In vivo affinity and target engagement in skin and blood in a first‐time‐in‐human study of an anti‐oncostatin M monoclonal antibody

Abstract

AimsThe oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first‐time‐in‐human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti‐OSM monoclonal antibody, in healthy subjects.MethodsThis was a phase I, randomized, double‐blind, placebo‐controlled, single‐dose escalation, first‐time‐in‐human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target‐mediated drug disposition (TMDD) models in combination with compartmental and physiology‐based pharmacokinetic (PBPK) models.ResultsThirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose‐dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1–6 mg kg–1. The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model.ConclusionsSingle subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome

“…Loss of OSM signaling may explain the severe congenital thrombocytopenia in A-II-2. Genetic ablation of either OSM (Sato et al, 2014) or OSM receptor (Tanaka et al, 2003) in mice is associated with thrombocytopenia, and a first-time-in-human study of an anti-OSM monoclonal antibody (GSK2330811) was associated with thrombocytopenia (Reid et al, 2018). Patient C-II-3 survived infancy and developed additional immunologic symptoms of eczematoid dermatitis reminiscent of defective IL-6/GP130/ STAT3 signaling, as observed in previous GP130 homozygous patients with missense variants in IL6ST (Schwerd et al, 2017;Shahin et al, 2019).…”

Novel Analgesics with Peripheral Targets

“…A wider use has been demonstrated with inflammatory heart failure [ 430 ]. A trial with oncostatin M monoclonal antibody GSK2330811 has completed phase I (phase II ongoing) [ 431 ]. Therapeutic options for a more general anti-inflammatory use can still be conceptualized.…”

Stromal Oncostatin M axis promotes breast cancer progression

“…Interestingly, anti-OSM humanized antibodies have proven to be safe and well tolerated 19 and are now in Phase 2 clinical trials for the treatment of inflammatory diseases, such as systemic sclerosis and Crohn's disease. Together, our findings further strengthen the case for the preclinical investigation of OSM:OSMR blocking antibodies as a targeted anti-cancer therapy.…”

“…antibodies against OSM are being tested in clinical trials for the treatment of inflammatory diseases and have shown to be safe and well tolerated 19 .…”