Sotatercept: A Novel drug to the manage Pulmonary Arterial Hypertension - Mechanistic Perspectives and Clinical Implications?

Details

Supervisors

Pouleur, Anne Catherine

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences pharmaceutiques, à finalité spécialisée

Abstract

Pulmonary arterial hypertension (PAH) is a serious disease characterised by elevated pulmonary arterial pressure (mPAP >20 mmHg) associated with pulmonary vascular resistance >2 Wood units. This progressive disease is defined by pulmonary vascular remodelling and, without effective treatment, leads to right heart failure and death. Its prevalence is approximately 3 cases per 100,000 people, with a predominance in women (ratio 2.3:1). PAH results from an imbalance between vasodilator (NO, prostacyclins) and vasoconstrictor (endothelin-1) signalling pathways, but above all from a fundamental dysregulation of the TGF-β superfamily pathways. Mutations or reduced expression of the BMPR2 receptor lead to a decrease in protective BMP/Smad1/5/8 signalling, favouring overactivation of the TGF-β/activin/Smad2/3 pathway, which promotes cell proliferation, inflammation and vascular fibrosis. Conventional therapies (PDE5 inhibitors, endothelin receptor antagonists, prostacyclin analogues, soluble guanylate cyclase stimulators) mainly target vasoconstriction and not the underlying vascular remodelling. Despite advances in triple therapy, these treatments remain symptomatic, slowing progression without fundamentally altering the course of the disease, with mortality rates remaining high (7% at one year for stages I-II, 19% for stages III-IV). Sotatercept (Winrevair) is an innovative fusion protein composed of the extracellular domain of the type IIA activin receptor (ActRIIA) linked to the Fc portion of human IgG1. It acts as a ‘ligand trap’ selectively sequestering activins A and B, GDF8 (myostatin) and GDF11, thereby inhibiting the pro-proliferative Smad2/3 pathway. This mechanism restores balance with the anti-proliferative BMP/Smad1/5/8 pathway, directly targeting the fundamental pathological process of PAH. The PULSAR trial (phase II) showed a significant reduction in pulmonary vascular resistance (-33.9%, p<0.001) and an improvement in 6-minute walk distance (+29.4m, p=0.03). The STELLAR study (phase III) confirmed these results with a placebo-corrected improvement of +40.8 metres in walking distance (p<0.001), as well as a significant improvement in 8 secondary endpoints including pulmonary vascular resistance, NT-proBNP levels, functional class and time to clinical worsening or death. These benefits were observed even in patients already receiving optimal dual or triple therapy. The main adverse effects included elevated haemoglobin, moderate thrombocytopenia, cutaneous telangiectasia and epistaxis, which were generally well tolerated with a low treatment discontinuation rate. Sotatercept represents a paradigm shift in the treatment of PAH by targeting not only the symptoms but also the fundamental mechanism of vascular remodelling. Its disease-modifying potential could transform the prognosis of this condition, which until now has been considered progressively fatal despite current treatments. This innovative, recently approved therapeutic approach opens up new prospects for significantly improving long-term outcomes in patients with PAH.