Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: antihypertensives, antihypertensives for pulmonary arterial hypertension
ATC code: C02KX06
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.
The efficacy of sotatercept was evaluated in adult patients with PAH in the pivotal STELLAR study. STELLAR was a double-blind, placebo-controlled, multicentre, parallel-group clinical study in which 323 patients with PAH (WHO Group 1 Functional Class II or III) were randomised 1:1 to sotatercept (starting dose 0.3 mg/kg escalated to target dose 0.7 mg/kg) (n=163) or placebo (n=160) administered subcutaneously once every 3 weeks. Patients continued their treatment assignment in the long-term double-blind treatment period until all patients completed Week 24.
Participants in this study were adults with a median age of 48.0 years (range: 18 to 82 years), of which 16.7% were ≥65 years of age. Median weight was 68.2 kg (range: 38.0 to 141.3 kg); 89.2% of participants were White, and 79.3% were not Hispanic or Latino; and 79.3% were female. The most common PAH aetiologies were idiopathic PAH (58.5%), heritable PAH (18.3%), and PAH associated with connective tissue diseases (14.9%), PAH associated with simple congenital heart disease with repaired systemic-to-pulmonary shunts (5%), or drug or toxin-induced PAH (3.4%). The mean time since PAH diagnosis to screening was 8.76 years.
Most participants were receiving either triple (61.3%) or double (34.7%) background PAH therapy, and more than one-third (39.9%) were receiving prostacyclin infusions. The proportions of participants in WHO FC II was 48.6% and in WHO FC III was 51.4%. The STELLAR study excluded patients diagnosed with HIV -associated PAH, PAH associated with portal hypertension, schistosomiasis-associated PAH, and PVOD.
The primary efficacy endpoint was the change from baseline at Week 24 in 6-Minute Walk Distance (6MWD). In the sotatercept treatment group, the median of the placebo-adjusted change in 6MWD from baseline at Week 24 was 40.8 meters (95% CI: 27.5, 54.1; p<0.001). The median of the placebo-adjusted changes in 6MWD at Week 24 were also evaluated in subgroups. The treatment effect was consistent across the different subgroups including sex, PAH diagnostic group, background therapy at baseline, prostacyclin infusion therapy at baseline, WHO FC, and baseline PVR.
The secondary endpoints included improvements in multicomponent improvement (MCI), PVR, N-terminal pro-B-type natriuretic peptide (NT-proBNP), WHO FC, time to death or first occurrence of clinical worsening events.
MCI was a pre-defined endpoint measured by the proportion of patients achieving all three of the following criteria at Week 24 relative to baseline: improvement in 6MWD (increase ≥30 m), improvement in NT-proBNP (decrease in NT-proBNP ≥30% or maintenance/achievement of NT-proBNP level <300 ng/L), and improvement in WHO FC or maintenance of WHO FC II.
Disease progression was measured by the time to death or first occurrence of a clinical worsening event. Clinical worsening events included worsening-related listing for lung and/or heart transplant, need to initiate rescue therapy with an appro ved background PAH therapy or the need to increase the dose of infusion prostacyclin by ≥10%, need for atrial septostomy, hospitali sation for worsening PAH (≥24 hours), or deterioration of PAH (worsened WHO FC and decrease in 6MWD ≥15% with both events occurring at the same time or different times). Clinical worsening events and death were captured until the last patient completed the Week 24 visit (data up to the data cutoff; median duration of exposure 33.6 weeks).
At Week 24, 38.9% of sotatercept-treated patients showed improvement in MCI versus 10.1% in the placebo group (p<0.001). The median treatment difference in PVR between sotatercept and placebo group was -234.6 dyn*sec/cm5 (95% CI: -288.4, -180.8; p<0.001). The median treatment difference in NT-proBNP between the sotatercept and placebo groups was -441.6 pg/mL (95% CI: -573.5, -309.6; p<0.001). Improvement in WHO FC from baseline occurred in 29% of patients in sotatercept versus 13.8% in placebo (p<0.001).
Treatment with sotatercept resulted in an 82% reduction (HR 0.182, 95% CI: 0.075, 0.441; p<0.001) in the occurrence of death or clinical worsening events compared to placebo (see Table 4). The treatment effect of sotatercept versus placebo started by Week 10 and continued for the duration of the study.
Table 4. Death or clinical worsening events:
| Placebo (N=160) | Sotatercept (N=163) | |
|---|---|---|
| Total number of subjects who experienced death or at least one clinical worsening event, n (%) | 29 (18.1) | 7 (4.3) |
| Assessment of death or first occurrence of clinical worsening events*, n (%) | ||
| Death | 6 (3.8) | 2 (1.2) |
| Worsening-related listing for lung and/or heart transplant | 1 (0.6) | 1 (0.6) |
| Need for atrial septostomy | 0 (0.0) | 0 (0.0) |
| PAH-specific hospitalisation (≥24 hours) | 8 (5.0) | 0 (0.0) |
| Deterioration of PAH† | 15 (9.4) | 4 (2.5) |
* A subject can have more than one assessment recorded for their first event of clinical worsening. There were 2 participants receiving placebo and no participant receiving sotatercept who had more than one assessment recorded for their first event of clinical worsening. This analysis excluded the component “need to initiate rescue therapy with an approved PAH therapy or need to increase the dose of infusion prostacyclin by 10% or more”.
† Deterioration of PAH is defined by both of the following events occ urring at any time, even if they began at different times, as compared to their baseline values: (a) Worsened WHO functional class (II to III, III to IV, II to IV, etc.); and (b) D ecrease in 6MWD by ≥15% (confirmed by two 6MWTs at least 4 hours apart but no more than one week).
N = number of subjects in FAS population; n = number of subjects in the category. Percentages are calculated as (n/N)*100.
At Week 24 in STELLAR, anti-drug antibodies (ADA) were detected in 44/163 (27%) of patients taking sotatercept. Among these 44 patients, 12 tested positive for neutrali sing antibodies against sotatercept. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
The European M edicines Agency has deferred the obligation to submit the results of studies with Winrevair in one or more subsets of the paediatric population in the treatment of pulmonary arterial hypertension (see section 4.2 for information on paediatric use).
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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