Granted Patent
B2
US 12,583,906 · App. 18/953,973 · Granted Mar 24, 2026
Actrii proteins and use in treating post-capillary pulmonary hypertension
Inventors:
Gang Li (Cambridge, MA); Ravindra Kumar (Cambridge, MA); Jonathan Toshi Lu (Cambridge, MA); Sachindra Joshi (Cambridge, MA); Patrick Andre (Cambridge, MA)
Assignee:
ACCELERON PHARMA INC.
View Patent ↗
Loading inventors, assignments & file history…
Abstract
In some aspects, the disclosure relates to compositions and methods comprising ActRII polypeptides to treat, prevent, or reduce the progression rate and/or severity of post-capillary pulmonary hypertension (PcPH), particularly treating, preventing or reducing the progression rate and/or severity of one or more PcPH-associated complications.
Claims (25)
1 . A method of treating combined pre- and postcapillary pulmonary hypertension (Cpc-PH) due to heart failure with preserved ejection fraction (HFpEF) in a apatient, comprising administering to the patient an effective amount of a fusion protein comprising:
(i) an ActRII polypeptide comprising the amino acid sequence of SEQ ID NO: 2;
(ii) an Fc domain comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 32; and
(iii) a linker domain positioned between the ActRII polypeptide and the Fc domain.
2 . The method of claim 1 , wherein the patient has a pulmonary vascular resistance (PVR) greater than 2 Woods Units.
3 . The method of claim 1 , wherein the Fc domain comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 32.
4 . The method of claim 3 , wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 32.
5 . The method of claim 3 , wherein the linker domain is selected from the group consisting of: TGGG (SEQ ID NO: 20), TGGGG (SEQ ID NO: 18), SGGGG (SEQ ID NO: 19), GGGGS (SEQ ID NO: 22), GGGG (SEQ ID NO: 17), and SGGG (SEQ ID NO: 21).
6 . The method of claim 5 , wherein the linker domain comprises SEQ ID NO: 20.
7 . The method of claim 1 , wherein the fusion protein comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NOs: 23 or 41.
8 . The method of claim 7 , wherein the fusion protein comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 23.
9 . The method of claim 8 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 23.
10 . The method of claim 7 , wherein the fusion protein comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 41.
11 . The method of claim 10 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 41.
12 . The method of claim 1 , wherein the patient has Group 2 pulmonary hypertension as recognized by the World Health Organization (WHO).
13 . The method of claim 1 , wherein the patient has a pulmonary vascular resistance (PVR) greater than or equal to 3 Wood Units.
14 . The method of claim 13 wherein the method reduces the PVR in the patient.
15 . The method of claim 14 , wherein the method reduces the PVR in the patient by at least 10%.
16 . The method of claim 1 , wherein the patient has preserved left ventricular ejection fraction.
17 . The method of claim 16 , wherein the preserved left ventricular ejection fraction is greater than 45%.
18 . The method of claim 1 , wherein the method increases the patient's 6-minute walk distance.
19 . The method of claim 18 , wherein the method increases the patient's 6-minute walk distance by at least 10 meters.
20 . The method of claim 1 , wherein the method delays clinical worsening of post-capillary pulmonary hypertension (PcPH).
21 . The method of claim 20 , wherein the method delays clinical worsening of PcPH in accordance with the World Health Organization's functional classification system for pulmonary hypertension.
22 . The method of claim 21 , wherein the method delays clinical worsening of PcPH in accordance with the New York Heart Association's functional classification system for pulmonary hypertension.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 26, 2026
From: LI, GANG; KUMAR, RAVINDRA; LU, JONATHAN TOSHI; JOSHI, SACHINDRA; ANDRE, PATRICK
To: ACCELERON PHARMA INC.
Reel/Frame 074985/0946 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 24, 2025
From: DE OLIVEIRA PENA, JANETHE; LINDE, PETER; JOSHI, SACHINDRA; LI, GANG; ANDRE, PATRICK; KUMAR, RAVINDRA
To: ACCELERON PHARMA INC.
Reel/Frame 072240/0880 →
Continuity (4)
Continuation
17921810
Provisional Application
63159253
· Mar 10, 2021
Provisional Application
63016942
· Apr 28, 2020
References Cited (223)
US 5288931A
· Chang et al.
· 1994
[cited by applicant]
US 7112660B1
· Domingues et al.
· 2006
[cited by applicant]
US 7709605B2
· Knopf et al.
· 2010
[cited by applicant]
US 7988973B2
· Sherman
· 2011
[cited by applicant]
US 8293881B2
· Seehra et al.
· 2012
[cited by applicant]
US 8895016B2
· Sherman et al.
· 2014
[cited by applicant]
US 9145433B2
· Bhamidipati et al.
· 2015
[cited by applicant]
US 20030144203A1
· Bowen
· 2003
[cited by applicant]
US 20050239719A1
· Zeldis
· 2005
[cited by applicant]
US 20070056050A1
· Clokie et al.
· 2007
[cited by applicant]
US 20090017019A1
· Shields et al.
· 2009
[cited by applicant]
US 20100015144A1
· Sherman et al.
· 2010
[cited by applicant]
US 20100056505A1
· Lee et al.
· 2010
[cited by applicant]
US 20110182904A1
· Zimmerman et al.
· 2011
[cited by applicant]
US 20140303068A1
· O'Hehir et al.
· 2014
[cited by applicant]
US 20150266950A1
· Sung et al.
· 2015
[cited by applicant]
US 20150306150A1
· Zhang et al.
· 2015
[cited by applicant]
US 20150361163A1
· Kumar et al.
· 2015
[cited by applicant]
US 20160075772A1
· Hatsell
· 2016
[cited by applicant]
US 20160347814A1
· Levine et al.
· 2016
[cited by applicant]
US 20170202918A1
· Yung et al.
· 2017
[cited by applicant]
US 20180008672A1
· Chalothorn et al.
· 2018
[cited by applicant]
US 20180125928A1
· Attie
· 2018
[cited by applicant]
US 20230226146A1
· de Oliveira Pena et al.
· 2023
[cited by applicant]
AU 2012244215A1
· 2012
[cited by applicant]
CN 103920139A
· 2014
[cited by applicant]
CN 107709357A
· 2018
[cited by applicant]
EP 2594280A1
· 2013
[cited by applicant]
KR 20150115961A
· 2015
[cited by applicant]
WO WO9411502A2
· 1994
[cited by applicant]
WO WO2003006057
· 2003
[cited by applicant]
WO WO2005084699A1
· 2005
[cited by applicant]
WO WO2006012627A2
· 2006
[cited by applicant]
WO WO2007062188A2
· 2007
[cited by applicant]
WO WO2008052734
· 2008
[cited by applicant]
WO WO2008073351A2
· 2008
[cited by applicant]
WO WO2008073928A1
· 2008
[cited by applicant]
WO WO2008076437A2
· 2008
[cited by applicant]
WO WO2008094708A2
· 2008
[cited by applicant]
WO WO2008097541A2
· 2008
[cited by applicant]
WO WO2008100384A2
· 2008
[cited by applicant]
WO WO2008109167
· 2008
[cited by applicant]
WO WO2009038745A1
· 2009
[cited by applicant]
WO WO2009133070
· 2009
[cited by applicant]
WO WO2009134428A2
· 2009
[cited by applicant]
WO WO2009158033A2
· 2009
[cited by applicant]
WO WO2009158035A2
· 2009
[cited by applicant]
WO WO2010019261A1
· 2010
[cited by applicant]
WO WO2010062640A1
· 2010
[cited by applicant]
WO WO2010083034A1
· 2010
[cited by applicant]
WO WO2010114860A1
· 2010
[cited by applicant]
WO WO2011056497A1
· 2011
[cited by applicant]
WO WO2011115922A1
· 2011
[cited by applicant]
WO WO2012051559A2
· 2012
[cited by applicant]
WO WO2013009140
· 2013
[cited by applicant]
WO WO2014071158A1
· 2014
[cited by applicant]
WO WO2014055955
· 2014
[cited by applicant]
WO WO2014160336A1
· 2014
[cited by applicant]
WO WO2015017576A1
· 2015
[cited by applicant]
WO WO2015148654
· 2015
[cited by applicant]
WO WO2015161220A1
· 2015
[cited by applicant]
WO WO2015192111A1
· 2015
[cited by applicant]
WO WO2016039796
· 2016
[cited by applicant]
WO WO2016069234
· 2016
[cited by applicant]
WO WO2016164089A2
· 2016
[cited by applicant]
WO WO2016164497A1
· 2016
[cited by applicant]
WO WO2016164501A1
· 2016
[cited by applicant]
WO WO2016171948A1
· 2016
[cited by applicant]
WO WO2016182813
· 2016
[cited by applicant]
WO WO2016183280A1
· 2016
[cited by applicant]
WO WO2016187378A1
· 2016
[cited by applicant]
WO WO2016205370
· 2016
[cited by applicant]
WO WO2017015622A2
· 2017
[cited by applicant]
WO WO2017156488
· 2017
[cited by applicant]
WO WO2018013936A1
· 2018
[cited by applicant]
WO WO2018075747
· 2018
[cited by applicant]
WO WO2018116201A1
· 2018
[cited by applicant]
WO WO2018144968A1
· 2018
[cited by applicant]
WO WO2018175460A1
· 2018
[cited by examiner]
WO WO2018195338
· 2018
[cited by applicant]
WO WO2019140283
· 2019
[cited by applicant]
WO WO2019217715A1
· 2019
[cited by examiner]
WO WO2021092079
· 2021
[cited by applicant]
WO WO2021158675A1
· 2021
[cited by applicant]
WO WO2021158695A1
· 2021
[cited by applicant]
WO WO2021262718
· 2021
[cited by applicant]
WO WO2022150590
· 2022
[cited by applicant]
WO WO2022192420
· 2022
[cited by applicant]
WO WO2022261436
· 2022
[cited by applicant]
WO WO2022271571
· 2022
[cited by applicant]
WO WO2024186418
· 2024
[cited by applicant]
WO WO2024186990
· 2024
[cited by applicant]
WO WO2024238263
· 2024
[cited by applicant]
Opitz et al. (2016, J Am Coll Cardiol 68(4):368-378).
[cited by examiner]
Lepida et al. (2018, Hellenic J Cardiol 58:160-165).
[cited by examiner]
Humbert et al., 2022, European Heart Journal 43:3618-3731.
[cited by examiner]
Galiè et al., 2015, Eur. Respir. J. 46:903-975.
[cited by examiner]
Koller et al., 2017, Heart, Lung & Circulation 26(5):433-441.
[cited by examiner]
Vachiéry et al., 2018, The European Respiratory Journal 51(2):1701886.
[cited by examiner]
Cao et al., 2018, International Journal of Cardiology 273:213-220.
[cited by examiner]
Keros Tropos Topline Data and Restructuring Press Release, 2025.
[cited by examiner]
Bermejo et al., 2018, European Heart Journal 39(15):1255-1264.
[cited by examiner]
Alaoui-Ismaili, M. and Falb, D., “Design of second generation therapeutic recombinant bone morphogenetic proteins,” Cytokine & Growth Factor Reviews, vol. 20(5-6): 501-507 (2009).
[cited by applicant]
Attie et al., “A phase I study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers,” American Journal of Hematology, vol. 89(7): 766-770 (2014).
[cited by applicant]
Bernier et al., “Pharmacological chaperone action on G-protein-coupled receptors,” Current Opinions in Pharmacology, vol. 4(5): 528-533 (2004).
[cited by applicant]
Bhattacharya et al., “Impact of genetic variation on three dimensional structure and function of proteins,” PLoS One, vol. 12(3): e0171355.
[cited by applicant]
Biosis Accession No. 2015:276893 & Piga, A. et al., ‘ACE-536 Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study’, Blood, vo…
[cited by applicant]
Cappellini et al., “A Phase 2a, Open-Label, Dose-Finding Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults with Beta(?)-Thalassemia: Interim Results,” Blood, vol. 122(21): 3448 (2013).
[cited by applicant]
Carrancio et al., “An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin,” British Journal of Haematology, vol. 165:870-882 (2014).
[cited by applicant]
Castonguay et al., “Soluble endoglin specifically binds bone morphongenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppress tumor growth,” The Journal of Biological Chemistry, vol.…
[cited by applicant]
“Efficacy Versus Potency”, https://step1.medbullets.com/pharmacology/107007/efficacy-vs-patency, accessed Jan. 2, 2019.
[cited by applicant]
Fenton, et al., “Rheostat positions: A new classification of protein positions relevant to pharmacogenomics”, Medicinal Chemistry Research 29: 1133-1146 (2020).
[cited by applicant]
Fox et al., “Pulmonary arterial hypertension: classification, diagnosis and contemporary management,” Postgrad Medicine J, vol. 82:717-722 (2006).
[cited by applicant]
Guazzi et al., “Pulmonary Hypertension Due to Left Heart Disease,” Circulation, vol. 126(8):975-990 (2012).
[cited by applicant]
Guo et al., “Protein tolerance to random amino acid change,” Proceedings of the National Academy of Sciences, vol. 101(25): 9205-9210 (2004).
[cited by applicant]
Hill et al., “Postoperative Pulmonary Hypertension: Etiology and Treatment of a Dangerous Complication,” Respiratory Care, vol. 54(7): 958-968 (2009).
[cited by applicant]
Humbert, Marc et al., “Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives,” The European Respiratory Journal, vol. 53: 1801887, 1-14 (2019).
[cited by applicant]
Humbert, M., “Update in Pulmonary Hypertension 2008,” American Journal of Respiratory Critical Care Medicine, vol. 179: 650-656 (2009).
[cited by applicant]
ISR PCT/US2021/029492 dated Jul. 13, 2021 (6 pages).
[cited by applicant]
Joshi, Sachindra R. et al., “Sotatercept analog improves cardiopulmonary remodeling and pulmonary hypertension in experimental left heart failure,” Frontiers in Cardiovascular Medicine, vol. 10, 1064290, 1-14 (2023).
[cited by applicant]
Kohno et al., “Binding Characteristics of Tumor Necrosis Factor Receptor-FC Fusion Proteins vs Anti-Tumor Necrosis Factor mAbs,” J. Investigative Dermatology, vol. 12(1): 5-8 (2007).
[cited by applicant]
Lai, Y.C. et al., “SIRT3-AMPK-Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated with Heart Failure With Preserved Ejection Fraction (PH-HF-pEF)”, Circulation, vo…
[cited by applicant]
Lis et al., “Tumor necrosis factor inhibitors—state of knowledge,” Arch Med Sci. vol. 10(6): 1175-1185 (2014).
[cited by applicant]
Long et al., “Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension,” Nature Medicine, vol. 21(7): 777-785 (2015).
[cited by applicant]
Montani, David et al., Pulmonary arterial hypertension, Orphanet Journal of Rare Diseases, vol. 8:97, 1-58 (2013).
[cited by applicant]
Myllarniemi et al., “Upregulation of activin-B and follistatin in pulmonary fibrosis—a translational study using human biopsies and a specific inhibior in mouse fibrosis models,” BMC Pulmonary Medicine, vol. 14(170): (1…
[cited by applicant]
Oba et al., “Pulmonary hypertension associated with left ventricular disease,” Medical Progress, vol. 255(1): 89-93 (2015).
[cited by applicant]
Optiz, Christian F. et al., “Pre-Capillary, Combined, and Post-Cappillary Pulmonary Hypertension A Pathophysiological Continuum,” Journal of the American College of Cardiology, Elsevier, Amsterdam, NL, vol. 68(4): 368-3…
[cited by applicant]
Pietra, et al., “Pathologic Assessment of Vasculopathies in Pulmonary Hypertension,” Journal of the American College of Cardiology, vol. 43(12) Suppl S: 25S-32S (2004).
[cited by applicant]
Project Information No. 5R01HL074352-07 “BMPR2 and the Pathogenesis of Pulmonary Hypertension”, NIH RePorter—NIH Research Portfolio Online Reporting Tool Expenditures and Results (Feb. 20, 2020) 2 pages.
[cited by applicant]
National Organization for Rare Disorders, “Pulmonary Arterial Hypertension”, The website downloaded Nov. 2, 2020 from https://rarediseases.org/rare-disease/pulmonary-arterial-hypertensin/; 13 pages (2020).
[cited by applicant]
Rose-Jones et al., “Pulmonary Hypertension: Types and Treatments,” Current Cardiology Reviews, vol. 11:73-79 (2015).
[cited by applicant]
Rubin, L.J., “Diagnosis and Management of Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines,” Chest, vol. 126(1): 7S-10S (2004).
[cited by applicant]
Sugimura et al., “Pulmonary hypertension associated with left ventricular disease,” Angiology Frontier, vol. 14(2): 117-122 (2015).
[cited by applicant]
Simonneau et al., “Updated Clinical Classification of Pulmonary Hypertension,” Journal of the American College of Cardiology, vol. 54(1) Suppl S: S43-S54 (2009).
[cited by applicant]
Sotatercept (https://www.genome.jp/dbget-bin/www_bget?dr:D09670; accessed Feb. 1, 2022).
[cited by applicant]
Spiess et al., “Alternative molecular formats and therapeutic applications for bispecific antibodies,” Molecular Immunology, vol. 67: 95-106 (2015).
[cited by applicant]
Supplementary EP Search Report No. EP 21 79 7514, dated Mar. 28, 2024 (2 pages).
[cited by applicant]
Tokuriki et al., “Stability effects of mutations and protein evolvability,” Current Opinions in Structural Biology, vol. 19(5): 596-604 (2009).
[cited by applicant]
Todd et al., “Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease,” Frontiers in Medicine, vol. 7:570016: 1-12 (2020).
[cited by applicant]
Ulloa-Aguirre et al., “Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease,” Traffic, vol. 5(11): 821-837 (2004).
[cited by applicant]
Vachiéry et al., Pulmonary hypertension due to left heart disease, Eur. Respir. Journal, vol. 53:1801897: pp. 1-12 (2019).
[cited by applicant]
Yndestad et al., Elevated levels of activin A in clinical and experimental pulmonary hypertension, J. Applied Physiology, vol. 106(4): 1356-1364 (2009).
[cited by applicant]
Yung et al., “ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension,” Science Translational Medicine, vol. 12(543): 5660 (2020).
[cited by applicant]
Cappellini et al. (Sotatercept, a novel transforming growth factor B ligand trap, improves anemia in B-thalassemia: a phase II, open-label, dose-finding study Haematologica 104:477-484. (2018).
[cited by applicant]
Hoeper et al. “Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension” New Engl. J. Med. 388: 1478-1490. (2023).
[cited by applicant]
Kenny, Jane R. et al., “Therapeutic Protein Drug-Drug Interactions: Navigating the Knowledge Gaps-Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop”, The AAPS Journal, vol. 15(4): 933-940 (2013…
[cited by applicant]
Maron et al., “Pulmonary hypertension associated with left heart disease”, European Respiratory Journal, vol. 64:2401344 (22 pages) (2024).
[cited by applicant]
Rath et al., “Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics,” Critical Reviews in Biotechnology, vol. 35(2): 235-254 (2015).
[cited by applicant]
Tyagi et al., “Chemical modification and chemical cross-linking for protein/enzyme stabilization”, Biochemistry (Mosc)P. vol. 63(3): 334-344 (1998).
[cited by applicant]
Sunamura et al., “Different Roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice,” PNAS, vol. 115:30: E7129-E7138 (2018).
[cited by applicant]
Acceleron Pharma: A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (Pah) (Pulsar), retrieved from the Internet: https://clinicaltrials.gov/study/NCT03496207 (2018).
[cited by applicant]
Badesch, David “Pulsar: A phase 2, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of sotatercept (ACE-11) when added to standard of care (SOC) for treatment of pulmonary arterial hy…
[cited by applicant]
Cottin, et al., “Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome”, Eur. Respir J., vol. 35:105-111; (2010).
[cited by applicant]
Guo, Wen et al., Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss, Bone, vol. 97:209-215 (2017).
[cited by applicant]
Humbert, Marc et al.: Sotatercept for the Treatment of Pulmonary /Arterial Hypertension, The New England Journal of Medicine, vol. 384(13); 1204-1215 (2021).
[cited by applicant]
Joshi, S. R., et al. “ACTRIIA-Fc (Sotatercept) Reverses Pulmonary Vascular Remodeling to Attenuate Pulmonary Arterial Hypertension (PAH) by Rebalancing TGF-b/BMP Signaling in a Preclinical Model” American Journal of Res…
[cited by applicant]
Joshi, S. R., et al. “Rap-011, a Murine Ortholog of ActRIIA-Fc (Sotatercept), Improves Pulmonary Hemodynamics and Restores Right Ventricular Structure and Function in a Preclinical Model of Severe Angio-Obliterative Pul…
[cited by applicant]
Karnati et al., “Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target,” Frontiers in Cardiovascular Medicine, vol. 8(649512): 1-26 (2021).
[cited by applicant]
Liu, Shao-Fei et al., “Animal models of pulmonary hypertension due to left heart disease”, Animal Models and Experimental Medicine, vol. 5(3): 197-206 (2022).
[cited by applicant]
Lombardi, Sandra et al., “Titration of pulmonary arterial hypertension therapeutics: Experience-based recommendations,” Respiratory Medicine, vol. 143: 139-156 (2018).
[cited by applicant]
Naeije, Robert et al., “Differentiating Precapillary From Postcapillary Pulmonary Hypertension: Pulmonary Artery Wedge Pressure Versus Left Ventricular End-Diastolic Pressure”, Circulation, vol. 140(9): 712-714 (2019).
[cited by applicant]
Oliviera et al., “Idiopathic Interstitial pneumonias: review of the latest American Thoracic Society/European Respiratory Society classification,” Radiologia Brasileira, vol. 51(5): 321-327 (2018).
[cited by applicant]
Patel, Nina M. et al., “Pulmonary hypertension in idopathic pulmonary fibrosis”, Chest, Elsevier, vol. 132(3): 998-1006 (2007).
[cited by applicant]
Roh, Jason D., et al., “Activin type II receptor signaling in cardiac aging and heart failure,” Sci. Transl. Med., vol. 11(482) (2019).
[cited by applicant]
Saito et al., “TGF-beta Signaling in Lung Health and Disease,” International Journal of Molecular Sciences, vol. 19(2460): 1-18 (2018).
[cited by applicant]
Schroll et al., “Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist”, Bosentan. Respir Physiol Neurobiol; vol. 170(1): 32-36 (2010).
[cited by applicant]
Shah, Sanjiv J., “Pulmonary Hypertension,” JAMA, vol. 308(13): 1366-1374 (2012).
[cited by applicant]
Simonneau et al., “Updated Clinical Classification of Pulmonary Hypertension,” Journal of the American College of Cardiology, vol. 62(52) Suppl D: D34-D41 (2013).
[cited by applicant]
Waxman et.al., “SPECTRA Phase 2b Study: Impact of Sotatercept on Exercise Tolerance and Right Ventricular Function in Pulmonary Arterial Hypertension”, Circulation: Heart Failure, vol. 17:3011227: 391-402 (2024).
[cited by applicant]
Xiong et al., “Models and Molecular Mechanisms of World Health Organization Group 2 to 4 Pulmonary Hypertension”, Hypertension, vol. 71(1): 34-55 (2018).
[cited by applicant]
Yung, Lai-Ming et al., “ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension”, Science Translational Medicine, vol. 12(543) (2020) (25 pages).
[cited by applicant]
Yung, L. M., et al. “ActRIIA-Fc Rebalances Activin/GDF and BMP9 Signaling to Attenuate Experimental Pulmonary Hypertension.” Circulation, vol. 138, No. Suppl_1, Abstract 17217 (2018).
[cited by applicant]
Yung et al., “ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension”, Science Translational Medicine, vol. 12, (543) 5660, pp. 1-12 (2020).
[cited by applicant]
Zu, L. et al., “Evidence for a Role of Immunoproteasomes in Regulating Cardiac Muscle Mass in Diabetic Mice”, Journal Mol. Cell Cardiol, vol. 49(1): 5-15 (2010).
[cited by applicant]
Supplementary EP Search Report EP 17 82 8540, dated Feb. 27, 2020 (2 pages).
[cited by applicant]
Supplementary EP Search Report EP 21 16 3839, dated Oct. 31, 2021 (2 pages).
[cited by applicant]
Supplementary EP Search Report EP 22 73 7173, dated Oct. 7, 2024.
[cited by applicant]
Supplementary EP Search Report (EP 22 82 1107) dated Mar. 4, 2025 (3 pages).
[cited by applicant]
Supplementary EP Search Report No. EP 22 84 6466 dated Mar. 26, 2025.
[cited by applicant]
Supplementary EP Search Report EP 21 82 8310, dated May 23, 2024 (2 pages).
[cited by applicant]
Supplementary EP Search Report EP 22 82 9068, dated Mar. 25, 2025 (3 pages).
[cited by applicant]
International Search Report PCT/US2021/038482 dated Sep. 16, 2021.
[cited by applicant]
ISR PCT/US2022/037479, dated Oct. 31, 2022 (4 pages).
[cited by applicant]
ISR PCT/US2022/034090, dated Sep. 14, 2022 (4 pages).
[cited by applicant]
ISR PCT/US22/33007 dated Nov. 22, 2022 (8 pages).
[cited by applicant]
ISR PCT/US2017/042157, dated Sep. 27, 2017 (9 pages).
[cited by applicant]
ISR/PCT2022/011619 dated Mar. 29, 2022 (5 pages).
[cited by applicant]