Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials

Abstract

Olamkicept selectively inhibits the cytokine interleukin-6 (IL-6) trans-signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first-in-human, randomized, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment-emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion-related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose-independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 μg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.

FIGURE 1

IL‐6 trans‐signaling and classic signaling. IL‐6, interleukin‐6; P, phosphorylation: STAT3, signal transducer and activator of transcription‐3.

FIGURE 2

Mean olamkicept serum concentration–time curves after single IV infusion and SC administration in the SAD trial for (a) healthy subjects, and (b) patients with Crohn's disease. IV, intravenous; SAD, single‐ascending dose; SC, subcutaneous.

FIGURE 3

Mean olamkicept serum concentration–time curves after multiple IV infusions in the MAD trial. IV, intravenous; MAD, multiple‐ascending dose.

FIGURE 4

The mean ratio of phosphorylated/non‐phosphorylated STAT3 versus time in (a) SAD part 1, (b) SAD part 2, (c) MAD trials for IV and SC administration, and (d) concentration‐dependent ratio of phosphorylated/non‐phosphorylated STAT3 in SAD and MAD trials. IV, intravenous; MAD, multiple‐ascending dose; SAD, single‐ascending dose; SC, subcutaneous; SE, standard error; STAT3, signal transducer and activator of transcription‐3.