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Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studies and one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: This study aims to assess the impact of sotatercept on exercise tolerance, exercise capacity, and right ventricular function in pulmonary arterial hypertension., Methods: SPECTRA (Sotatercept Phase 2 Exploratory Clinical Trial in PAH) was a phase 2a, single-arm, open-label, multicenter exploratory study that evaluated the effects of sotatercept by invasive cardiopulmonary exercise testing in participants with pulmonary arterial hypertension and World Health Organization functional class III on combination background therapy. The primary end point was the change in peak oxygen uptake from baseline to week 24. Cardiac magnetic resonance imaging was performed to assess right ventricular function., Results: Among the 21 participants completing 24 weeks of treatment, there was a significant improvement from baseline in peak oxygen uptake, with a mean change of 102.74 mL/min ([95% CIs, 27.72-177.76]; P =0.0097). Sotatercept demonstrated improvements in secondary end points, including resting and peak exercise hemodynamics, and 6-minute walk distance versus baseline measures. Cardiac magnetic resonance imaging showed improvements from baseline at week 24 in right ventricular function., Conclusions: The clinical efficacy and safety of sotatercept demonstrated in the SPECTRA study emphasize the potential of this therapy as a new treatment option for patients with pulmonary arterial hypertension. Improvements in right ventricular structure and function underscore the potential for sotatercept as a disease-modifying agent with reverse-remodeling capabilities., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03738150., Competing Interests: Disclosures Dr Waxman is a Steering Committee member for Acceleron Pharma, a wholly owned subsidiary of Merck & Co Inc (Rahway, NJ) and United Therapeutics; and is an investigator and principal investigator for Acceleron Pharma, Aria CV, OrphAI, and United Therapeutics. Dr Manimaran is an employee of Acceleron Pharma. Dr de Oliveira Pena is an employee of Oorja Bio Inc and a former employee of Acceleron Pharma. Dr Lu is an employee of SalioGen Therapeutics and a former employee of Acceleron Pharma. F. P. Rischard has been a consultant for Acceleron Pharma and United Therapeutics. He has received research support from Acceleron Pharma, Bayer, ISMed, Janssen, the National Heart, Lung, and Blood Institute, the National Institutes of Health, and United Therapeutics. The other author reports no conflicts.

Sotatercept, a soluble fusion protein comprising the extracellular domain of activin receptor type IIA linked to the Fc portion of human IgG1, is a first-in-class activin signaling inhibitor under development for the treatment of pulmonary arterial hypertension (PAH). We evaluated antidrug antibody (ADA) development and determined the effects of immunogenicity on the pharmacokinetics (PKs), efficacy, and safety of sotatercept in STELLAR, a multicenter, double-blind phase III trial (NCT04576988) wherein participants with PAH were randomized 1:1 to receive sotatercept (starting dose 0.3; target dose 0.7 mg/kg) or placebo subcutaneously every 3 weeks in combination with background therapies for ≤ 72 weeks. ADA-positive (ADA-POS) participants were identified and characterized for neutralizing antibodies (NAbs). PKs, efficacy, and safety were evaluated by ADA and NAb status. Of 162 evaluable participants, 42 (25.9%) were ADA-POS through week 24, of whom 11 (6.8%) were also NAb-POS. Median onset of ADAs was 3.29 weeks (interquartile range (IQR): 3.14-6.14), and median duration was 6 weeks (IQR: 3.14-17.86). No clinically meaningful differences were found across subgroups that were ADA-NEG, ADA-POS/NAb-NEG, and ADA-POS/NAb-POS, in terms of PKs (sotatercept trough concentration over time, mean postdose trough concentration at the end of treatment, and clearance), efficacy (changes from baseline in 6-minute walk distance, pulmonary vascular resistance, and N-terminal pro-B-type natriuretic peptide levels), and safety (incidence of hypersensitivity, anaphylactic reactions, and administration site reactions). We conclude that ADA incidence from sotatercept treatment was 25.9% and did not meaningfully affect the PKs, efficacy, or safety of sotatercept in participants with PAH., (© 2023 Merck Sharp & Dohme LLC. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity and mortality. The phase 3 STELLAR trial tested sotatercept plus background therapy (BGT) versus placebo plus BGT. BGT was comprised of mono-, double-, or triple-PAH targeted therapy. Building on STELLAR findings, we employed a population health model to assess the potential long-term clinical impact of sotatercept., Methods: Based on the well-established ESC/ERS 4-strata risk assessment approach, we developed a six-state Markov-type model (low risk, intermediate-low risk, intermediate-high risk, high risk, lung/heart-lung transplant, and death) to compare the clinical outcomes of sotatercept plus BGT versus BGT alone over a lifetime horizon. State-transition probabilities were obtained from STELLAR. Risk stratum-adjusted mortality and lung/heart-lung transplant probabilities were based on COMPERA PAH registry data, and the post-transplant mortality probability was obtained from existing literature. Model outcomes were discounted at 3% annually. Sensitivity analyses were conducted to examine model robustness., Results: In the base case, sotatercept plus BGT was associated with longer life expectancy from model baseline (16.5 vs 5.1 years) versus BGT alone, leading to 11.5 years gained per patient. Compared with BGT alone, sotatercept plus BGT was further associated with a gain in infused prostacyclin-free life years per patient, along with 683 PAH hospitalizations and 4 lung/heart-lung transplant avoided per 1000 patients., Conclusions: According to this model, adding sotatercept to BGT increased life expectancy by roughly threefold among patients with PAH while reducing utilization of infused prostacyclin, PAH hospitalizations, and lung/heart-lung transplants. Real-world data are needed to confirm these findings., Trial Registration: ClinicalTrials.gov identifier, NCT04576988 (STELLAR)., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Background: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension., Methods: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit., Results: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure., Conclusions: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept., Methods: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg -1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose., Results: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group., Conclusion: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension., Competing Interests: Conflict of interest: M. Humbert is a consultant and an advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aerovate, Altavant, AOP Orphan, Bayer, Ferrer, Janssen, Merck & Co., Inc., Rahway, NJ, USA, MorphogenIX and United Therapeutics, and has received research grants for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, and Merck & Co., Inc., Rahway, NJ, USA. V. McLaughlin is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aerovate, Altavant, Bayer, Caremark LLC, CiVi Bioharma Inc., Corvista, Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, has received grant(s) from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, Sonovie, United Therapeutics, is involved in CME programs for Impact PH and PHA, and on the board of directors for CiVi Biopharma Inc., and for Clene. J.S.R. Gibbs is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Aerovate, Bayer, Complexa, Janssen, Merck & Co., Inc., Rahway, NJ, USA, MSD, Pfizer and United Therapeutics. M. Gomberg-Maitland is a consultant for Altavant, Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, and Entelligence Young for Janssen, is part of the advisory committee for United Therapeutics and the data safety monitoring board for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, has received grant(s) and/or reports GW with funds from Altavant, Bayer and United Therapeutics. M.M. Hoeper is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. I.R. Preston is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Pfizer, Respira and United Therapeutics, a steering committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has received grant(s) from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Complexa, Liquidia, PhaseBio, Tenax and United Therapeutics. R. Souza is an advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. A.B. Waxman is steering committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Altavant, Gossamer Bio, United Therapeutics, an investigator and/or principal investigator for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aria-CV and United Therapeutics, and has received grant(s) from Acceleron, a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. H-A. Ghofrani is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Gossamer Bio, Jansson, MorphogenIX, MSD and Pfizer. P. Escribano Subias has received consulting fees from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, MSD and Gossamer Bio, has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Janssen, MSD, Ferrer, Bayer and AOT, has received support for attending meetings from Janssen and MSD, has received equipment, materials, drugs, medical writing or other services from Janssen, and has participated on data safety monitoring or advisory boards for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway NJ, USA, Janssen, MSD and Gossamer Bio. J. Feldman reports consulting fees from Merck, Aerovate, Altavant, United Therapeutics, Liquidia, Corsair and Janssen. G. Meyer has received payment or honoraria for lectures, presentations, and speakers’ bureaus from Bayer and Janssen and has participated on advisory boards for Bayer and Janssen. D. Montani has received grant(s) from and is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Chesi, GlaxoSmithKline, MSD and Pfizer. K.M. Olsson is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. S. Manimaran and J. de Oliveira Pena are employees of Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. D.B. Badesch is a consultant for Pfizer, is a consultant and advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Altavant, Arena, Bayer, Liquidia, Merck & Co., Inc., Rahway, NJ, USA, United Therapeutics, has received research grant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Altavant, Arena, Belleraphon, Janssen, Liquidia, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, sits on the data safety monitoring board for United Therapeutics, and is a long-term holder of common stock for Johnson and Johnson., (Copyright ©The authors 2023.)

Background: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways., Methods: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance., Results: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm -5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm -5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest., Conclusions: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.)., (Copyright © 2021 Massachusetts Medical Society.)