For 30 years, pulmonary arterial hypertension (World Health Organisation, WHO, Group 1 pulmonary hypertension) treatment relied on three vasodilator-based pathways: endothelin receptor antagonists (bosentan, ambrisentan, macitentan), the nitric oxide/cGMP pathway (sildenafil, tadalafil, riociguat), and prostacyclin pathway agents (treprostinil, epoprostenol, selexipag, etc.). These improve symptoms and slow progression but don’t modify the underlying vascular disease, and carry a significant side-effect burden (headache, hypotension, gastrointestinal issues) — especially as most patients need combination therapy.
Our comment: Pain isn’t mentioned here, but we believe it should be: it’s a significant side effect of parenteral therapy with sub-cutaneous treprostinil.
In 2024, sotatercept became the first approved activin signaling inhibitor (ASI) — a genuinely new mechanism targeting the TGF-β pathway involved in vascular remodeling, rather than just vasodilation.
The substantial pipeline of pulmonary arterial hypertension drugs targeting new mechanisms offers hope for a shift away from therapies acting primarily on vascular tone, toward ones addressing the underlying molecular drivers of abnormal vascular remodeling.
Progress on new medicines for World Health Organisation (WHO) Groups 2–5 pulmonary hypertension remains comparatively slow, though several new pulmonary arterial hypertension drug classes are in development.
Read more at this link on Clinical and Translational Science
Citation
S. Ayalasomayajula, E. K. Bajwa, A. G. Cornell, et al., “ The Evolving Landscape of Pulmonary Hypertension Treatment: From Vasodilation to Disease Modification,” Clinical and Translational Science 19, no. 8 (2026): e70685, https://doi.org/10.1111/cts.70685.