SOC against placebo + SOC in Mayo stage IV patients with AL amyloidosis over a 9-month period.
Methods:
Up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis will be included in the phase 3, double-blind, placebo-controlled AFFIRM-AL research. Every 28 days, patients will receive either 24 mg/kg intravenous birtamimab or placebo (both arms will also receive SOC, defined as concomitant chemotherapy with a first-line bortezomib-containing regimen). Patients will be randomly randomized 2:1 to birtamimab or placebo and stratified based on their 6MWT distance (300 meters versus 300 meters) at randomization. Using a log-rank test, the primary effectiveness outcome of AFFIRM-AL is time to ACM. Changes in SF-36v2 and 6MWT distance from baseline to month 9 are secondary objectives. Adverse events, clinical laboratory findings, and immunogenicity analyses are all examples of safety endpoints. When 50% of the events have happened, an interim efficacy analysis will be conducted.
Results:
The phase 3 AFFIRM-AL research is being conducted under a Special Protocol Assessment agreement with the US FDA to confirm the >50% relative risk reduction for ACM seen in the post hoc analysis of VITAL for the AL amyloidosis subset of patients with Mayo stage IV illness.
Conclusion/Summary:
Because the median overall life for people with Mayo stage IV illness is roughly 6-9 months, effective treatments to increase survival in AL amyloidosis are essential, particularly for patients with severe cardiac involvement. In a post hoc subgroup analysis of VITAL in patients with AL amyloidosis and advanced cardiac involvement, birtamimab was the only experimental treatment that showed a survival advantage. The first phase of AFFIRM-AL is expected to begin in mid-2021. (NCT04973137)