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- Title
The Impact of Immunogenicity on the Pharmacokinetics, Efficacy, and Safety of Sotatercept in a Phase III Study of Pulmonary Arterial Hypertension.
- Authors
Liao, Karen; Mackenzie, Harald; Ait‐Oudhia, Sihem; Manimaran, Solaiappan; Zeng, Yiyuan; Akers, Tad; Yun, Tatyana; de Oliveira Pena, Janethe
- Abstract
Sotatercept, a soluble fusion protein comprising the extracellular domain of activin receptor type IIA linked to the Fc portion of human IgG1, is a first‐in‐class activin signaling inhibitor under development for the treatment of pulmonary arterial hypertension (PAH). We evaluated antidrug antibody (ADA) development and determined the effects of immunogenicity on the pharmacokinetics (PKs), efficacy, and safety of sotatercept in STELLAR, a multicenter, double‐blind phase III trial (NCT04576988) wherein participants with PAH were randomized 1:1 to receive sotatercept (starting dose 0.3; target dose 0.7 mg/kg) or placebo subcutaneously every 3 weeks in combination with background therapies for ≤ 72 weeks. ADA‐positive (ADA‐POS) participants were identified and characterized for neutralizing antibodies (NAbs). PKs, efficacy, and safety were evaluated by ADA and NAb status. Of 162 evaluable participants, 42 (25.9%) were ADA‐POS through week 24, of whom 11 (6.8%) were also NAb‐POS. Median onset of ADAs was 3.29 weeks (interquartile range (IQR): 3.14–6.14), and median duration was 6 weeks (IQR: 3.14–17.86). No clinically meaningful differences were found across subgroups that were ADA‐NEG, ADA‐POS/NAb‐NEG, and ADA‐POS/NAb‐POS, in terms of PKs (sotatercept trough concentration over time, mean postdose trough concentration at the end of treatment, and clearance), efficacy (changes from baseline in 6‐minute walk distance, pulmonary vascular resistance, and N‐terminal pro‐B‐type natriuretic peptide levels), and safety (incidence of hypersensitivity, anaphylactic reactions, and administration site reactions). We conclude that ADA incidence from sotatercept treatment was 25.9% and did not meaningfully affect the PKs, efficacy, or safety of sotatercept in participants with PAH.
- Subjects
PULMONARY arterial hypertension; BRAIN natriuretic factor; IMMUNE response; CLINICAL trials; ACTIVIN receptors; ENDOTHELIN receptors; END of treatment
- Publication
Clinical Pharmacology & Therapeutics, 2024, Vol 115, Issue 3, p478
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1002/cpt.3116