Beta-thalassaemia is a hereditary hemoglobinopathy caused by a defect in β-globin chain synthesis, leading to ineffective erythropoiesis and anaemia.1,2 The standard of care for β-thalassemia is lifelong regular red blood cell transfusions and iron chelation therapy, which impose a substantial treatment burden. Iron overload is associated with numerous toxicities and excess mortality,3 There is, therefore, a need for new therapeutic options for these patients. Luspatercept, a recombinant fusion protein, has been found to enhance erythroid maturation and reduce the transfusion burden in patients with β-thalassemia.4
In an expert interview at the virtual edition of the 25th European Hematology Association Annual Congress (EHA25 Virtual), Professor Maria Domenica Cappellini provides an overview of luspatercept and the BELIEVE study, which evaluated its efficacy.
Q. Please could you give a brief overview of luspatercept and its mechanism of action
Luspatercept is an investigational first-in-class erythroid maturation agent that neutralises selected transforming growth factor β superfamily ligands, in order to inhibit a pathway of Smad2/3 signalling; through these effects it enhances the late stage of erythropoiesis. Luspatercept is, therefore, a good candidate to treat anaemia in conditions of ineffective erythropoiesis. Luspatercept is expected to promote correction of anaemia and improve the late stage of erythropoiesis. Thalassemia is an ideal prototype for the investigation of luspatercept and it has the potential to be used in other conditions of chronic anaemia due to ineffective erythropoiesis.
Q. Could you tell us a little about the BELIEVE study and its major findings?
The BELIEVE study is a randomised, placebo-controlled double-blind phase III study in which luspatercept was given to patients with β-thalassemia aged over 18 years and requiring regular blood transfusion.4 A total of 336 patients were enrolled. Randomisation was 2:1 luspatercept: placebo, i.e. 224 patients received luspatercept and 112 received placebo. In both cohorts, standard of care was maintained and modified according to the efficacy of the treatment. The study duration was 48 weeks, after which the study was unblinded and patients receiving placebo were allowed to crossover to luspatercept treatment. The primary endpoint of the study was a reduction of at least 33% from baseline of the transfusion burden from week 13 to week 24. Secondary endpoints were a reduction of at least 33% between week 37 and 48, and a reduction of 50% or more in the same two periods. We also looked at the reduction of 33% or more at any 12- or 24-week period on the study. All primary and secondary endpoints achieved statistical significance. In particular, more than 40% achieved the endpoint of the reduction of 33% or more at any 12- or 24-week period on the study.4 These results are noteworthy in terms of reduction of units of blood transfusion required and increasing the intervals between transfusions. These results require longer observation to determine whether these reductions are maintained over the long term.
Q. What has been the impact of these findings on people living with beta-thalassaemia?
During the clinical trial, patients didn’t experience a significant improvement in quality of life because during the study patients had to adhere to the protocol, which involved regular hospital visits. However, as soon as the drug is made available in clinical practice, we expect patients will experience a significant improvement in their quality of life, which will be related to a reduction of the number of units of blood per transfusion, but will be mainly in terms of increasing the treatment interval.
Q. Could you give us an overview of the data you are presenting at EHA25 virtual?
These data are from a subanalysis of the results of the BELIEVE study (ClinicalTrials.gov Identifier: NCT02604433).5 We evaluated the responses to luspatercept in different genotype subgroups, including those with a very severe β globin genotype (β0/β0), less severe (β0/β+), even less severe (β+/β+) and haemoglobin E/β-thalassemia. A greater proportion of luspatercept-treated patients achieved the primary endpoint and secondary endpoints regardless of the β globin genotype, which means that even the most severe patients have a significant response to luspatercept. This is an important observation because so far for other treatments, including gene therapy, the approval is restricted to non-β0/β0 patients. We need to collect more data, but so far we have observed that, although the response rate is not as high as in non β0/β0 patients, a proportion of β0/β0 are responding to luspatercept.6
Q. What proportion of patients have the β0/β0 genotype and what are options for patients who do not respond to luspatercept?
Around 50% of patients have the β0/β0 genotype; however, the prevalence varies around the world, for example in the Sardinia region of Italy, which has a high prevalence of beta-thalassaemia, the majority (almost 90%) have the β0/β0 genotype. In the remainder of Italy, the incidence is much lower. They therefore represent a significant proportion of patients with beta-thalassaemia. For those who do not respond to luspatercept or other treatments, the best option is bone marrow transplantation, which is a well-established procedure and is generally affordable around the world. It is applicable to patients of all genotypes but has limitations as the greatest success rates are achieved in patients ages under 14 years using a human leukocyte antigen (HLA)-identical donor. At present we don’t have an ideal treatment for patients with the β0/β0 genotype. However, luspatercept remains a good candidate in terms of responses observed.
Abstract S295, Assessment of Response to luspatercept by B-globin genotype in adult patients in the BELIEVE Trial, was presented at: the 25th European Hematology Association Annual Congress (EHA25 Virtual), 11–21 June 2020.
- Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet 2012;379:373–83.
- Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391:155–67.
- Saliba AN, Harb AR, Taher AT. Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions. J Blood Med. 2015;6:197–209.
- Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2020;382:1219–31.
- ClinicalTrials.gov. An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta (β) Thalassemia (BELIEVE). ClinicalTrials.gov Identifier: NCT02604433. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02604433 (accessed 6 July 2020).
- Cappellini MD, Hermine O, Piga A, et al. Assessment of response to luspatercept by B globin genotype in adult patients in the BELIEVE trial. Presented at: 25th European Hematology Association Annual Congress (EHA25 Virtual), 11–21 June 2020. Abstract S295.
Author profile: Maria Domenica Cappellini is Professor of Internal Medicine at the University of Milan, and has previously held the role of Chief of the Rare Diseases Centre at the Fondazione IRCCS Policlinico Hospital, Milan, Italy. She qualified as a doctor of medicine (MD) at the University of Milan, Italy, and has been active in the fields of thalassaemia, haemoglobinopathies and the haematological biosynthetic pathway for over 40 years. She is also a member of the European Gaucher Registry. Prof Cappellini has been an active researcher in the field of rare diseases, including thalassaemia, haemoglobinopathies, porphyrias and lysosomal diseases (mainly Gaucher and Fabry diseases). She has focused on the phenotypic expression of thalassaemia intermedia and identified the mechanisms underlying the thrombotic risks associated with the disease. Prof Cappellini has published a large number of peer-reviewed original articles in these areas and is a regular contributor and invited speaker at national and international meetings. She contributed to the characterisation of the molecular defects of thalassaemia globin genes in Italy; of note, she defined the genotypes of Italian patients with thalassaemia intermedia that became nationally important for prenatal diagnosis. Prof Cappellini is a member of a number of societies, including the European Hematology Association (EHA), the American Society of Hematology (ASH), the Italian Society of Hematology (SIE), the Italian Society of Internal Medicine (SIMI) and the International BioIron Society (IBIS). She is scientific advisor to the Thalassaemia International Federation (TIF) and contributes to establish guidelines for the clinical management of thalassaemia. Prof Cappellini is a past president of the European Federation of Internal Medicine (EFIM). She is also a member of the European School of Haematology Strategy Board (Paris, France) and a member of EHA’s Fellowships & Grants Committee for EHA 2018. She is an honorary fellow of the Royal College of Physicians and American College of Physicians. She received a Sultan Bin Khalifa International Thalassemia Award – Grand International Award, in Abu Dhabi, United Arab Emirates in November 2015 and the ‘Precious Rubies’ award from the Thalassaemia International Federation in Nicosia, Cyprus in May 2015.
Disclosure: Maria Domenica Cappellini has served on the advisory board for Celgene, Sanofi Genzyme, Novartis, Vifor Pharma and CRISPR Therapeutics.
Support: Commissioned, edited and supported by Touch Medical Media, who commissioned the interview in liaison with BCW Global. Medical writing assistance was provided by Katrina Mountfort of Touch Medical Media, and supported by Touch Medical Media.
Published: 27 August 2020
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