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Clinical Trial
. 2025 May 6;65(5):2401424.
doi: 10.1183/13993003.01424-2024. Print 2025 May.

Efficacy and safety of the activin signalling inhibitor, sotatercept, in a pooled analysis of PULSAR and STELLAR studies

Marius M Hoeper  1 , Mardi Gomberg-Maitland  2 , David B Badesch  3 , J Simon R Gibbs  4 , Ekkehard Grünig  5 , Grzegorz Kopeć  6 , Vallerie V McLaughlin  7 , Gisela Meyer  8 , Karen M Olsson  9 , Ioana R Preston  10 , Stephan Rosenkranz  11 , Rogerio Souza  12 , Aaron B Waxman  13 , Loïc Perchenet  14 , James Strait  14 , Aiwen Xing  14 , Solaiappan Manimaran  14 , Xuelong Wang  14 , Barry Miller  14 , Alexandra G Cornell  14 , Janethe de Oliveira Pena  14 , H Ardeschir Ghofrani  15 , Marc Humbert  16
Affiliations
Clinical Trial

Efficacy and safety of the activin signalling inhibitor, sotatercept, in a pooled analysis of PULSAR and STELLAR studies

Marius M Hoeper et al. Eur Respir J. .

Abstract

Introduction: Pulmonary arterial hypertension is a progressive disease associated with significant morbidity and mortality. Sotatercept is a first-in-class activin signalling inhibitor that acts to restore the balance between the growth-promoting and growth-inhibiting signalling pathways.

Methods: This post hoc, exploratory, pooled analysis combines data from the double-blind placebo periods of the phase 2 PULSAR (NCT03496207) and phase 3 STELLAR (NCT04576988) studies. Both studies were international, multicentre, randomised, double-blind, placebo-controlled trials in patients with pulmonary arterial hypertension. Efficacy and safety parameters common to both studies were analysed.

Results: A total of 429 patients were randomised and treated; 237 received sotatercept and 192 received placebo. Adding sotatercept to background pulmonary arterial hypertension therapy for 24 weeks improved exercise capacity (as assessed by 6-min walk distance), pulmonary vascular resistance and World Health Organization functional class, and delayed time to first occurrence of death or clinical worsening event. There were clinically important reductions in both pulmonary and right heart pressures; improvements in right ventricle size during both systole and diastole; and enhancements in right ventricle contractility and right ventricular-pulmonary artery coupling. The number of patients who experienced at least one adverse event of interest or special interest (increased haemoglobin, thrombocytopenia, bleeding events (mostly epistaxis), increased blood pressure and telangiectasia) was higher in the sotatercept group than the placebo group.

Conclusion: This pooled analysis confirms that sotatercept delivers therapeutic benefit across a range of efficacy end-points and has favourable safety in patients with pulmonary arterial hypertension. Increased duration of follow-up will provide further insight into long-term outcomes of sotatercept in patients with pulmonary arterial hypertension.

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Conflict of interest statement

Conflicts of interest: M.M. Hoeper reports fees for lectures or consultations from Acceleron, Actelion, Aerami, Aerovate, AOP Health, Bayer, Ferrer, Gossamer, Janssen, MSD and Novartis. M. Gomberg-Maitland reports scientific consulting for Acceleron Pharma and Merck & Co., Inc., AeramiI, Bayer HealthCare Pharmaceuticals, Janssen Biotech, Jucabio, Keros and United Therapeutics Corporation; and receiving grants or contracts to her institution from Aerovate, Altavant, Acceleron Pharma Gossamer Bio and MSD; her spouse is an employee of Intellia Therapeutics. D.B. Badesch has served as a steering committee member and consultant to MSD; has received grant support from MSD, AI Therapeutics, Arena/United Therapeutics, Altavant and Liquidia; and is a distinguished advisor to the Pulmonary Hypertension Association's Scientific Leadership Council; his wife is a long-term holder of stock in Johnson & Johnson in a family trust. J.S.R. Gibbs is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Actelion, Aerovate, Gossamer Bio, Janssen, Merck & Co., Inc., MSD, Keros, LG Chem, Pfizer and United Therapeutics. E. Grünig has received honoraria for serving as a speaker and/or consultant from Bayer HealthCare, Ferrer, GEBRO, GlaxoSmithKline, Janssen Biotech, MSD and OMT; and received research funding for clinical studies from Acceleron, Actelion Pharmaceuticals, Bayer HealthCare, MSD, Bellerophon, Gossamer Bio, Janssen, Novartis, OMT, Pfizer, REATA and United Therapeutics. G. Kopeć reports consulting fees from MSD; and lecture fees from MSD, Janssen, AOP Orphan, Pfizer, Bayer and Aerovate. V.V. McLaughlin reports grant support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck & Co., Inc. and Sonovie; and consultancy fees from 35 Pharma, Aerami, Aerovate, Caremark, LLC, Corvista, Enzyvant, Gossamer Bio, Janssen, Keros, Liquidia, Merck & Co., Inc., United Therapeutics, Respira and Vertex. G. Meyer reports grant or contract support from Bayer, Pulmovant, Janssen, Merck & Co., Inc. and Gossamer Bio; consulting fees from Bayer, Gossamer Bio, Janssen and Pulmovant; payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Gossamer Bio, Janssen and Merck & Co., Inc.; support for attending meetings from Janssen, Bayer and Gossamer Bio; and participation on a data safety monitoring board or advisory board from Bayer, Liquidia, Janssen, Pulmovant and Gossamer Bio. K.M. Olsson reports research funding to her institution from Acceleron, MSD and Janssen; consulting fees from Acceleron, Actelion, Janssen, Ferrer, Merck & Co., Inc., AOP Health, Gossamer and Bayer; speaking honoraria from Acceleron, Actelion, AOP Health, Janssen, Bayer, MSD, Ferrer and Gossamer; and travel support from Acceleron/MSD and Janssen/Actelion. I.R. Preston reports grant or contract support from Merck & Co., Inc., Janssen, United Therapeutics, Keros and Tenax; consulting fees from Merck & Co., Inc., Janssen, United Therapeutics, Liquidia, Gossamer, Aerovate and Insmed; and participation in educational events for Medscape and NACE. S. Rosenkranz reports speaker or consultant fees from Abbott, Acceleron, Actelion, Aerovate, Altavant, AOP, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards, Ferrer, Gossamer, Inari, Janssen, Lilly, MSD and United Therapeutics; and research grants (paid to his institution) from AstraZeneca, Bayer, Janssen, Lempo and MSD. R. Souza reports lecture fees from Bayer, Janssen and MSD; and participation in an advisory board for Bayer, Janssen and MSD. A.B. Waxman has served as a steering committee member/investigator for MSD and United Therapeutics; investigator for OrphAI and ARIA-CV; and data safety monitoring board chair for INSMED. L. Perchenet, J. Strait, A. Xing, S. Manimaran, X. Wang, B. Miller and A.G. Cornell are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. J. de Oliveira Pena was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, during the conduct and readout of the studies. H.A. Ghofrani reports consultancy fees from Aerovate, Altavant, Bayer AG, Attgeno, Gossamer, Janssen/Actelion, Keros, Liquidia, Morphic, MSD/Acceleron and Pfizer; payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer AG, Gossamer, Janssen/Actelion, Keros and MSD/Acceleron; participation as an advisory committee member for Aerovate, Altavant, Attgeno, Bayer AG, Janssen/Actelion, MSD/Acceleron and Pfizer; and as a data and safety monitoring board member for Insmed; his spouse is an employee of Liquidia. M. Humbert reports grants or contracts (paid to institution) from Gossamer and Merck & Co., Inc.; consulting fees from 35 Pharma, Aerovate, AOP Orphan, Chiesi, Ferrer, Gossamer, Janssen, Keros, Liquidia, Merck & Co., Inc., Respira and United Therapeutics; payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen and Merck & Co., Inc.; and participation on a data safety monitoring board or advisory board for 35 Pharma, Aerovate, Janssen, Keros, Merck & Co., Inc. and United Therapeutics.

Figures

None
Overview of the study. #: p<0.001 for comparison of sotatercept with placebo on the basis of aligned-rank stratified Wilcoxon test, stratified according to randomisation factors of background therapy (monotherapy or dual therapy versus triple therapy) and baseline World Health Organization functional class (WHO FC) (II versus III); : p<0.001 for comparison of sotatercept with placebo on basis of a Cochran–Mantel–Haenszel method, stratified according to randomisation factors. 6MWD: 6-min walk distance; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance.
FIGURE 1
FIGURE 1
a) Kaplan–Meier plot of time to first occurrence of clinical worsening events or death overall and b) forest plot of time to first occurrence of clinical worsening events or death in subgroups (full analysis set). hPAH: heritable PAH; iPAH: idiopathic PAH; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; WHO FC: World Health Organization functional class. #: treatment effect is the hazard ratio derived from a Cox proportional hazard model with treatment group as the covariate stratified by WHO FC and PAH background therapy; : hazard ratio is 0 and confidence interval is not evaluable (NE) due to small number of events, or no events occurring, in the subgroup.
FIGURE 2
FIGURE 2
Forest plot for change from baseline at week 24 in subgroups in a) 6-min walk distance (6MWD), b) pulmonary vascular resistance (PVR) and c) N-terminal pro-brain natriuretic peptide (NT-proBNP) level (full analysis set). ASE: asymptotic standard error; H-L: Hodges–Lehmann; hPAH: heritable PAH; iPAH: idiopathic PAH; PAH: pulmonary arterial hypertension; WHO FC: World Health Organization functional class.
FIGURE 2
FIGURE 2
Continued.
See this image and copyright information in PMC

Comment in

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