Sotatercept Safety and Effects on Hemoglobin, Bone, and Vascular Calcification

Abstract

IntroductionPatients with end-stage kidney disease (ESKD) exhibit anemia, chronic kidney disease‒mineral bone disorder (CKD–MBD), and cardiovascular disease. The REN-001 and REN-002 phase II, multicenter, randomized studies examined safety, tolerability, and effects of sotatercept, an ActRIIA-IgG1 fusion protein trap, on hemoglobin concentration; REN-001 also explored effects on bone mineral density (BMD) and abdominal aortic vascular calcification.MethodsForty-three patients were treated in REN-001 (dose range: sotatercept 0.3‒0.7 mg/kg or placebo subcutaneously [s.c.] for 200 days) and 50 in REN-002 (dose range: 0.1‒0.4 mg/kg i.v. and 0.13‒0.5 mg/kg s.c. for 99 days).ResultsIn REN-001, frequency of achieving target hemoglobin response (>10 g/dl [6.21 mmol/l]) with sotatercept was dose-related and greater than placebo (0.3 mg/kg: 33.3%; 0.5 mg/kg: 62.5%; 0.7 mg/kg: 77.8%; 0.7 mg/kg [doses 1 and 2]/0.4 mg/kg [doses 3‒15]: 33.3%; placebo: 27.3%). REN-002 hemoglobin findings were similar (i.v.: 16.7%−57.1%; s.c.: 11.1%‒42.9%). Dose-related achievement of ≥2% increase in femoral neck cortical BMD was seen among only REN-001 patients receiving sotatercept (0.3‒0.7 mg/kg: 20.0%‒57.1%; placebo: 0.0%). Abdominal aortic vascular calcification was slowed in a dose-related manner, with a ≤15% increase in Agatston score achieved by more REN-001 sotatercept versus placebo patients (60%‒100% vs. 16.7%). The most common adverse events during treatment were hypertension, muscle spasm, headache, arteriovenous fistula site complication, and influenza observed in both treatment and placebo groups.ConclusionIn patients with ESKD, sotatercept exhibited a favorable safety profile and was associated with trends in dose-related slowing of vascular calcification. Less-consistent trends in improved hemoglobin concentration and BMD were observed.

Therapeutic Approaches for Treating Pulmonary Arterial Hypertension by Correcting Imbalanced TGF-β Superfamily Signaling

“…It was also associated with clinically meaningful improvements in 6-min walk distance and circulating levels of N-terminal pro-B-type natriuretic peptide, a marker for cardiac dysfunction. Sotatercept has previously been evaluated in healthy volunteers and patients with conditions characterized by dysfunctional TGF-β superfamily signaling, including anemia associated with myelodysplastic syndromes, anemia associated with β-thalassemia, chemotherapy-induced anemia, end-stage kidney disease, bone loss, and multiple myeloma ( 168 – 174 ). As a result, substantial data are already available regarding sotatercept's safety profile.…”

“…Ongoing clinical studies of sotatercept in PAH patients include a phase 2 study for detailed characterization of cardiopulmonary status by right heart catheterization with exercise (NCT03738150) and several phase 3 registration-enabling studies (NCT04576988, NCT04811092, NCT04896008). Interestingly, several clinical studies have determined that sotatercept increases circulating hemoglobin concentrations under diverse conditions ( 169 , 171 – 174 ). It has been observed that a large proportion of PAH patients exhibits anemia and could therefore receive sotatercept with acceptable erythropoietic effects ( 175 ).…”

Clinical Approach to Vascular Calcification in Patients With Non-dialysis Dependent Chronic Kidney Disease: Mineral-Bone Disorder-Related Aspects

“…Finally, the fact that a statin paradox exists (statins promoted coronary atheroma calcification but improved clinical outcomes) (149) means that the implication of VC may be reconsidered (150). Nevertheless, many experimental and/or preliminary clinical studies on VC with different compounds are ongoing (151)(152)(153)(154)(155)(156)(157)(158)(159)(160). Thus, other factors (directly or indirectly related with CKD-MBD) such as magnesium, vitamin K, inhibitors of intestinal P transporters, bisphosphonates, denosumab, sodium thiosulfate, alkaline phosphatase inhibitors, apabetalone, sotatercept, recombinant BMP-7, as well as metformin, antioxidants, spironolactone, senolytics, zinc, and the recently tested SNF472 (35, 161, 162) have been shown to potentially attenuate VC.…”

Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

“…Interestingly, sotatercept was also tested in HD patients in two phase II, multicenter, randomized trials, REN-001 and REN-002 [124]. In these studies, the safety, tolerability, and effects of different dosages of sotatercept (from 0.1 to 0.7 mg/kg) on hemoglobin concentration were evaluated; in addition, in REN-001, the effects of sotatercept on bone mineral density (BMD) and abdominal aortic vascular calcification were also explored.…”