Pulmonary arterial hypertension (PAH) is a severe disease characterized by proliferative remodeling of the small pulmonary arteries, leading to progressive luminal narrowing. This results in elevated pulmonary artery pressure, which strains the heart and can eventually lead to right ventricular failure and death. Available treatments for PAH include phosphodiesterase-5 inhibitors, endothelin-receptor antagonists, soluble guanylate cyclase stimulators, and compounds targeting the prostacyclin pathway.
These treatments have shown improvements in pulmonary hemodynamics, exercise capacity, and progression-free survival, but median survival remains limited to 5-7 years after diagnosis, with no significant improvements in recent years. The STELLAR trial published in The New England Journal Of Medicine showed that the addition of 24-week treatment with sotatercept to background therapy with currently available medications improved exercise capacity, as assessed by the 6-minute walk distance, in patients with pulmonary arterial hypertension (PAH).
This improvement was observed along with other positive outcomes, including reductions in pulmonary vascular resistance, improvements in WHO functional class, NT-proBNP levels, and risk of death assessed using the simplified French risk model. The trial also showed improved quality of life as measured by the PAH-SYMPACT tool. The risk of death or nonfatal clinical worsening events was 84% lower with sotatercept compared to placebo. The safety profile of sotatercept was consistent with previous studies, with the most notable side effects being telangiectasia and bleeding (mainly epistaxis and gingival bleeding).
The benefit of sotatercept was observed across most prespecified subgroups, including patients receiving triple background therapy with subcutaneous or intravenous prostacyclin analogs, currently considered the maximum therapy for patients with PAH. The trial also used a multicomponent measurement to define clinical improvement, which encompassed treatment effects on 6-minute walk distance, NT-proBNP levels, and WHO functional class.
This approach is based on a recent registry analysis that showed multi-component improvement to be associated with a more than 50% reduction in the relative risk of death. However, whether multi-component improvement represents a robust surrogate endpoint for clinical outcomes, including functional impairment, clinical worsening events, and death, will require validation in larger, prospectively designed studies.
The adverse-event profile observed with sotatercept treatment was generally consistent with previous studies. Increases in hemoglobin levels, a known effect of sotatercept, were reported as adverse events in a small percentage of patients and were manageable with dose interruptions or reductions. The incidence of telangiectasia, an adverse event of particular interest, was higher among patients who received sotatercept compared to placebo, and ongoing and future studies will continue to evaluate the incidence and clinical relevance of this side effect with longer-term treatment.
There are some limitations to the generalizability of the trial results, including the enrollment of only WHO functional class II or III patients with certain forms of PAH, underrepresentation of patients with PAH associated with connective-tissue disease, congenital heart disease, or drugs and toxins, as well as minority groups and patients from outside North America and Europe.
The trial also excluded patients with baseline pulmonary vascular resistance values below a certain threshold, which may not reflect the broader hemodynamic definition of PAH in updated guidelines. The clinical importance of the improvements observed in the quality-of-life scores is still being determined due to the lack of established minimal clinically significant differences.
Potential unblinding could have occurred due to side effects such as telangiectasia or hematologic changes. The median treatment period of 7.5 months reported in the trial may not establish the long-term durability of treatment response, including safety and adverse-event profile during long-term administration. These aspects will be further explored in ongoing studies.
Finally, the trial was not designed nor powered to study the effects of sotatercept on mortality. Overall, the STELLAR trial demonstrated that treatment with sotatercept improved exercise capacity and showed clinical benefit across multiple efficacy endpoints in patients with PAH. The benefit-to-risk ratio was favorable, confirming and extending the results of previous studies.