Sotatercept is an activin signalling inhibitor with high selectivity for Activin-A, a dimeric glycoprotein which belongs to the transforming growth factor-β (TGF-β) superfamily of ligands. Activin-A binds to the activin receptor type IIA (ActRIIA) regulating key signalling for inflammation, cell proliferation, apoptosis, and tissue homeostasis.
Activin-A levels are increased in PAH patients. Activin binding to ActRIIA promotes proliferative signalling while there is a decrease in anti-proliferative bone morphogenetic protein receptor type II (BMPRII) signalling. The imbalance of ActRIIA-BMPRII signalling underlying PAH results in vascular cell hyperproliferation, causing pathological remodelling of the pulmonary arterial wall, narrowing the arterial lumen, increasing pulmonary vascular resistance, and leads to increased pulmonary artery pressure and right ventricular dysfunction.
Sotatercept consists of a recombinant homodimeric activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein, which acts as a ligand trap that scavenges excess Activin-A and other ligands for ActRIIA to inhibit activin signalling. As a result, sotatercept rebalances the pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signalling to modulate vascular proliferation.
A phase 2 clinical study (PULSAR) assessed pulmonary vascular resistance (PVR) in patients with PAH after 24 weeks of treatment with sotatercept. The decrease from baseline in PVR was significantly greater in the sotatercept 0.7 mg/kg and 0.3 mg/kg groups compared with the placebo group. The placebo-adjusted least squares (LS) mean difference from baseline was -269.4 dyn*sec/cm5 (95% CI: -365.8, -173.0) for the sotatercept 0.7 mg/kg group and -151.1 dyn*sec/cm5 (95% CI: -249.6, -52.6) for the sotatercept 0.3 mg/kg group.
In rat models of PAH, a sotatercept analogue reduced expression of pro-inflammatory markers at the pulmonary arterial wall, reduced leucocyte recruitment, inhibited proliferation of endothelial and smooth muscle cells, and promoted apoptosis in diseased vasculature. These cellular changes we re associated with thinner vessel walls, reversed arterial and right ventricular remodelling, and improved haemodynamics.
In patients with PAH, the geometric mean (% Coefficient of variation (CV )) steady-state AUC and steady-state peak concentration (Cmax) at the dose of 0.7 mg/kg every 3 weeks were 171.3 mcg×d/mL (34.2) and 9.7 mcg/mL (30%), res pectively. Sotatercept AUC and Cmax increase proportionally with dose. Steady state is achieved after approximately 15 weeks of treatment. The accumulation ratio of sotatercept AUC was approximately 2.2.
The subcutaneous (SC) formulation has an absolute bioavailability of approximately 66% based on population pharmacokinetics analysis. The maximum sotatercept concentration is achieved at a median time to peak drug concentration (Tmax) of approximately 7 days (range from 2 to 8 days) after multiple dosing every 4 weeks.
The central volume of distribution (CV%) of sotatercept is approximately 3.6 L (24.7%). The peripheral volume of distribution (CV%) is approximately 1.7 L (73.3%).
Sotatercept is catabolised by general protein degradation processes.
Sotatercept clearance is approximately 0.18 L/day. The geometric mean terminal half-life (CV%) is approximately 21 days (33.8%).
No clinically signi ficant differences in sotatercept pharmacokinetics (PK) were observed based on age (18 to 81 years of age), sex, or ethnic origin (82.9% Caucasian, 3.1% Black, 7.1% Asian, and 6.9% other).
The clearance and central volume of distribution of sotatercept increase with increasing body weight. The recommended weight-based dosing regimen results in consistent sotatercept exposures.
Sotatercept pharmacokinetics was comparable in PAH patients with mild to moderate renal impairment (eGFR ranging from 30 to 89 mL/min/1.73m²) to those with normal renal function (eGFR ≥90 mL/min/1.73m²). Additionally, sotatercept PK is comparable between non-PAH end-stage renal disease (ESRD) patients and patients with normal renal function. Sotatercept is not dialyzable during haemodialysis. Sotatercept has not been studied in PAH patients with severe renal impairment (eGFR <30 mL/min/1.73m²).
Sotatercept has not been studied in PAH patients with hepatic impairment (Child-Pugh Classification A to C). Hepatic impairment is not expected to influence sotatercept metabolism since sotatercept is metabolised via cellular catabolism.
No carcinogenicity or mutagenicity studies have been conducted with sotatercept.
In rats and monkeys, the longest SC toxicity studies were 3 months and 9 months in duration, respectively. In rats, adverse findings included efferent duct/testicular degeneration, adrenal gland congestion/necrosis, and membranoproliferative glomerulonephritis and tubulointerstitial nephritis in the kidneys. Kidney changes were not reversible following a 1-month recovery period. In monkeys, adverse changes included increased interstitial matrix at the corticomedullary junction, decreased glomerular tuft size, glomerulonephritis and tubulointerstitial nephritis in the kidney. Kidney changes in monkeys partially resolved following a 3-month recovery period. At the no observed adverse effect level (NOAEL) in rats and monkeys, sotatercept exposures were ≤2-times the clinical exposure at the maximum recommended human dose (MRHD). Other findings that occurred at clinical exposure margins in monkeys included hepatic inflammatory infiltrates, lymphoid depl etion in spleen, and inflammatory infiltrates in the choroid plexus.
In a female fertility study, oestrous cycle duration was increased, pregnancy rates were decreased, there were increases in pre-implantation and post-implantation loss and reductions in live litter size. At the NOAEL for female fertility endpoints, sotatercept exposure was 2-times the clinical AUC at the MRHD.
In males, there were non-reversible histologic changes in the efferent ducts, testes, and epididymides. Histomorphologic changes in rat testes correlated to decreased fertility index that reversed during the 13-week treatment-free period. A NOAEL for testicular histologic changes was not established and the NOAEL for male fertility functional changes provides a systemic exposure 2-times the clinical exposure at the MRHD.
In embryo-fetal developmental toxicity studies, effects in rats and rabbits included reductions in numbers of live foetuses and fetal body weights, delays in ossification, and increases in resorptions and post-implantation losses. In rats only, there were also skeletal variations (increased number of supernumerary ribs and changes in the number of thoracic or lumbar vertebrae). At the NOAEL in rats and rabbits, sotatercept exposures were 2-times and 0.4-times, respectively, the clinical exposure at the MRHD.
In a pre- and postnatal development study in rats, no sotatercept related adverse effects were observed in first filial generation (F1) pups from dams dosed during gestation at estimated exposures up to 2-times the MRHD. In F1 pups from dams dosed during lactation, decreases in pup weight correlated with delays in sexual maturation. The NOAEL for effects on growth and maturation in pups provides a systemic exposure 0.6-times the clinical exposure at the MRHD.
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