The use of luspatercept for thalassemia in adults

Abstract

Luspatercept is an activin receptor ligand trap that has been shown to enhance late-stage erythropoiesis in animal models of β-thalassemia. A multicenter, international, phase 2 dose-finding study was initiated in adult patients with β-thalassemia, either non-transfusion-dependent thalassemia (NTDT) or transfusion-dependent thalassemia (TDT). Positive results of the phase 2 study paved the way to a randomized phase 3 clinical trial (BELIEVE) to assess the efficacy and safety of luspatercept. The BELIEVE trial is a randomized, double-blind, placebo-controlled phase 3 trial. Three hundred thirty-six patients aged ≥18 years with TDT (regularly transfused, 6-20 red blood cell units within 24 weeks before randomization) were included in the trial. Patients received luspatercept or placebo subcutaneously every 21 days for ≥48 weeks and best supportive care. Forty-eight of 224 patients (21.4%) in the luspatercept group achieved the primary end points (≥33% reduction in transfusion burden) compared with those in the placebo group (4.5%; P < .001). Moreover, more patients had a ≥33% reduction in transfusion burden during any rolling 12-week interval (70.5% vs 29.5%) or any 24-week interval (41.1% vs 2.7%) with luspatercept than with the placebo. Transfusion independence was achieved by 11% of patients in the luspatercept group. Transient adverse events were more frequent with luspatercept than with placebo, but were manageable. Luspatercept was approved by the US Food and Drug Administration in 2019 and by the European Medicines Agency in 2020. The luspatercept trial is registered on www.clinicaltrials.gov at #NCT01749540 and the BELIEVE trial at #NCT02604433.

Figure 1.

Current understanding of the mechanism of action of luspatercept. The SMAD-2/3 signaling pathway is the target of activin receptor ligand trap molecules. Members of the TGF-β superfamily ligand binding lead to the multimerization of type 1 and 2 receptors. Upon the activation of the type 1 receptor, phosphorylation of SMAD-2 and SMAD-3 takes place. Luspatercept prevents the binding of the ligand, thus inhibiting this pathway and promoting late-stage erythropoiesis.

Figure 2.

Percentage of patients who had a reduction in the transfusion burden of at least 33% or at least 50% from baseline. Reductions in the transfusion burden (defined as the total number of red-cell units transfused in a specified time interval) were assessed in the intention-to-treat population. (A) The percentages of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 (primary end point), during weeks 37 through 48 (first key secondary end point), and during any 12-week or 24-week interval. (B) The percentages of patients who had a reduction in the transfusion burden of at least 50% from baseline during weeks 13 through 24 (second key secondary end point), during weeks 37 through 48 (third key secondary end point), and during any 12-week or 24-week interval. A reduction of at least 2 red-cell units over the fixed and nonfixed 12-week intervals was also required for those end points. To control for multiple comparisons, key secondary end points were evaluated in sequential order once the primary efficacy analysis had shown statistical significance. Reprinted with permission from Cappellini et al.²⁴ Copyright © 2020 Massachusetts Medical Society.

Figure 3.

Swimmer plot of response periods for patients who had a reduction in the transfusion burden of at least 50% from baseline during any 12-week interval in the intention-to-treat population. Each row (swim lane) on the y-axis represents an individual patient in the luspatercept group (A) or the placebo group (B). A response period was defined as a continuous period in which a patient had a reduction in the transfusion burden of at least 50% from baseline during any 12-week interval. Different response periods may have overlapped. All patients received best supportive care in addition to luspatercept or placebo. Reprinted with permission from Cappellini et al.²⁴ Copyright © 2020 Massachusetts Medical Society.

Figure 4.

Kaplan-Meier plot of duration of response in responding patients achieving ≥33% transfusion reduction (any 12-week interval), ≥50% transfusion reduction (any 12-week interval), and transfusion independence (any ≥8-week interval). Only patients who achieved an erythroid response were included in the Kaplan–Meier analyses. Transfusion reduction was defined as ≥33% (A) or ≥50% (B) reduction in total RBC units from baseline (12 weeks prior to randomization) and ≥2 RBC units in any consecutive 12-week intervals throughout the study period. (C) Transfusion independence was defined as the absence of any transfusion during any consecutive 8-week intervals throughout the study period. BSC denotes best supportive care, RBC red blood cell. Reprinted with permission from Cappellini et al.²⁴ Copyright © 2020 Massachusetts Medical Society.