Randomized Phase 1 Studies Evaluating the Safety, Tolerability, Pharmacokinetics, and Target Occupancy of Zampilimab...

Zampilimab (UCB7858) is a humanized monoclonal immunoglobulin G4P, transglutaminase 2 (TG2) inhibiting antibody. We investigated safety, tolerability, pharmacokinetics, and target occupancy of zampilimab (intravenous ≤2000 mg; subcutaneous ≤1000 mg) in healthy participants in a randomized, placebo‑controlled, single-ascending-dose Phase 1 study (UP0029; NCT02879877). Of 78 participants (58 zampilimab; 20 placebo), treatment-emergent adverse events (TEAEs) occurred in 42 (72.4%) versus 14 (70%), respectively. One participant (intravenous zampilimab 2000 mg) reported a serious TEAE of moderate infusion-related reaction (a protocol-defined stopping criterion), leading to a temporary study hold. Although the reaction resolved within 3 days, and the participant completed follow up, dose-escalation was suspended, and the study terminated. Zampilimab demonstrated dose-proportional, linear pharmacokinetics (t_1/2 17-23 days; subcutaneous bioavailability 77%). TG2 target occupancy in skin directly correlated with serum zampilimab concentration, near-maximal occupancy ≥250 µg/mL, corresponding to intravenous doses ≥1000 mg between Days 2 and 5. A subsequent randomized, placebo‑controlled, Phase 1 study (UP0105; NCT04705350) investigated single intravenous doses of zampilimab (2000 and 3000 mg) at a lower concentration and slower infusion rate versus UP0029, using learnings from the administration strategy. Of 16 participants (12 zampilimab; four placebo), TEAEs occurred in eight (66.7%) versus one (25%), respectively. TEAEs were mild/moderate; none were drug related. No infusion-related reactions occurred. Zampilimab safety profile was acceptable after single intravenous and subcutaneous doses ≤1000 mg (UP0029) and intravenous doses ≤3000 mg (UP0105) following optimization of maximum concentration (10 mg/mL) at an infusion rate of 25 mg/min over 120 min. These studies support the ongoing development of zampilimab.