Therapeutic innovation in the fight against pulmonary arterial hypertension
Pulmonary arterial hypertension is a rare and serious cardiopulmonary disease characterised by intense remodelling of the small-calibre pulmonary arteries. Either idiopathic (without a proven cause) or hereditary (linked to a genetic abnormality), it affects approximately 15 people per million inhabitants in France. While current treatments improve the symptoms of the disease, none of them leads to a cure. Recently however, as part of the international PULSAR study, researchers from the Pulmonary Hypertension: Physiopathology and Therapeutic Innovation laboratory (HPPIT - Université Paris-Saclay, Inserm), in collaboration with their colleagues from the Bicêtre Hospital (AP-HP) and other international research and medical departments, have succeeded in identifying a promising new therapeutic target. Based on an in-depth understanding of the familial forms of the disease, the research team has taken a decisive step towards the development of a new treatment to complement reference treatment for the disease.
A rare lung disease, pulmonary arterial hypertension (PAH) is characterised by increased blood pressure in the arteries that connect the right side of the heart to the lungs. During the course of the disease, small pulmonary arteries of less than 0.5 mm thicken and become blocked due to a progressive accumulation of cells in the vessel wall – a process known as vascular remodelling. As this remodelling impedes the flow of blood through the vessels of the lungs, the pulmonary arterial pressure increases. This resistance puts strain on the heart, which may eventually stop functioning normally, resulting in right heart failure. Without effective treatment, PAH causes progressive shortness of breath on exertion and then when resting, and life-threatening discomfort and syncope in the short to medium term.
Current treatments mainly include vasodilators, which improve patients' exercise tolerance and quality of life, slow disease progression and prolong survival. However, none of these treatments can cure patients. Despite the combination of vasodilators, half of patients die within seven years of being diagnosed with PAH.
A key receptor
Nonetheless, great strides have been made in the last 20 years in understanding the cellular and molecular mechanisms of the disease, particularly in its inherited (or familial) forms. These mainly originate from mutations in the gene coding for the bone morphogenetic protein receptor type II (BMPR-II). BMPR-II, a member of the transforming growth factor TGF- superfamily, limits cell proliferation and accumulation of vascular cells in pulmonary artery walls. Defects in this signalling pathway remove a physiological brake, disrupting the homeostasis of the lung vessels. Recently, studies have shown that ligands of the activin type IIA receptor (ActRIIA) are responsible for this surge in cell proliferation when the BMPR-II pathway malfunctions. Similar mechanisms are also involved in other forms of non-familial PAH.
Equipped with this detailed understanding of the disease, a team of researchers from the Pulmonary Hypertension: Physiopathology and Therapeutic Innovation laboratory (HPPIT - Université Paris-Saclay, Inserm), the Bicêtre Hospital AP-HP and other American, English, German, Brazilian and Spanish research and medical departments, decided to explore the therapeutic potential of sotatercept, a compound developed by the American laboratory Acceleron. A fusion of the extracellular portion of the ActRIIA receptor and the constant fragment of a human immunoglobulin IgG1, sotatercept works like an ActRIIA ligand trap. By trapping these ligands, it prevents the excessive activation of vascular proliferation pathways released from the BMPR-II brake and restores pulmonary vascular homeostasis.
Sotatercept, a clinical trial with promising results
To demonstrate this, the team conducted a multi-centre, 24-week, phase 2 trial. The 106 adult patients involved in the trial received background treatment for PAH beforehand, including two or three vasodilators for the majority of them. The team then administered either sotatercept subcutaneously at a dose of 0.3 mg per kilogram or 0.7 mg per kilogram of body weight every 3 weeks or a placebo (PULSAR study, NCT03496207). The results showed that sotatercept, which was relatively safe and well tolerated, reduces pulmonary vascular resistance, as measured by a cardiac catheter. The trial also demonstrated improved exercise capacity in patients treated with sotatercept, measured by a six-minute walk test, and an improvement in various biomarkers of heart function.
Based on these conclusive results, patients have now entered an extension phase to evaluate the long-term safety and efficacy of sotatercept. New phase 3 studies have begun or are planned for this therapeutic innovation, which is already a promising step forward in the treatment of PAH and a beacon of hope for patients.
- Humbert, Marc ; McLaughlin, Vallerie ; Gibbs, J. Simon R. ; Gomberg-Maitland, Mardi ; Hoeper, Marius M. ; Preston, Ioana R.; Souza, Rogerio ; Waxman, Aaron ; Escribano Subias, Pilar ; Feldman, Jeremy ; Meyer, Gisela ; Montani, David ; Olsson, Karen M. ; Manimaran, Solaiappan ; Barnes, Jennifer ; Linde, Peter G. ; de Oliveira Pena, Janethe ; Badesch, David B. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2021; 384:1204-15.
- Guignabert C, Humbert M. Targeting transforming growth factor-β receptors in pulmonary hypertension. Eur Respir J. 2021 Feb 4;57(2):2002341.