Background/Purpose: AZD1163 is a novel bispecific antibody that inhibits the activity of extracellular Peptidyl Arginine Deiminases (PADs) 2 and 4, enzymes responsible for protein citrullination in patients with Rheumatoid Arthritis (RA). In susceptible individuals, citrullinated proteins activate a cascade of T cell driven events, promoting B cell maturation and activation, leading to the production of pathogenic anti-citrullinated protein antibodies (ACPA). ACPAs are associated with a worse prognosis, often translating to more severe joint damage and a rapidly progressing disease course. In vitro, AZD1163 inhibits protein citrullination and increased PAD activity present in serum and synovial fluid from patients with RA. The aim is to present the first clinical findings on AZD1163 safety and tolerability, pharmacokinetic properties, and pharmacodynamic effect of AZD1163 on systemic PAD enzyme activity in healthy volunteers.

Methods: This randomized, double-blind, placebo-controlled Phase I study (NCT06103877) in healthy participants comprised of two parts: Part A consisted of nine single-ascending dose (SAD) cohorts, each receiving AZD1163 mg intravenous infusion or placebo, where one dose level was administered subcutaneously (SC). In the first two cohorts, 2 participants received AZD1163 and 1 received placebo. Subsequent cohorts had 6 (or 8 for the SC cohort) participants on AZD1163 and 2 (or 3 for the SC cohort) on placebo. Part B included two multiple-ascending dose (MAD) cohorts dosed twice, two weeks apart (Q2W), with either AZD1163 SC or placebo. In each cohort, 6 participants received AZD1163 and 3 received placebo. Safety and tolerability were assessed through the evaluation of adverse events, clinical chemistry/hematology, ECG, and vital signs. PK characteristics and immunogenic profile of AZD1163 were evaluated through repeated sampling in serum. Inhibition of solid phase bound histone H3 citrullination (% change from baseline) was used to demonstrate ex vivo AZD1163 target engagement.

Results: Sixty-five participants were included in the SAD and eighteen in the MAD. A dose proportional exposure increase was observed for AZD1163, with maximum concentration occurring 10 days post-SC dose. The bioavailability following SC dosing was estimated at 65 %. Mean systemic clearance was 0.15 L/day and the mean elimination half-life was 38 days. A significant, dose dependent inhibition of PAD2/4 activity was observed, with maximum inhibition exceeding 95%, confirming target engagement. Anti-drug antibodies (ADA) incidence was low at 6.7% among AZD1163 recipients. Adverse events were few and escalating doses were well-tolerated. No trends were evident in vital assessments, lab values, or ECGs.

Conclusion: This first-in-human study of a novel bispecific antibody inhibiting PAD 2 and 4 enzymes, demonstrated that Q2W dosing of AZD1163 was well tolerated in healthy volunteers, with favorable PK characteristics in the dose range studied. Target engagement was demonstrated by inhibition of PAD2/4 activity ex vivo in plasma. Results generated from this Phase I study, supports the further evaluation of AZD1163 in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/azd1163-a-novel-bispecific-human-antibody-targeting-pad2-4-enzymes-responsible-for-generating-citrullinated-protein-auto-antigens-in-rheumatoid-arthritis-demonstrates-dose-dependent-inhibition-of-sy/