Luspatercept induces clinically significant and sustained improvements of anaemia in adults with non-transfusion dependent thalassaemia

At EHA 2021, the first results of the phase II BEYOND study, evaluating luspatercept in adult patients with non-transfusion dependent (NTD) β-thalassemia, were presented. Results demonstrated that 77.1% of patients treated with luspatercept achieved a haemoglobin (Hb) increase of at least 1.0 g/dL compared to 0% of patients in the placebo arm. Furthermore, luspatercept improved the quality of life of patients and was correlated with increases in Hb levels.

Β-thalassaemia is a hereditary blood disorder characterised by impaired Hb production and chronic anaemia of varying severity. An imbalance in α- and β-chains leads to ineffective erythropoiesis and can cause anaemia and iron overload. Tailored red blood cell (RBC) transfusions, iron chelation therapy (ICT) and novel therapies target key pathophysiologic mechanisms in transfusion dependent thalassaemia (TDT) and non-transfusion dependent thalassaemia (NTDT). Patients with NTDT do not require lifelong regular RBC transfusions for survival, however, they may require occasional RBC transfusions during surgery or infections. Patients with NTDT with baseline haemoglobin (Hb) levels ≥10 g/dL have significantly longer morbidity-free survival than patients with <10 g/dL (p< 0.001). Unfortunately, there are currently no effective management options for anaemia in patients with NTDT. Luspatercept is a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to diminish Smad2/3 signalling and enhance late-stage erythropoiesis. While luspatercept previously proved its worth in patients with TDT (BELIEVE study), the BEYOND study now aims to assess the safety and efficacy of luspatercept vs. placebo in adult patients with NTDT.

BEYOND study design

In this phase II, multicentre, double-blind, placebo-controlled trial, 145 patients with NTDT were randomised (2:1) to luspatercept 1 mg/kg (titration up to 1.25 mg/kg) or placebo subcutaneously every 3 weeks for ≥48 weeks. Patients in both arms continued to receive best supportive care, including sporadic RBC transfusions and iron chelation therapy. Primary endpoint of the study was the achievement of ≥1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval during weeks 13-24 in the absence of RBC transfusions. Demographic and baseline characteristics were well balanced between both arms, with approximately 60% of patients with baseline Hb levels below 8.5 g/dL.

Increase in haemoglobin levels

In total, 74 patients (77.1%) in the luspatercept arm achieved a mean Hb increase of at least 1.0 g/dL from baseline over a continuous 12-week interval during weeks 13-24 in the absence of RBC transfusions (p< 0.0001). In contrast, none of the patients in the placebo arm obtained this endpoint. In total, 52.1% of patients receiving luspatercept achieved a mean Hb increase of at least 1.5 g/dL. Regardless of patients’ splenectomy status, gender, baseline Hb levels, baseline NTDT-PRO tiredness and weakness (T/W) domain score, and β-thalassemia genotype, achievement of mean Hb increase from baseline to weeks 13-24 in the absence of RBC transfusions was in favour of luspatercept. In addition, change from baseline in NTDT-PRO T/W scores in luspatercept vs. placebo arms were −0.92 vs. −0.47 (least squares mean difference [LSMD] −0.48, p= 0.0924) at weeks 13–24 and −1.00 vs. −0.16 (LSMD −0.79, p= 0.051) at weeks 37–48, respectively. Interestingly, this improvement in quality of life was correlated with the Hb increase (R= -0.29, p< 2.2 x 10^-16). Mean change from baseline in NTDT-PRO T/W score by visit demonstrated a gradual and consistent improvement in the luspatercept group, which was maintained through week 78. Finally, 89.6% of patients in the luspatercept arm remained transfusion-free at weeks 1–24 vs. 67.3% placebo patients (p= 0.0013).

The most common treatment-emergent adverse events (TEAEs) occurring in at least 5% of patients were bone pain (36.5% in the luspatercept arm vs. 6.1% in the placebo arm), headache (30.2% vs. 20.4%), and arthralgia (29.2% vs. 14.3%). No deaths were reported. Finally, no malignancies or thromboembolic events were reported in patients treated with luspatercept.

Conclusion

In the BEYOND study, treatment with luspatercept resulted in a clinically significant and sustained improvement of anaemia in adults with NTDT, as measured by Hb levels, with 52.1% of patients receiving luspatercept achieving and maintaining a mean Hb increase of at least 1.5 g/dL. Furthermore, improvement in quality of life, favoured luspatercept and was correlated with increases in Hb levels. Finally, luspatercept was well tolerated over a prolonged period of time.

Reference

Taher A, et al. The BEYOND study: results of a phase 2, double-blind, randomized, placebo-controlled multicenter study of luspatercept in adult patients with non-transfusion dependent beta-thalassemia. Presented at EHA 2021; abstract S101.