A Phase I, Randomized, Multi-Dose Study to Evaluate the Enteric Selectivity and Safety of JAK Inhibitor,...

Janus kinase (JAK) signaling has been implicated in human inflammatory diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Lorpucitinib (JNJ-64251330) is an oral, small molecule, pan-JAK inhibitor. Unlike systemic JAK antagonists, lorpucitinib was found to have enteric (gut)-selective properties, providing possible applications in diseases of the human gastrointestinal tract. Here, lorpucitinib was evaluated in a phase I, two-part, dosing study (NCT04552197) to assess pharmacokinetics, pharmacodynamic biomarkers, and safety in healthy participants. In part 1, 24 participants were randomized to 1 of 4 treatment arms receiving either lorpucitinib (30 mg daily, 30 mg every 12 hours (q12h), or 75 mg q12h) or tofacitinib (5 mg q12h) for 5 days. Part 2 was a food-effect study in which 12 participants received a single 75-mg dose of lorpucitinib under either fasting or fed conditions. In part 1, plasma and gut tissue concentrations of lorpucitinib showed approximately dose-proportional increases. At all doses, lorpucitinib concentrations were significantly higher (392- to 1928-fold) in the gut mucosal biopsies vs. the corresponding plasma samples, demonstrating high enteric selectivity and significantly exceeding both the tissue concentrations (> 200-fold) and tissue/plasma ratios observed with tofacitinib. JAK inhibition in biopsies was confirmed via reduction in pSTAT-3 levels. In part 2, lorpucitinib plasma concentrations were detectable but at low levels, with no statistical differences in PK parameters between the fed and fasted groups. Lorpucitinib was safe and well-tolerated, and the data may be useful in designing studies to evaluate lorpucitinib in patients with JAK/STAT-driven gastrointestinal diseases.