Sotatercept: A first-in-class PAH medication approved in HK

Sotatercept, a first-in-class ac­tivin signalling inhibitor for pul­monary arterial hypertension (PAH), is approved in Hong Kong in August 2025,following regulatory ap­provals in Macau, the US, and the EU in February 2025.

The fourth pathway: A potential game-changer?
PAH is a rare, severe progressive disorder characterized by prolifera­tive remodelling of small pulmonary arteries and progressive luminal nar­rowing. This stems from an imbal­ance in the antiproliferative (BMPR-II– mediated) and proproliferative (ac­tivin receptor type IIA [ActRIIA]– mediated) signalling pathways. [Car­diol Clin 2016;34:363-374; N Engl J Med 2023;388:1478-1490; Eur Re­spir J 2023;61:2201347]

Over the past 20 years, PAH therapies have primarily focused on promoting vasodilation through tar­geting the endothelin-1 (ET-1), nitric oxide (NO), and prostacyclin (PGI2) pathways. Although the treatment approach has shifted from target­ing an individual pathway to more aggressive, earlier use of combina­tion therapy, morbidity and mortality have remained high, underscoring the need for new treatment op­tions that target pathways involved in pulmonary vascular remodelling. [N Engl J Med 2023;388:1478- 1490; Int J Cardiol Congenital Heart Disease 2025;doi:10.1016/j.ijc­chd.2025.100594]

Sotatercept, a first-in-class activ­in signalling inhibitor, aims to restore the balance between the antiprolif­erative and proproliferative signalling pathways. Unlike current vasodilatory therapies, sotatercept holds prom­ise as a disease-modifying therapy because it targets the underlying pathophysiological mechanism in PAH. [Int J Cardiol Congenital Heart Disease 2025;doi:10.1016/j.ijc­chd.2025.100594; Expert Opin Ther Targets 2025;29:327-343]

Improved exercise capacity
STELLAR, a multicentre, double-blind, phase III trial, evaluated the efficacy and safety of sotatercept in 323 adult patients (median age, 47.9 years; female, 79.3 percent) with PAH (WHO Group 1, function­al class II [48.6 percent] or III [51.4 percent]) who were receiving stable background therapy (triple therapy, 61.3 percent; prostacyclin infusion therapy, 39.9 percent; double thera­py, 34.7 percent; monotherapy, 4.0 percent). Patients were randomized 1:1 to receive subcutaneous sota­tercept (starting dose, 0.3 mg/kg of body weight; target dose, 0.7 mg/ kg) or placebo Q3W. [N Engl J Med 2023;388:1478-1490]

STELLAR met its primary end­point by demonstrating a significant improvement from baseline in 6-min­ute walk distance (6MWD) at week 24 with sotatercept vs placebo (40.8 meters; 95 percent confidence inter­val [CI], 27.5–54.1; p<0.001), indicat­ing improved exercise capacity.

Reduced risk of death or clinical worsening
Notably, treatment with sotater­cept resulted in an 84 percent lower risk of a composite of death from any cause or nonfatal clinical worsening event (a secondary endpoint) (5.5 vs 26.2 percent; hazard ratio [HR], 0.16; 95 percent CI, 0.08–0.35; p<0.001) vs placebo.

At week 24, statistically signifi­cant improvements with sotatercept were also reported in the majority of other prespecified secondary end­points, including:

• Multicomponent improvement (defined as meeting all three crite­ria: 6MWD, N-terminal pro-B-type natriuretic peptide [NT-proBNP] level, and WHO functional class; 38.9 vs 10.1 percent; p<0.001);
• Pulmonary vascular resistance (PVR; difference, -234.6 dyn·sec/ cm5; p<0.001);
• NT-proBNP level (difference, -441.6 pg/mL; p<0.001);
• WHO functional class improve­ment (29.4 vs 13.8 percent; p<0.001);
• French low-risk risk score (39.5 vs 18.2 percent; p<0.001);
• PAH–Symptoms and Impact (PAH-SYMPACT) Physical Im­pacts domain score (difference, -0.26; p<0.05);
• PAH-SYMPACT Cardiopulmo­nary Symptoms domain score (difference, -0.13; p<0.05).

However, the PAH-SYMPACT Cognitive/Emotional Impacts do­main score, which was assessed as the final secondary outcome measure, did not show a statistical­ly significant difference between the sotatercept and placebo groups (p>0.05).

Improved haemodynamics and right heart function
A post-hoc analysis of STELLAR demon­strated improvements in right heart catheter­ization (RHC) and echocardiographic parameters with sotatercept vs pla­cebo, which may reflect partial re­modelling of pulmonary arteries. [Eur Respir J 2023;62:2301107]