Pulmonary arterial hypertension: treatment and sotatercept

What is pulmonary arterial hypertension?

Pulmonary hypertension is a hemodynamic condition defined by a mean pulmonary arterial pressure (mPAP) above 20 mmHg, measured by right heart catheterization². Pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR) separate pre-capillary disease (PAWP ≤15 mmHg and PVR >2 Wood units) from post-capillary forms². Pulmonary arterial hypertension (PAH), group 1 of the clinical classification, is the pre-capillary form: the pulmonary arterioles remodel, their resistance rises, and the right ventricle works against a growing load²³.

It is a rare disease. A systematic review done for the Global Burden of Disease study found 65 population-level sources and reported prevalence ranging from 0.37 to 15 cases per 100,000 persons depending on the study, summarized as 0.4 to 1.4 per 100,000; incidence ranged from 0.008 to 1.4 per 100,000 person-years, and 1-year survival from 67% to 99%³. All studies that gave sex-specific estimates reported higher levels in females³. Registries differ in methods, so these figures are approximate.

Symptoms and how it is diagnosed

Early symptoms are nonspecific (breathlessness on exertion, fatigue, dizziness or fainting with exercise), which is why diagnosis is often delayed¹. Clinical suspicion and echocardiography guide the work-up, but confirmation requires right heart catheterization, which measures mPAP, PAWP and PVR¹². The cause must then be identified: the current classification keeps five major groups and adds changes such as subgroups in groups 2 and 3 and the reintroduction of "long-term responders to calcium channel blockers" within idiopathic PAH². The distinction matters because PAH-specific drugs have been studied in group 1 and should not be extrapolated to pulmonary hypertension from left heart or lung disease¹².

In practice, European guidelines call for referral to an experienced center and for risk stratification of 1-year mortality before choosing treatment, with periodic reassessment that includes the 6-minute walk test, functional class and the natriuretic peptide NT-proBNP¹. The latter is a reminder that peptides are already part of pulmonary cardiology as biomarkers: in the sotatercept trials and in the ambrisentan plus tadalafil trial, the fall in NT-proBNP was a secondary endpoint⁸⁹.

Standard treatment today

Treatment is not a single drug. It includes supportive measures, management of fluid overload, treatment of associated causes and, in selected patients with a vasoreactive response, calcium channel blockers¹². For everyone else, the 2022 ESC/ERS guideline proposes a risk-guided strategy that combines drugs acting on three pathways: endothelin, nitric oxide and prostacyclin¹. In low- or intermediate-risk patients without associated heart disease, initial combination therapy is the reference option¹.

The AMBITION trial illustrates this. In the primary analysis of 500 participants, the primary event (death, hospitalization for PAH, disease progression or unsatisfactory clinical response) occurred in 18% with ambrisentan plus tadalafil, 34% with ambrisentan alone and 28% with tadalafil alone; against pooled monotherapy (31%) the hazard ratio was 0.50 (95% CI, 0.35 to 0.72)⁸. The combination also lowered NT-proBNP more (−67.2% vs. −50.4%) and improved the 6-minute walk more (median 48.98 m vs. 23.80 m)⁸. Refractory cases are evaluated for lung transplantation at specialized centers¹. For PAH, drug treatment changed from 2024 with the approval of sotatercept as an add-on to background therapy¹⁸¹⁹²⁰.

Endothelin and its antagonists: a peptide at the center of the disease

Endothelin-1 is a vasoconstrictor peptide produced by endothelial cells, described in Nature in 1988⁴. It is a smooth-muscle mitogen and a potent vasoconstrictor, which made it a therapeutic target in PAH⁵. To be precise: endothelin receptor antagonists (bosentan, ambrisentan and macitentan) are oral small molecules; what is peptide about this pathway is the ligand they block.

The first large trial, BREATHE-1, randomly assigned 213 patients with PAH (primary or associated with connective-tissue disease) to placebo or bosentan for at least 16 weeks. The mean difference in 6-minute walk between placebo and the combined bosentan groups was 44 m (95% CI, 21 to 67; P<0.001), and dyspnea, functional class and time to clinical worsening also improved⁵. Ambrisentan was evaluated in ARIES 1 and 2, randomized, double-blind, placebo-controlled studies⁶.

SERAPHIN was the first endothelin antagonist trial with a composite morbidity and mortality endpoint. It assigned 250 patients to placebo, 250 to macitentan 3 mg and 242 to macitentan 10 mg; the primary event occurred in 46.4%, 38.0% and 31.4%, with hazard ratios of 0.70 (97.5% CI, 0.52 to 0.96) for 3 mg and 0.55 for 10 mg versus placebo⁷. This is the strongest level of evidence for the endothelin pathway.

Sotatercept: the new treatment that changed outcomes

Sotatercept is an activin signaling inhibitor given subcutaneously every 3 weeks⁹¹⁸. The phase 3 trials studied it as an add-on to background therapy, not a replacement. In STELLAR (323 adults, functional class II or III), the median change at week 24 in 6-minute walk was 34.4 m with sotatercept and 1.0 m with placebo; the Hodges-Lehmann estimate of the difference was 40.8 m (95% CI, 27.5 to 54.1; P<0.001)⁹. Eight of nine secondary endpoints improved, including pulmonary vascular resistance and NT-proBNP; the one that did not was the PAH-SYMPACT cognitive/emotional domain⁹.

The phase 2 PULSAR study was an earlier randomized trial of sotatercept in PAH¹⁰. Its open-label extension (106 participants, 97 continued) suggested durability of benefit, with 3 deaths (2.9%) judged unrelated to the study drug¹¹. ZENITH enrolled 172 patients at high risk of death (class III or IV): the composite of death, lung transplantation or hospitalization for PAH occurred in 17.4% with sotatercept and 54.7% with placebo (hazard ratio, 0.24; 95% CI, 0.13 to 0.43)¹². It was stopped early after a prespecified interim analysis. HYPERION enrolled 320 patients diagnosed less than a year earlier at intermediate or high risk: clinical worsening occurred in 10.6% with sotatercept and 36.9% with placebo (hazard ratio, 0.24; 95% CI, 0.14 to 0.41), with median follow-up of 13.2 months; it also ended early, in this case because of loss of clinical equipoise after the earlier positive results¹³.

The FDA approved sotatercept (Winrevair) for adults with PAH in March 2024²⁰; the current label describes it as an activin signaling inhibitor indicated for adults with group 1 PAH¹⁸. The EMA authorized it on 22 August 2024 to improve exercise capacity in adults in functional class II to IV, alongside other PAH medicines¹⁹. It is therefore an approved drug, although it is a biologic and not a peptide in the strict sense.

Vasoactive intestinal peptide (aviptadil): a hypothesis that remains weak

Vasoactive intestinal peptide (VIP) is a neuropeptide that dilates systemic and pulmonary vessels. In 2003 a group reported a VIP deficiency in serum and lung tissue of patients with primary pulmonary hypertension, with upregulation of the corresponding receptors, and treated 8 patients with the peptide: a decrease in mean pulmonary artery pressure and increases in cardiac output and mixed venous oxygen saturation were observed¹⁴. It was a small, uncontrolled study, and the authors themselves called for more investigation¹⁴. Alterations of the VIP gene have also been described in patients with idiopathic PAH¹⁵. In the searches done for this article, no randomized phase 3 trial of aviptadil in PAH was identified, so the human evidence should be considered preliminary and no approved indication for this disease appears in the sources reviewed.

To place this case in a wider context, medicine already uses peptides and peptide-derived drugs in other areas with varying levels of support: see the history in A century of therapeutic peptides, the approved agents in Approved peptides in oncology, and an example of a hormone analog with phase 3 trials in Tesamorelin, the GHRH analog that did go through the FDA. The comparison is a reminder that, in every disease, the category "peptide" does not replace the key question: which randomized trial supports the drug, and with what clinical result.

Safety and contraindications

The 2024 label for macitentan with tadalafil carries a boxed warning for embryo-fetal toxicity: it must not be given to pregnant women because of the risk of fetal harm, and that label ties it to a risk evaluation and mitigation strategy (REMS)²¹. Pharmacovigilance studies based on post-marketing reports have described liver injury associated with endothelin receptor antagonists, which reinforces liver-test follow-up¹⁶¹⁷. In trials, the adverse events more frequent with macitentan than placebo were headache, nasopharyngitis and anemia⁷.

With sotatercept, the events more frequent than placebo in STELLAR were epistaxis, dizziness, telangiectasia, increased hemoglobin, thrombocytopenia and increased blood pressure⁹. The FDA label calls for monitoring hemoglobin and platelets before each of the first 5 doses, or longer if values are unstable, and not starting treatment with platelets below 50,000/mm³¹⁸. The EMA lists thrombocytopenia, epistaxis and dizziness as the most frequent serious side effects, advises against use in pregnancy, and notes that cardiovascular safety data are limited¹⁹.

Summary by agent

Frequently asked questions

Is pulmonary arterial hypertension curable? No established cure exists in most cases; current treatments aim to improve exercise capacity, reduce clinical events and delay worsening, and lung transplantation is reserved for refractory cases¹¹².

Are endothelin antagonists peptides? No. Endothelin-1 is a peptide, but bosentan, ambrisentan and macitentan are small molecules that block its receptors⁴⁵.

Is sotatercept approved? Yes. The FDA approved it in March 2024 for adults with group 1 PAH and the EMA authorized it in August 2024¹⁸¹⁹²⁰.

Are there experimental peptides for pulmonary hypertension? Vasoactive intestinal peptide was tested in 8 patients in 2003 with hemodynamic improvement, but no later randomized trial in PAH was identified, so its evidence is weak¹⁴.

What is NT-proBNP and why is it measured? It is a natriuretic peptide released when the heart is under strain; in PAH it is used to follow progress and was a secondary endpoint in the ambrisentan plus tadalafil and sotatercept trials¹⁸⁹.