Luspatercept: known and unknown promises Open Access

The extension of the phase 3 BELIEVE trial, led by Cappellini et al, offers strong evidence for the long-term efficacy and safety of luspatercept (Reblozyl) in treating anemia in patients with transfusion-dependent β-thalassemia (TDT).¹ β-Thalassemia, an inherited blood disorder characterized by reduced β-globin chain synthesis, leads to chronic anemia. Although red blood cell (RBC) transfusions are the primary treatment, they can cause iron overload and related complications, underscoring the need for therapies that enhance RBC production and/or decrease transfusion burden.² Luspatercept, a transforming growth factor β superfamily ligand trap, has emerged as a promising treatment option.³ 

The BELIEVE trial enrolled 336 adult patients with TDT, randomizing them (2:1) to receive either luspatercept (1.0-1.25 mg/kg) or placebo subcutaneously every 21 days. The primary end point, a ≥33% reduction in RBC transfusion burden from baseline over ≥2 RBC units during weeks 13 to 24, was previously reported.³ This long-term study now confirms that luspatercept sustains a reduction in RBC transfusion burden. Specifically, patients in the luspatercept group showed a sustained reduction in RBC transfusion burden from baseline through week 192. A ≥33% reduction in transfusion burden from baseline was observed in 77% of patients over any 12-week interval and 52% over any 24-week interval (see figure panel A). These findings highlight the durable effect of luspatercept in reducing the need for transfusions, a critical outcome for patients often requiring lifelong treatment. Luspatercept treatment led to a sustained decrease in mean serum ferritin concentration over time (at weeks 144 and 192), particularly in patients who experienced a significant decrease (≥33%) in their RBC transfusion burden (see figure panel A). However, this study did not find significant reductions in liver iron concentration at weeks 48 and 96 (see figure panel A). These results were similar to those observed in an independent study, in which luspatercept administration in transfusion-dependent β-thalassemia was associated with increased erythropoietic markers, decreased hepcidin levels, and increased liver iron content.⁴ Although luspatercept has been shown to improve anemia and reduce the need for blood transfusion in many patients with β-thalassemia, not all showed the expected increase in hemoglobin levels or reduction in transfusion burden.^1,4 These studies suggest that luspatercept may necessitate additional drugs for improved erythroid and iron management, as shown in preclinical models.⁵ Moreover, considering that the original application of luspatercept or its therapeutic equivalent, sotatercept, was to increase bone mineral density (BMD), total hip and lumbar spine BMD were analyzed, but no significant differences were observed.^1,6 

In terms of safety, the most common grade 3 or worse treatment-emergent adverse events (TEAEs) in patients receiving luspatercept were anemia (3%), increased liver iron concentration (2%), and bone pain (2%).¹ Serious TEAEs occurred in 23% of patients, and no treatment-related deaths were reported.¹ This safety profile is generally consistent with previous findings and supports the long-term use of luspatercept (see figure panel A).⁴ The manageable safety profile is essential for a chronic condition such as β-thalassemia, in which patients may require treatment for many years.

The study has some limitations.¹ Due to the difference in treatment duration between the luspatercept and placebo groups, comparative analyses between the 2 groups were not performed after week 96.¹ Although this is understandable, it limits the ability to directly compare the long-term effects of luspatercept vs placebo. In addition, although the study reports several significant efficacy and safety outcomes, more detailed data on specific complications of β-thalassemia and their potential mitigation by luspatercept would be beneficial.

Despite the clinical benefits observed with luspatercept in treating anemia in certain hematological disorders, significant gaps remain in our understanding of its precise mechanism of action. Although luspatercept or its therapeutic equivalent, sotatercept, is known to act as a trap ligand binding to and reducing signaling of growth differentiation factor 11, it is unclear whether this is the sole or the primary target mediating its effects (see figure panel B), what receptors are involved in this pathway (see figure panel C), and which cells express these receptors (see figure panel D).^6,7 Furthermore, these compounds have been shown to increase RBC production not only in patients affected by β-thalassemia and myelodysplastic syndromes but also healthy individuals.^3,6,8 In addition, increased RBC synthesis was associated with a paradoxical increase in erythropoietin levels.^4,6 Therefore, we lack a comprehensive understanding of how these drugs increase RBC production (see figure panel E). Identifying additional ligands that may interact with luspatercept and investigating the drug's impact on erythroid cell metabolism in both normal and abnormal erythropoiesis (how the RBC quality improves in ineffective erythropoiesis) are crucial steps toward a more complete understanding of this therapeutic agent. Furthermore, it is unknown whether luspatercept acts directly on erythroid precursor cells or indirectly through interactions with other cells within the bone marrow, its niche, or other cell types (see figure panels D,F). For instance, the intriguing observation of improved ulcer healing in some patients treated with luspatercept⁹ warrants further investigation into the underlying mechanisms and whether this could represent an additional therapeutic benefit of the drug. The role of luspatercept in regulating bone and iron metabolism has also been proposed.^4,6 Finally, the safety profile of luspatercept in pediatric populations has not yet been established (see figure panel G).

Given the clinical success of luspatercept in treating anemia and improving patients’ quality of life, it would be desirable for the pharmaceutical companies responsible for its development and distribution to invest significantly in research aimed at fully elucidating its mechanism of action. A comprehensive understanding of how this drug works, including a complete characterization of its safety profile and the precise pathways it modulates, is essential for optimizing its use and potentially expanding its therapeutic applications.

Despite these limitations, the BELIEVE trial provides strong evidence for the long-term benefits of luspatercept in patients with TDT. The sustained reduction in transfusion burden and the manageable safety profile suggest that luspatercept can address key unmet needs in this patient population. Long-term data are essential for evaluating treatments for chronic conditions such as β-thalassemia, and the results of this study support the use of luspatercept as an effective long-term treatment option. Further research may explore the optimal duration of luspatercept therapy, its effects on long-term complications, and its potential use in combination with other treatments.

Conflict-of-interest disclosure: S.R. reports, over the past 5 years, membership in scientific advisory board for Ionis Pharmaceuticals, MeiraGTx, Vifor, Disc Medicine, and San Rocco Therapeutics; and has served or currently serves a consultant for GlaxoSmithKline, Bristol Myers Squibb, Incyte, Cambridge Healthcare Research, Celgene Corporation, Catenion, First Manhattan Co, Forma Therapeutics, Ghost Tree Capital, Keros Therapeutics, Noble Insight, Protagonist Therapeutics, Sanofi Aventis US, Slingshot Insight, Spexis AG, Techspert, BVF Partners L.P., Rallybio, LLC, venBio Select LLC, ExpertConnect LLC, and LifeSci Capital.