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Sotatercept improves exercise capacity in patients with PAH

Presented By
Prof. Marius Hoeper, Hannover Medical School, Germany
ACC 2023
Phase 3, STELLAR

Adding the novel, first-in-class sotatercept to background pulmonary arterial hypertension (PAH) therapy led to significant and clinically relevant improvements in exercise capacity and other endpoints in the placebo-controlled, phase 3 STELLAR trial.

Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in PAH. The first of 3 phase 3 trials evaluating this novel agent is the multicentre, randomised, double-blind, parallel-group STELLAR study (NCT04576988) [1,2]. The study, presented by Prof. Marius Hoeper (Hannover Medical School, Germany), included adults with PAH (WHO functional class II or III) on stable background therapy. Their mean age was 48 years, and 79% were women. They were randomised 1:1 to subcutaneous sotatercept (starting dose 0.3 mg/kg; target dose 0.7 mg/kg; n=163) or placebo (n=160) every 3 weeks. The primary endpoint was the median change from baseline at week 24 in the 6-minute walk distance (6MWD) test.

At 24 weeks, the observed change in the placebo group was -1.4 metres (95% CI -13.2 to 10.3) and 40.1 metres (95% CI 29.9–50.2) in the sotatercept group. The Hodges–Lehmann estimate of the difference between the 2 groups was 40.8 metres (95% CI 27.5–54.1; P<0.001). This exceeded the minimum of 33 metres that, according to earlier research, patients experienced as a noticeable improvement in their walking capacity, Prof. Hoeper said. From the 9 secondary endpoints, ranging from pulmonary vascular resistance to patient-reported symptoms, 8 were significantly improved with sotatercept versus placebo, including 2 of 3 domain scores of the Pulmonary Arterial Hypertension–Symptoms and Impact (PAH-SYMPACT) questionnaire. Prof. Hoeper stressed: “We also saw a decline in the exploratory endpoint of least-squares mean pulmonary artery pressure of 13.9 mmHg, which we have never seen before with any add-on therapy used for PAH.”

After a mean follow-up of 32.7 weeks, the number of patients who died or experienced at least 1 clinical worsening event was 42 (32.9%) in the placebo group and 9 (5.5%) in the sotatercept group, which equals a relative risk reduction of 84% (95% CI 0.08–0.35; P<0.001). Sotatercept was generally well-tolerated. Adverse events, such as bleeding events (31.9% vs 15.6%), telangiectasia (14.1% vs 3.8%), increased haemoglobin levels (6.1% vs 0%), and epistaxis (20.2% vs 1.9%), were more common in the sotatercept group.

“These results establish the clinical utility of sotatercept as a new approach to the treatment of PAH in combination with existing approved therapies,” Prof. Hoeper concluded. He expects these results to cause a paradigm shift in the treatment of PAH.

    1. Hoeper MM, et al. The STELLAR Phase III Trial: A Study Of Sotatercept In Combination With Background Therapy For The Treatment Of Pulmonary Arterial Hypertension. Session 410-14, ACC Scientific Session 2023, 4–6 March, New Orleans, USA.
    2. Hoeper MM, et al. New J Engl Med 2023; March 6. DOI: 10.1056/NEJMoa2213558.


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