Identification

Summary

Luspatercept is an erythroid maturation agent used to treat anemia secondary to beta thalassemia in patients requiring regular red blood cell transfusions.

Brand Names
Reblozyl
Generic Name
Luspatercept
DrugBank Accession Number
DB12281
Background

Luspatercept is a recombinant fusion protein comprised of a modified extracellular domain of activin receptor type IIB fused to the FC domain of human IgG1.2,6 It was first approved for use in the United States in November 2019 under the brand name Reblozyl® for the treatment of anemia in patients with beta thalassemia who require regular blood transfusions.6 Luspatercept is novel in that it ameliorates anemia via action on late-stage erythropoiesis, in contrast to typical erythropoiesis-stimulating agents (ESAs), such as darbepoetin alfa and epoetin alfa, which act only on early-stage erythropoiesis.4 Luspatercept's novel mechanism of action, then, is uniquely suited for the treatment of conditions in which late-stage erythropoiesis is defective, such as beta thalassemia and other myelodysplastic diseases.4,5

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Fusion proteins
Protein Chemical Formula
Not Available
Protein Average Weight
76000.0 Da
Sequences
Not Available
Synonyms
  • Luspatercept
  • luspatercept-aamt
External IDs
  • ACE-536

Pharmacology

Indication

Luspatercept is indicated for the treatment of anemia in adults with beta thalassemia who require regular red blood cell transfusions.6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Luspatercept binds to, and inhibits, several ligands that act as negative regulators of late-stage erythropoiesis, thereby alleviating the ineffective erythropoiesis observed in patients with beta thalassemia.6,2 Thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, ischemic stroke) have been reported in patients with beta thalassemia receiving luspatercept - patients with a greater baseline risk of thromboembolism may benefit from concomitant thromboprophylaxis while undergoing therapy with luspatercept.6 Luspatercept may carry some degree of embryo-fetal toxicity and should therefore be avoided in pregnancy. Women of child-bearing age should use an effective form of contraception during therapy and for 3 months after completion of therapy.6

Mechanism of action

Beta thalassemia is a genetic red blood cell disorder caused by mutations in the β-globin gene - these mutations cause oxidative stress and premature apoptosis of erythroblasts, thereby leading to ineffective erythropoesis.2 The transforming growth factor beta (TGF-β) superfamily of endogenous ligands (including activins, growth differentiation factors, and bone morphogenetic proteins) are involved in the inhibition of erythroid differentiation via activation of the Smad2/3 subfamily of intracellular effectors.2,1,4

Luspatercept is a fusion protein comprising a modified extracellular domain of activin receptor type IIB (a target for many TGF-β ligands) fused to the FC domain of human IgG1.1,2,3 Luspatercept ameliorates ineffective erythropoiesis in patients with beta thalassemia by acting as a "ligand trap" for various members of the TGF-β superfamily, preventing their downstream signalling and subsequent inhibition of late-stage erythroid maturation. The specific members of the TGF-β superfamily targeted by luspatercept are currently unknown, though growth differentiation factor 11 (GDF11) has been experimentally excluded as a potential target.3

Absorption

At doses of 1 mg/kg and 1.25 mg/kg, the average steady-state AUC was 126 day•μg/mL and 157 day•μg/mL and the average Cmax was 8.17 μg/mL and 10.2 μg/mL, respectively.6 Steady-state was reached after 3 doses given every 3 weeks. Tmax is reached approximately 7 days after administration.6 Absorption pharmacokinetics do not appear to be affected by the site of subcutaneous injection.

Volume of distribution

The average apparent volume of distribution is 7.1 L.6

Protein binding

Not Available

Metabolism

As luspatercept is a fusion protein, it is expected to undergo catabolism into amino acids by general protein degradation processes.6

Route of elimination

Not Available

Half-life

The average half-life of luspatercept is approximately 11 days.6

Clearance

The total apparent clearance of luspatercept is 0.44 L/day.6

Adverse Effects
Adverseeffects
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Toxicity

Repeat-dose toxicity studies in juvenile rats showed an increase in the development of hematologic malignancies at doses of 10 mg/kg, a dose approximately 8-fold higher than the maximum recommended human dose (MRHD).6 Fertility studies in rats observed effects on female (but not male) fertility at doses approximately 7-fold higher than the MRHD.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ReblozylPowder, for solution25 mg / vialSubcutaneousCelgene2020-11-23Not applicableCanada flag
ReblozylInjection, powder, for solution25 mgSubcutaneousBristol Myers Squibb Pharma Eeig2020-12-16Not applicableEU flag
ReblozylInjection, powder, lyophilized, for solution75 mg/1SubcutaneousCelgene Corporation2019-11-08Not applicableUS flag
ReblozylPowder, for solution75 mg / vialSubcutaneousCelgene2020-11-23Not applicableCanada flag
ReblozylInjection, powder, lyophilized, for solution25 mg/1SubcutaneousCelgene Corporation2019-11-08Not applicableUS flag
ReblozylInjection, powder, for solution75 mgSubcutaneousBristol Myers Squibb Pharma Eeig2020-12-16Not applicableEU flag

Categories

ATC Codes
B03XA06 — Luspatercept
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
AQK7UBA1LS
CAS number
1373715-00-4

References

General References
  1. Mies A, Platzbecker U: Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-beta superfamily inhibitors. Semin Hematol. 2017 Jul;54(3):141-146. doi: 10.1053/j.seminhematol.2017.06.004. Epub 2017 Jul 4. [Article]
  2. Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM: Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7. [Article]
  3. Camaschella C: GDF11 is not the target of luspatercept. Blood. 2019 Aug 8;134(6):500-501. doi: 10.1182/blood.2019001983. [Article]
  4. Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, Davies MV, Alexander MJ, Devine M, Loveday KS, Underwood KW, Grinberg AV, Quisel JD, Chopra R, Pearsall RS, Seehra J, Kumar R: Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014 Apr;20(4):408-14. doi: 10.1038/nm.3512. Epub 2014 Mar 23. [Article]
  5. Kubasch AS, Platzbecker U: Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes. Int J Mol Sci. 2019 Aug 7;20(16). pii: ijms20163853. doi: 10.3390/ijms20163853. [Article]
  6. FDA Approved Drug Products: Reblozyl (luspatercept-aamt) for subcutaneous injection [Link]
PubChem Substance
347911311
RxNav
2262544
Wikipedia
Luspatercept

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentErythrocyte Transfusion / Β Thalassemia1
3CompletedTreatmentMyelodysplastic Syndromes (MDS)1
3RecruitingTreatmentAgnogenic Myeloid Metaplasia / Anemia / Myeloproliferative Disorders (MPD) / Post Polycythemia Vera Myelofibrosis / Primary Myelofibrosis (PMF)1
3RecruitingTreatmentAgnogenic Myeloid Metaplasia / Post-Polycythaemia Vera / Primary Myelofibrosis (PMF)1
3RecruitingTreatmentMyelodysplastic Syndromes (MDS)2
3RecruitingTreatmentMyelodysplastic Syndromes (MDS) / Myeloproliferative Neoplasm(MPN)-Associated Myelofibrosis / Β Thalassemia1
2Active Not RecruitingTreatmentThalassaemic disorders1
2CompletedTreatmentAnemia1
2CompletedTreatmentMyelodysplastic Syndromes (MDS)1
2CompletedTreatmentΒ Thalassemia2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionSubcutaneous25 MG
Injection, powder, for solutionSubcutaneous75 MG
Injection, powder, lyophilized, for solutionSubcutaneous25 mg/1
Injection, powder, lyophilized, for solutionSubcutaneous75 mg/1
Powder, for solutionSubcutaneous25 mg / vial
Powder, for solutionSubcutaneous75 mg / vial
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Drug created at October 20, 2016 21:49 / Updated at January 16, 2022 18:54