Long-term use of sotatercept may allow patients with pulmonary arterial hypertension (PAH) to maintain significantly reduced pulmonary vascular resistance, according to results of an 18- to 24- month open-label extension trial published in The European Respiratory Journal.
The previously conducted 24-week, placebo-controlled, phase 2 PULSAR clinical trial (ClinicalTrials.gov Identifier: NCT03496207) found that patients with PAH taking sotatercept in addition to standard background therapy for PAH experienced a significant reduction in pulmonary vascular resistance. PULSAR investigators followed up this research with an open-label extension trial to characterize the longer-term safety and efficacy of sotatercept for PAH over 18 to 24 months.
A total of 97 of the 106 original PULSAR participants continued to the extension period. In this follow-up study, participants who received placebo in the initial trial were re-randomized to receive sotatercept at 0.3 or 0.7 mg·kg−1, while those who received sotatercept in the initial trial continued with their same dosage. Demographic and clinical characteristics were balanced between the 2 cohorts (92% White; 89% female; mean age, 47.6±14.2 years; 56% idiopathic PAH; mean time since PAH diagnosis, 7.8±5.6 years). Before starting sotatercept treatment, all participants were in World Health Organization functional classes (WHO FC) II and III for PAH. Most participants received either triple (56.7%) or double (36.1%) background therapy for PAH; 36% received prostacyclin infusion therapy.
The primary efficacy endpoint for the open-label extension study was change in pulmonary vascular resistance from baseline to months 18 to 24; 6-minute walking distance (6MWD) and functional class were secondary endpoints. Safety was assessed based on the level of treatment-emergent adverse events (TEAEs).
With respect to safety, investigators found that 98.1% of all participants reported TEAEs, with 30.8% experiencing serious TEAEs. Treatment-emergent adverse events led 9.6% of participants to discontinue the study; however these TEAEs were not considered serious. Although 2 participants died during the extension trial, their deaths were deemed unrelated to sotatercept. Notably, the level of TEAEs decreased as the duration of sotatercept treatment increased. Thrombocytopenia and increased haemoglobin were the most common hematological adverse events during both the initial and extension studies.
With respect to efficacy, the researchers found that those who had been on sotatercept in the intial PULSAR trial maintained their improvements throughout the extension study. In previous placebo participants, significant improvements were seen in pulmonary vascular resistance, 6MWD, WHO FC, and N-terminal pro-B-type natriuretic peptide.
Limitations of the extension trial include selection bias, due to the self-selected nature of the study population from the original placebo group; the open-label design; and the absence of a placebo arm.
Investigators noted that “The longer-term safety profile of sotatercept was generally consistent with that observed during the initial 24-week placebo-controlled treatment period,” and that “About 90% of the participants were classified as WHO [functional class] I or II at months 18–24.” Study authors concluded that their results “support the longer-term safety and durability of clinical benefit of sotatercept in patients with PAH.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Humbert M, McLaughlin V, Gibbs SR, et al. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J. Published online August 30, 2022. doi:10.1183/13993003.01347-2022