NAV

Sotatercept

Identification

Summary

Sotatercept is a recombinant activin receptor fusion protein used to treat pulmonary arterial hypertension.

Generic Name
Sotatercept
DrugBank Accession Number
DB12118
Background

Sotatercept is an activin signalling inhibitor. It is a homodimeric recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA (ActRIIA) linked to the human IgG1 Fc domain.5

On March 26, 2024, sotatercept was approved by the FDA for the treatment of pulmonary arterial hypertension (PAH).6 Sotatercept works to resolve the imbalance in activin–growth differentiation factor and BMP pathway signalling observed in PAH.1

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Fusion proteins
Protein Chemical Formula
C3448H5264N920O1058S42
Protein Average Weight
78000.0 Da (approximate)
Sequences
>Sotatercept sequence
ILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCWL
DDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQPTSNPVTPKPPTGGGT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE
VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPVPIEKTISKAKGQP
REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS
FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
References:
  1. KEGG DRUG: Sotatercept [Link]
Download FASTA Format
Synonyms
  • (HUMAN ACTIVIN RECEPTOR TYPE-2A PRECURSOR-(21-135)-PEPTIDYL)-THREONYLTRIGLYCYL-(HUMAN IMMUNOGLOBULIN HEAVY CONSTANT .GAMMA.1 FC FRAGMENT: (8-15)-HINGE-(A-100>V)-CH2-CH3 OF HOMO SAPIENS IGHG1*03), (123-123':126-126')-BISDISULFIDE DIMER
  • (HUMAN ACTIVIN RECEPTOR TYPE-2A PRECURSOR-(21-135)-PEPTIDYL)-THREONYLTRIGLYCYL-(HUMAN IMMUNOGLOBULIN HEAVY CONSTANT .GAMMA.1 FC FRAGMENT: (8-15)-HINGE-(A-100>V)-CH2-CH3 OF HOMO SAPIENS IGHG1*03), (123-123':126-126')-BISDISULPHIDE DIMER
  • ACTIVIN RECEPTOR TYPE IIA (SYNTHETIC HUMAN EXTRACELLULAR DOMAIN-CONTAINING FRAGMENT) FUSION PROTEIN WITH IMMUNOGLOBULIN G1 (SYNTHETIC HUMAN HEAVY CHAIN FC FRAGMENT), DIMER
  • Sotatercept
External IDs
  • ACE 011
  • ACE-011
  • ACE011
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Pharmacology

Indication

Sotatercept is indicated for the treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofPulmonary arterial hypertension who functional class i•••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In clinical trials, sotatercept reduced pulmonary vascular resistance in patients with PAH.1 In pre-clinical models of PAH, it reversed pulmonary arterial wall and right ventricular remodelling.3 In rat models of PAH, an analog of sotatercept reduced inflammation and inhibited the proliferation of endothelial and smooth muscle cells in diseased vasculature. These cellular changes were associated with thinner vessel walls, partial reversal of right ventricular remodelling, and improved hemodynamics.5

Increased hemoglobin levels and thrombocytopenia were observed with sotatercept use.5

Mechanism of action

There are several members of the transforming growth factor β (TGF-β) superfamily, including the bone morphogenetic protein (BMP) receptor type 2 (BMPRII), activin receptor type IIA (ActRIIA), and the ActRIIA ligands activin A, activin B, growth differentiation factor 8 (GDF8), and GDF11.2 These TGF-β superfamily ligands promote pro-proliferative (ActRIIA/Smad2/3-mediated) or anti-proliferative (BMPRII/Smad1/5/8-mediated) signalling pathways to regulate vascular proliferation and maintain the endothelial integrity in pulmonary arteries.1,5 Altered signal transduction by TGF-β ligands has been implicated in the pathophysiology of PAH, where there is a dominance of proliferative and antiapoptotic signalling.2 As a result, endothelial dysfunction, increased cellular proliferation, and pulmonary vascular remodelling occur.1

Sotatercept is a recombinant activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein.5 It acts as a ligand trap for multiple activin-class ligands by directing binding to and sequestering them,4 thereby improving the balance between the growth-promoting activin growth differentiation factor pathway and the growth-inhibiting BMP pathway.3,5

TargetActionsOrganism
UActivin receptor type-2A
binder
Humans
UActivin receptor type-1B
binder
Humans
UGrowth/differentiation factor 8
binder
Humans
UGrowth/differentiation factor 11
binder
Humans
Absorption

Following subcutaneous administration, the absolute bioavailability of sotatercept is approximately 66%. The Tmax is approximately seven days (range: 2-8 days) following multiple subcutaneous administration every four weeks.5

Following subcutaneous administration of 0.7 mg/kg sotatercept every three weeks to PAH patients, the steady state geometric mean (%CV) area under the time concentration curve (AUC) is 172 mcg × d/mL (34.2%), and peak concentration (Cmax) is 9.7 mcg/mL (30%). The AUC and Cmax increased proportionally with dose. Steady-state is achieved after approximately 15 weeks following initiation of multiple dosing. The accumulation ratio of sotatercept AUC is approximately 2.2.5

Volume of distribution

The population PK model estimated volume of distribution (%CV) of sotatercept at steady state is approximately 5.3 L (27.3%) in patients with PAH.5

Protein binding

Not Available

Metabolism

Sotatercept is expected to be metabolized into small peptides by catabolic pathways.5

Route of elimination

Not Available

Half-life

The effective half-life is approximately 24 days.5

Clearance

Clearance is approximately 0.18 L/day.5

Adverse Effects
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Toxicity

There is no information regarding the acute toxicity (LD50) of sotatercept. In healthy volunteers, a dose of 1 mg/kg resulted in cases of increased Hgb associated with hypertension, which improved with phlebotomy. In the event of an overdosage, monitor closely for increases in Hgb and blood pressure, and provide supportive care as appropriate. Sotatercept is not dialyzable and there is no known antidote for this drug.5

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.
DrugInteraction
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interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Sotatercept.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Sotatercept.
AducanumabThe risk or severity of adverse effects can be increased when Sotatercept is combined with Aducanumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Sotatercept.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Sotatercept.
Food Interactions
No interactions found.

Products

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
WinrevairSotatercept (60 mg/1mL) + Water (1.3 mL/1.3mL)Injection, powder, lyophilized, for solution; Injection, solution; KitSubcutaneousMerck Sharp & Dohme LLC2024-03-26Not applicableUS flag
WinrevairSotatercept (60 mg/1mL) + Water (1.3 mL/1.3mL)Injection, powder, lyophilized, for solution; Injection, solution; KitSubcutaneousMerck Sharp & Dohme LLC2024-03-26Not applicableUS flag
WinrevairSotatercept (45 mg/1mL) + Water (1 mL/1mL)Injection, powder, lyophilized, for solution; Injection, solution; KitSubcutaneousMerck Sharp & Dohme LLC2024-03-26Not applicableUS flag
WinrevairSotatercept (45 mg/1mL) + Water (1 mL/1mL)Injection, powder, lyophilized, for solution; Injection, solution; KitSubcutaneousMerck Sharp & Dohme LLC2024-03-26Not applicableUS flag

Categories

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
0QI90BTJ37
CAS number
1001080-50-7

References

General References
  1. Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman A, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira Pena J, Badesch DB: Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021 Apr 1;384(13):1204-1215. doi: 10.1056/NEJMoa2024277. [Article]
  2. Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza R, Waxman AB, Grunig E, Kopec G, Meyer G, Olsson KM, Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J, de Oliveira Pena J, Humbert M: Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023 Apr 20;388(16):1478-1490. doi: 10.1056/NEJMoa2213558. Epub 2023 Mar 6. [Article]
  3. Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman AB, Ghofrani HA, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, de Oliveira Pena J, Badesch DB: Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J. 2023 Jan 6;61(1):2201347. doi: 10.1183/13993003.01347-2022. Print 2023 Jan. [Article]
  4. Joshi SR, Liu J, Bloom T, Karaca Atabay E, Kuo TH, Lee M, Belcheva E, Spaits M, Grenha R, Maguire MC, Frost JL, Wang K, Briscoe SD, Alexander MJ, Herrin BR, Castonguay R, Pearsall RS, Andre P, Yu PB, Kumar R, Li G: Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci Rep. 2022 May 12;12(1):7803. doi: 10.1038/s41598-022-11435-x. [Article]
  5. FDA Approved Drug Products: WINREVAIR (sotatercept-csrk) for injection, for subcutaneous use [Link]
  6. BioSpace: FDA Approves Merck’s WINREVAIR™ (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1) [Link]
PubChem Substance
347911284
Wikipedia
Sotatercept

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentPulmonary Arterial Hypertension (PAH)2
3CompletedTreatmentPulmonary Arterial Hypertension (PAH)1
3RecruitingTreatmentPulmonary Arterial Hypertension (PAH)2
2CompletedTreatmentAnemia1
2CompletedTreatmentAnemia / Chronic Myelomonocytic Leukemia / Low to Intermediate-1 MDS / Myelodysplastic Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solution; injection, solution; kitSubcutaneous
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. Activin receptor type-2A
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Transmembrane receptor protein serine/threonine kinase activity
Specific Function
On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which auto...
Gene Name
ACVR2A
Uniprot ID
P27037
Uniprot Name
Activin receptor type-2A
Molecular Weight
57847.12 Da
References
  1. Joshi SR, Liu J, Bloom T, Karaca Atabay E, Kuo TH, Lee M, Belcheva E, Spaits M, Grenha R, Maguire MC, Frost JL, Wang K, Briscoe SD, Alexander MJ, Herrin BR, Castonguay R, Pearsall RS, Andre P, Yu PB, Kumar R, Li G: Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci Rep. 2022 May 12;12(1):7803. doi: 10.1038/s41598-022-11435-x. [Article]
Details2. Activin receptor type-1B
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Ubiquitin protein ligase binding
Specific Function
Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Transduces the activin signal from the cell surfac...
Gene Name
ACVR1B
Uniprot ID
P36896
Uniprot Name
Activin receptor type-1B
Molecular Weight
56806.05 Da
References
  1. Joshi SR, Liu J, Bloom T, Karaca Atabay E, Kuo TH, Lee M, Belcheva E, Spaits M, Grenha R, Maguire MC, Frost JL, Wang K, Briscoe SD, Alexander MJ, Herrin BR, Castonguay R, Pearsall RS, Andre P, Yu PB, Kumar R, Li G: Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci Rep. 2022 May 12;12(1):7803. doi: 10.1038/s41598-022-11435-x. [Article]
Details3. Growth/differentiation factor 8
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Transforming growth factor beta receptor binding
Specific Function
Acts specifically as a negative regulator of skeletal muscle growth.
Gene Name
MSTN
Uniprot ID
O14793
Uniprot Name
Growth/differentiation factor 8
Molecular Weight
42749.8 Da
References
  1. Joshi SR, Liu J, Bloom T, Karaca Atabay E, Kuo TH, Lee M, Belcheva E, Spaits M, Grenha R, Maguire MC, Frost JL, Wang K, Briscoe SD, Alexander MJ, Herrin BR, Castonguay R, Pearsall RS, Andre P, Yu PB, Kumar R, Li G: Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci Rep. 2022 May 12;12(1):7803. doi: 10.1038/s41598-022-11435-x. [Article]
Details4. Growth/differentiation factor 11
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Secreted signal that acts globally to regulate anterior/posterior axial patterning during development. May play critical roles in patterning both mesodermal and neural tissues (By similarity). It is required for proper vertebral patterning and orofacial development (PubMed:31215115). Signals through activin receptors type-2, ACVR2A and ACVR2B, and activin receptors type-1, ACVR1B, ACVR1C and TGFBR1 leading to the phosphorylation of SMAD2 and SMAD3 (PubMed:28257634).
Specific Function
Cytokine activity
Gene Name
GDF11
Uniprot ID
O95390
Uniprot Name
Growth/differentiation factor 11
Molecular Weight
45090.36 Da
References
  1. Joshi SR, Liu J, Bloom T, Karaca Atabay E, Kuo TH, Lee M, Belcheva E, Spaits M, Grenha R, Maguire MC, Frost JL, Wang K, Briscoe SD, Alexander MJ, Herrin BR, Castonguay R, Pearsall RS, Andre P, Yu PB, Kumar R, Li G: Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci Rep. 2022 May 12;12(1):7803. doi: 10.1038/s41598-022-11435-x. [Article]

Drug created at October 20, 2016 21:23 / Updated at April 11, 2024 14:54