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
Download FASTA FormatReferences:
- KEGG DRUG: Sotatercept [Link]
- 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
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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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Pulmonary 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
Target Actions Organism UActivin receptor type-2A binderHumans UActivin receptor type-1B binderHumans UGrowth/differentiation factor 8 binderHumans UGrowth/differentiation factor 11 binderHumans - 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Sotatercept. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Sotatercept. Aducanumab The risk or severity of adverse effects can be increased when Sotatercept is combined with Aducanumab. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Sotatercept. Alirocumab The risk or severity of adverse effects can be increased when Alirocumab is combined with Sotatercept. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Winrevair Sotatercept (45 mg/1mL) + Water (1 mL/1mL) Injection, powder, lyophilized, for solution; Injection, solution; Kit Subcutaneous Merck Sharp & Dohme LLC 2024-03-26 Not applicable US Winrevair Sotatercept (45 mg/1mL) + Water (1 mL/1mL) Injection, powder, lyophilized, for solution; Injection, solution; Kit Subcutaneous Merck Sharp & Dohme LLC 2024-03-26 Not applicable US Winrevair Sotatercept (60 mg/1mL) + Water (1.3 mL/1.3mL) Injection, powder, lyophilized, for solution; Injection, solution; Kit Subcutaneous Merck Sharp & Dohme LLC 2024-03-26 Not applicable US Winrevair Sotatercept (60 mg/1mL) + Water (1.3 mL/1.3mL) Injection, powder, lyophilized, for solution; Injection, solution; Kit Subcutaneous Merck Sharp & Dohme LLC 2024-03-26 Not applicable US
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
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: WINREVAIR (sotatercept-csrk) for injection, for subcutaneous use [Link]
- BioSpace: FDA Approves Merck’s WINREVAIR™ (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1) [Link]
- External Links
- PubChem Substance
- 347911284
- Wikipedia
- Sotatercept
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Pulmonary Arterial Hypertension (PAH) 2 3 Completed Treatment Pulmonary Arterial Hypertension (PAH) 1 3 Recruiting Treatment Pulmonary Arterial Hypertension (PAH) 2 2 Completed Treatment Anemia 1 2 Completed Treatment Anemia / Chronic Myelomonocytic Leukemia / Low to Intermediate-1 MDS / Myelodysplastic Syndrome 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, lyophilized, for solution; injection, solution; kit Subcutaneous - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- 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
- 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]
- 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
- 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]
- 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
- 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]
- 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
- 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