Development of luspatercept to treat ineffective erythropoiesis

Abstract

Luspatercept (Reblozyl) was recently approved for treating patients with transfusion-dependent lower-risk myelodysplastic syndrome (MDS) with ring sideroblasts (RS) and/or SF3B1 mutation who were not eligible for erythropoiesis-stimulating agents (ESAs) or patients for whom those agents failed. Luspatercept acts as an activin receptor type IIB fusion protein ligand trap that targets the altered transforming growth factor beta pathway in MDS, which is associated with impaired terminal erythroid maturation. Treatment with luspatercept results in decreased SMAD signaling, which enables erythroid maturation by means of late-stage erythroblast differentiation and thus improves anemia. ESAs, the current standard first-line therapeutic option for anemic lower-risk patients with MDS, also improve red cell parameters mainly by expanding proliferation of early erythroid progenitor cells. However, erythropoietin (EPO) and its receptor (EPO-R) are also required for survival of late-stage definitive erythroid cells, and they play an essential role in promoting proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. Thus, luspatercept joins the mechanism of ESAs in promoting erythroid maturation. Especially in the subgroup of MDS patients with RS, luspatercept showed high clinical activity for the treatment of anemia in the phase 2 (PACE-MDS) trial and subsequently in the phase 3 (MEDALIST) trial, which resulted in approval by both the US Food and Drug Administration and the European Medicines Agency in April 2020. Additional studies are needed to better understand the mechanism of action and pharmacodynamics of this novel agent in MDS.

Conflict of interest statement

Conflict-of-interest disclosure: A.S.K. received lecture fees from Novartis and Janssen Biotech. P.F. received consulting fees from Celgene. U.P. received grant support from Amgen; lecture fees, grant support, fees for serving on a steering committee, consulting fees, and travel support from Celgene; grant support from Janssen Biotech; grant support from Merck and Novartis; and lecture fees from Novartis.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Putative mechanism of action of luspatercept, a TGF-β superfamily ligand trap, to improve ineffective erythropoiesis. Baso, basophilic erythroblast; BFU-E, burst-forming unit–erythroid; CFU-E, colony-forming unit–erythroid; Erythro, erythrocyte; m, mature; OrthoC, orthochromatic erythroblast; p, primitive; PolyC, polychromatic erythroblast; ProEbl, proerythroblast; Reti, reticulocyte. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 2.

Drug development milestones. BLA, Biologics License Application; EU, European Union; MAA, Marketing Authorization Application; USA, United States of America. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 3.

Luspatercept presumed mechanism of action. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 4.

Regulators of erythropoiesis. EPO-R, EPO receptor. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 5.

Historical overview of MDS-specific new drug registrations in the European Union and the United States. Professional illustration by Patrick Lane, ScEYEnce Studios.