Introduction

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, inflammation, and proliferation of small pulmonary arteries leading to elevated pulmonary artery pressure and increased pulmonary vascular resistance (PVR), ultimately causing right heart dysfunction.¹ Despite the availability of highly effective therapies,² morbidity/mortality associated with PAH remains high and there is a need for additional therapeutic options, targeting the disease process and aiming for reverse right ventricular remodeling and disease-modifying agents.^3-5 Sotatercept is a novel first-in-class drug acting as a ligand trap for members of the transforming growth factor-beta superfamily, thus restoring balance between the growth-promoting activin growth differentiation factor pathway and the growth-inhibiting bone morphogenetic protein pathway. In a phase 2 trial, sotatercept was shown to significantly decrease PVR and increase 6-min walking distance (6MWD) compared with placebo.⁶

The STELLAR

Methods

The STELLAR (A Study of Sotatercept in Combination With Background Therapy for the Treatment of Pulmonary Arterial Hypertension) is a multicenter, double-blinded, randomized phase 3 trial of sotatercept on top of background therapy for PAH.⁷ Patients with PAH with World Health Organization (WHO) functional class (FC) II or III receiving stable background therapy for ≥90 days were randomized to receive subcutaneous sotatercept (target dose 0.7 mg/kg every 3 weeks) or placebo. The primary endpoint was the change in 6MWD from baseline at week 24. Secondary endpoints were assessed in hierarchical order.

Results

A total of 323 adults were enrolled in the STELLAR. Baseline characteristics were similar among groups, with 79.3% female sex, mean age 47.9±14.8 years, 48.6% WHO FC II and 51.4% WHO FC III, 61.3% receiving triple combination therapy, and 39.9% receiving parenteral prostacyclins. Sotatercept was associated with an increase in 6MWD of 34.4 m (95% confidence interval [CI], 33-35.5 m) whereas placebo was associated with a change in 6MWD of 1 m (95% CI, -0.3 to 3.5). Sotatercept was associated with improvement in eight of nine secondary endpoints, including a reduction in PVR (-165.1 dyn·sec·cm⁻⁵; 95% CI, -176 to -152 dyn·sec·cm⁻⁵), decrease in N-terminal B-type natriuretic peptide level (-230.3 pg/mL; 95% CI, -236 to -223 pg/mL]), and improvement in WHO FC (29.4% vs. 13.8%; p < 0.001). There was also a significant improvement in time-to-death or nonfatal clinical worsening with sotatercept (hazard ratio, 0.16; 95% CI, 0.08-0.35). Severe (8% vs. 13.1%) and serious (14.1% vs. 22.5%) adverse events were less common in the sotatercept group than in the placebo group. Adverse events noted with sotatercept included bleeding events (epistaxis and gingival bleeding; 21.5%), telangiectasias (10.4%), thrombocytopenia (6.1%), increase in hemoglobin level (5.5%), and increase in blood pressure (3.7%).

Discussion

The STELLAR showed that adding sotatercept to background PAH therapy is associated with further improvement in exercise capacity, hemodynamics symptomatology, quality-of-life metrics, and time to clinical worsening. The results of the study are particularly exciting because, at the time of enrollment, most patients were receiving maximal medical therapy by today's standards. In other words, the clinical improvement noticed in the study could not have been obtained by the current standard of care. Sotatercept could thus become the fourth pillar of PAH therapies.

However, a few questions remain, such as the correct timing of starting sotatercept. On the basis of the study results, sotatercept should be added to stable patients with WHO FC II/III already receiving background therapy. As only 40% of patients were receiving parenteral prostacyclins, one could wonder whether the remaining 60% would have further improvement by switching to a parenteral route of a prostacyclin or whether sotatercept would achieve this goal by itself. The HYPERION (Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants) and ZENITH (A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality) trials will hopefully shine some light. Questions also remain about the long-term efficacy and safety of sotatercept, which will be addressed in the ongoing SOTERIA (A Long-term Follow-up Study of Sotatercept for PAH Treatment) trial. Magnificent results, and a "STELLAR" future in pulmonary vascular disease.

References

1. Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 2019;Jan 24:[ePub ahead of print].
2. Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019;Jan 24:[ePub ahead of print].
3. Vizza CD, Lang IM, Badagliacca R, et al. Aggressive afterload lowering to improve the right ventricle: a new target for medical therapy in pulmonary arterial hypertension? Am J Respir Crit Care Med 2022;205:751-60.
4. Toshner M, Spiekerkoetter E, Bogaard H, Hansmann G, Nikkho S, Prins KW. Repurposing of medications for pulmonary arterial hypertension. Pulm Circ 2020;10:[ePub ahead of print].
5. Medrek S, Melendres-Groves L. Evolving nonvasodilator treatment options for pulmonary arterial hypertension. Curr Opin Pulm Med 2022;28:361-8.
6. Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med 2021;384:1204-15.
7. Hoeper MM, Badesch DB, Ghofrani HA, et al.; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med 2023;388:1478-90.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Lipid Metabolism, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension

Keywords: Angiotensin-Converting Enzyme Inhibitors, Activins, Pulmonary Arterial Hypertension, Familial Primary Pulmonary Hypertension, Bone Morphogenetic Proteins, Morbidity, Inflammation, World Health Organization, Transforming Growth Factors, Epoprostenol, Prostaglandins I, Follow-Up Studies, Natriuretic Peptide, Brain, Epistaxis, Confidence Intervals, Goals, Vascular Diseases, Telangiectasis, Thrombocytopenia, Hemodynamics, Hemoglobins, ACC Annual Scientific Session, ACC23

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