Sotatercept: A novel therapeutic approach for pulmonary arterial hypertension through transforming growth factor-β signaling modulation

Table 1 Clinical trials evaluating the role of sotatercept in pulmonary hypertension

Study	Type of study	No. of patients	Dose	Primary end point	Adverse events	Serious adverse events	Outcome	Type of PAH	Background regimen
Pulsar	Phase 2 randomized, double-blind	106 patients at 43 sites in 8 countries	0.3 or 0.7 mg/kg-1 mg/kg	To compare the efficacy and safety of sotatercept vs placebo when added to standard of care	Thrombocytopenia was the most common; Hemoglobin increase in 1 patient (3%) in the sotatercept 0.3-mg group and in 7 patients (17%) in sotatercept 0.7-mg group but in no in the placebo group	24% in 0.7 mg group	162.2 dyn. sec. cm (-5) in the sotatercept 0.3-mg group and a decrease of 255.9 dyn. sec. cm (-5) in the sotatercept 0.7-mg group, as compared with a decrease of 16.4 dyn. sec. cm (-5) in placebo	Idiopathic (58%), heritable (14%), connective tissue disorder (17%), and drug induced (7%)	Prostacyclin infusion (39%), triple therapy (57%), double therapy (34%)
Pulsar open	Phase 2, multicentre, randomised, placebo-controlled, double-blind study	106 participants	0.3 mg/kg-1 mg/kg or 0.7 mg/kg-1mg/kg	Change from baseline to months 18-24 in PVR, as measured by RHC. Change from baseline to months 18-24 in 6MWD, WHO-FC, and NT-proBNP were secondary endpoints. The study protocol was amended in July 2020 with the third RHC to be performed at month 18	TEAEs were reported in 102 (98.1%) participants, and 72 (69.2%) of these experienced TEAEs considered treatment-related	Serious TEAEs were reported in 32 (30.8%) participants. Five (4.8%) participants reported six serious TEAEs that were considered related to the study drug: Pyrexia, red blood cell increased, systemic lupus erythematosus, ischaemic stroke, pleural effusion and pulmonary hypertension	Statistically significant improvements occurred in all primary and secondary efficacy endpoints from baseline to months 18-24	Idiopathic (58%), heritable (14%), connective tissue disorder (17%), and drug induced (7%)	Triple (56.7%) or double (36.1%) background PAH therapy, and more than a third (36%) were receiving prostacyclin infusion therapy
Stellar	Phase 3 randomized, double-blind	323 underwent randomization (163 received sotatercept or 160 placebo at 91 sites in 21 countries	Starting dose of 0.3 mg/kg at visit 1 and was escalated to the target dose of 0.7 mg/kg at visit 2 (day 21, with a window of ± 3 days). Patients continued to receive a dose of 0.7 mg/kg for the duration of the trial	The change from baseline at week 24 in the 6MWD	10% of the patients in either group during the 24-week treatment period. Epistaxis, dizziness, telangiectasia, in- creased hemoglobin levels, thrombocytopenia, and increased blood pressure were common adverse events	Serious adverse events occurred in 23 patients (14.1%) in the sotatercept group and 36 patients (22.5%) in the placebo group	Sotatercept and placebo groups the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (0.001 < P)	Idiopathic (50.9%), heritable (21.5%), drug-induced (4.3%), connective-tissue disease-associated (17.8%), or after shunt correction (5.5%)	Monotherapy (5.5%), double therapy (34.4%), or triple therapy (60.1%)
Spectra	Phase 2 open label	21	Sotatercept 0.3 mg/kg	Change from baseline to week 24 in peak oxygen uptake	16 (76%)	3 (14%). Three serious TEAEs were reported (hematochezia, complication associated with central line, and fluid overload)	There was a significant improvement from baseline in peak oxygen uptake, with a mean change of 102.74 mL/min (95% CIs: 27.72-177.76; P = 0.0097)	Idiopathic (6%), heritable (4%). Associated with connetive tissue disorder (14%)	Prostacyclin infusion therapy (57%), double therapy (57%), triple therapy (43%)

PVR: Pulmonary vascular resistance; RHC: Right heart catheterisation; 6MWD: 6-minute walk distance; WHO-FC: World Health Organization functional class; NT-proBNP: N-terminal pro-B-type natriuretic peptide; TEAEs: Treatment-emergent adverse events; PAH: Pulmonary arterial hypertension.