Population Pharmacokinetics and Exposure‐Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β‐Thalassemia

Chen, Nianhang; Kassir, Nastya; Laadem, Abderrahmane; Giuseppi, Ana Carolina; Shetty, Jeevan K.; Maxwell, Stephen E.; Sriraman, Priya; Ritland, S; Linde, Peter G.; Budda, Balasubrahmanyam; Reynolds, Joseph G.; Zhou, Simon; Palmisano, Maria

doi:10.1002/jcph.1696

Cited by 9 publications

(10 citation statements)

References 11 publications

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“…It is well known that GATA-1 is indispensable for erythroid maturation. 18,19 A recent article by Chen et al 20 showed that the mean elimination half-life of luspatercept is ;11 days.…”

Section: Luspatercept Pharmacologymentioning

confidence: 99%

The use of luspatercept for thalassemia in adults

Cappellini

Taher

2021

Blood Advances

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Luspatercept is an activin receptor ligand trap that has been shown to enhance late-stage erythropoiesis in animal models of β-thalassemia. A multicenter, international, phase 2 dose-finding study was initiated in adult patients with β-thalassemia, either non–transfusion-dependent thalassemia (NTDT) or transfusion-dependent thalassemia (TDT). Positive results of the phase 2 study paved the way to a randomized phase 3 clinical trial (BELIEVE) to assess the efficacy and safety of luspatercept. The BELIEVE trial is a randomized, double-blind, placebo-controlled phase 3 trial. Three hundred thirty-six patients aged ≥18 years with TDT (regularly transfused, 6-20 red blood cell units within 24 weeks before randomization) were included in the trial. Patients received luspatercept or placebo subcutaneously every 21 days for ≥48 weeks and best supportive care. Forty-eight of 224 patients (21.4%) in the luspatercept group achieved the primary end points (≥33% reduction in transfusion burden) compared with those in the placebo group (4.5%; P < .001). Moreover, more patients had a ≥33% reduction in transfusion burden during any rolling 12-week interval (70.5% vs 29.5%) or any 24-week interval (41.1% vs 2.7%) with luspatercept than with the placebo. Transfusion independence was achieved by 11% of patients in the luspatercept group. Transient adverse events were more frequent with luspatercept than with placebo, but were manageable. Luspatercept was approved by the US Food and Drug Administration in 2019 and by the European Medicines Agency in 2020. The luspatercept trial is registered on www.clinicaltrials.gov at #NCT01749540 and the BELIEVE trial at #NCT02604433.

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“…It is well known that GATA-1 is indispensable for erythroid maturation. 18,19 A recent article by Chen et al 20 showed that the mean elimination half-life of luspatercept is ;11 days.…”

Section: Luspatercept Pharmacologymentioning

confidence: 99%

The use of luspatercept for thalassemia in adults

Cappellini

Taher

2021

Blood Advances

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“…The recommended doses for thalassaemia patients are 1 or 1.25 mg/Kg, administered subcutaneously every 21 days. As confirmed by pharmacokinetic studies, this dosing scheme allows a stable plasma concentration to be reached over time, independently of factors such as age, sex, ethnicity, or renal or hepatic impairment [67]. Parallelly, a phase 2, double-blind, placebo-controlled trial of luspatercept in NTDT (NCT03342404) recently completed the blinded phase [68].…”

Section: Luspatercept (Ace-536)mentioning

confidence: 99%

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

Longo

Piolatto

Ferrero

et al. 2021

IJMS

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β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-β superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in β-thalassaemia from bench to bedside.

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“…Luspatercept was approved via the Food and Drug Administration (FDA) on November 8, 2019 [ 10 ]. It was also authorized in 2020 via the European Medicines Agency [ 11 ]. Luspatercept was used to cure β-thalassemia and treat myelodysplastic syndrome [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Luspatercept in the Treatment of β-Thalassemia: A Systematic Review

Dighriri¹,

Alrabghi²,

Sulaiman³

et al. 2022

Cureus

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β-thalassemia is characterized by the faulty generation of hemoglobin resulting in an elevated α/β globin ratio; this led to several patients needing red blood cell (RBC) transfusions for the rest of their lives. Luspatercept is an erythroid maturation test for treating various types of anemia, including β-thalassemia. It inhibits the Smad2/3 cascade and treats β-thalassemia by downregulating the transforming growth factorbeta (TGF-β) pathway. Luspatercept was evaluated in randomized controlled trials (RCTs). However, there is still limited data. Therefore, the study aims to review the current literature to assess the efficacy of luspatercept in cure β-thalassemia and its safety. From 2015 to 2022, searches were undertaken in PubMed, Google Scholar, and Cochrane. Only RCTs published in English were eligible for inclusion. The Cochrane Collaboration tool for bias assessment was used to analyze the quality of the publications. Our search strategy revealed 94 publications, of which 12 full-text papers were read and five were chosen for this review. All five trials included 1161 participants. Of whom, 153 (13.18%) entered phase 2, and 1008 (86.82%) entered phase 3. Two articles included 153 participants, of whom 70 (45.75%) were transfusion-dependent beta-thalassemia (TD) and 83 (54.25%) were non-transfusion-dependent beta-thalassemia (NTD) of phase 2. Three articles included 1008 participants, of whom 672 (66.67%) were given luspatercept and 336 (33.33%) were given a placebo. All participants in RCTs were 18 years of age or older. In phase 2, 0.2 to 1.25 mg/kg of luspatercept was given, and in phase 3, 1.0 to 1.25 mg/kg of luspatercept was given once every three weeks. In beta-thalassemia patients, luspatercept was more effective than a placebo and well tolerated. The high dose has shown promising results in the erythroid response, measured by a drop in blood transfusions or an average rise in hemoglobin levels. Luspatercept might make patients less likely to need RBC transfusions, improve their clinical results, and improve their quality of life. Adverse events were hyperuricemia, arthralgia, dizziness, influenza hypertension, and bone pain, but they were manageable.

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Population Pharmacokinetics and Exposure‐Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β‐Thalassemia

Cited by 9 publications

References 11 publications

The use of luspatercept for thalassemia in adults

The use of luspatercept for thalassemia in adults

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

Efficacy and Safety of Luspatercept in the Treatment of β-Thalassemia: A Systematic Review

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