Beta-thalassemia is a hereditary blood disease in which a defect in globin chain synthesis production leads to ineffective production of red blood cells (RBCs) and anaemia.1 Beta-thalassemia is common in the Mediterranean region, South-East Asia, the Indian subcontinent and the Middle East and has now become a global problem, spreading to much of Europe, America and Australia owing to migration of people from these regions. Approximately 1.5% of the global population are carriers of beta-thalassemia.2
Patients with transfusion-dependent beta-thalassemia require regular, lifelong RBC transfusions (every 2–4 weeks) and iron chelation therapy.3 Patients also need to undergo regular blood tests such as complete blood counts, iron studies; and tests for heart, kidney, and liver function. Repeated blood transfusions carry the risk of infections4 and lead to accumulation of iron which, if not removed by daily iron chelation, can lead to organ damage and death.5 The long-term management of this disease presents a substantial burden to patients in terms of healthcare visits and quality of life.6,7 Improved survival due to advances in disease management means that patients are exposed to the harmful effects of ineffective erythropoiesis, anaemia, and iron overload for longer durations, and new or more frequent complications are being reported in adult patients.8 Apart from bone marrow transplantation, which is available only to a minority of patients due to a lack of human leukocyte antigen-matched donors as well as financial constraints in developing countries, there are no curative treatment options. Therefore, there is a need for new treatment options for patients with beta thalassemia.
Luspatercept is a first-in-class erythroid maturation agent that is in clinical development by Acceleron (Cambridge, MA, US) and Celgene (Summit, NJ, US) for the treatment of adult patients with beta-thalassemia or myelodysplastic syndrome-associated anaemia. It binds to select transforming growth factor beta (TGFβ) superfamily ligands to reduce abnormal Smad 2/3 signalling and enhance late-stage RBC maturation.9 Data from a phase II study has shown that luspatercept improves haemoglobin levels and blood transfusion requirements in patients with beta-thalassemia.10
Results from the BELIEVE study were presented at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, CA.11 BELIEVE was a phase III clinical trial involving 336 patients aged ≥18 years who had beta-thalassemia or haemoglobin E/beta‑thalassemia and who required regular RBC transfusions (defined as: 6–20 RBC units in the 24 weeks prior to randomisation with no ≥35-day transfusion-free period during that time). These were randomly assigned 2:1 to receive luspatercept, at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for at least 48 weeks. Patients in both treatment groups continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline haemoglobin level. Patients were followed over 48 weeks, with investigators monitoring the number of units of blood that each study participant required. Patients had received a median of 6 RBC units in the 12 weeks prior to treatment.11
By the final quarter of the trial follow-up period (weeks 37–48), 19.6% of patients were able to reduce their number of transfusion units by at least one-third, compared with 3.6% of patients receiving placebo (p<0.0001), and 10.3% of patients had reduced their number of transfusion units by at least half, compared with 0.9% of patients receiving placebo (p=0.0017). A secondary endpoint, which captured a rolling response over 12-week periods, provided the most useful measure of efficacy, since each patient’s disease is different and may respond in a different time and outside of the fixed observation period. Using this methodology, 70.5% of patients treated with luspatercept reduced their blood transfusions by at least one-third over any consecutive 12-week period, compared to 29.5% receiving placebo (odds ratio 5.79, p<0.0001). During any 24-week period, 41.1% of luspatercept-treated patients were able to reduce their treatment burden by more than a third compared to 2.7% of those receiving placebo (p<0.0001). Additional endpoints showed significant reductions in serum ferritin in patients treated with luspatercept compared with placebo.11
Luspatercept was well tolerated in this patient population. Adverse events (AEs) were generally mild to moderate and manageable, and did not require dose modifications or interruptions. Grade 3 or higher AEs were reported in 29.1% of patients receiving luspatercept and 15.6% of patients receiving placebo. Serious AEs were reported in 15.2% of patients receiving luspatercept and 5.5% of patients receiving placebo. No luspatercept-treated patients died due to treatment-related AEs.11
The presentation of the BELIEVE data was among the 'Best of ASH' selections, which are chosen from the thousands of meeting abstracts, and considered the biggest breakthroughs from the meeting's scientific presentations. In a press release, lead investigator Maria Domenica Cappellini University of Milan – Fondazione IRCCS commented: ‘These findings from the BELIEVE study are exciting because they suggest that luspatercept may help patients reduce their dependence on red blood cell transfusions.’12
While research is ongoing into gene therapy that could ultimately result in a cure for beta thalassaemia,13 results of the BELIEVE study represent an important breakthrough that will significantly improve the quality of life of people living with this very demanding disease. The use of luspatercept will greatly reduce the transfusion burden of patients and reduce the complications that patients experience due to iron toxicity. Luspatercept has the potential to impact a range of diseases associated with chronic anaemia. The next step in the clinical development of luspatercept is a phase II clinical study (BEYOND; ClinicalTrials.gov Identifier: NCT03342404)14 that will investigate the efficacy and safety of luspatercept in adults with non-transfusion dependent beta-thalassemia.
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11. Cappellini MD, Viprakasit V, Taher A, et al. The Believe Trial: Results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. Presented at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, CA, 1 December 2018. Abstract #163.
12. Accleleron. Celgene Corporation and Acceleron Pharma Announce Results of the Phase 3 BELIEVE Trial Evaluating Luspatercept in Adult Patients with Beta-Thalassemia at ASH 2018. Available at: http://investor.acceleronpharma.com/news-releases/news-release-details/celgene-corporation-and-acceleron-pharma-announce-results-phase (accessed 15 January 2019).
13. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2018;378:1479–93.
14. ClinicalTrials.gov. A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta (β)-Thalassemia (BEYOND). ClinicalTrials.gov Identifier: NCT03342404. Available at: https://clinicaltrials.gov/ct2/show/NCT03342404 (accessed 17 January 2019).