AZD1163 is a novel bispecific antibody that suppresses the function of extracellular Peptidyl Arginine Deiminases (PAD) 2 and 4, the enzymes responsible for generating citrullinated protein auto-antigens in rheumatoid arthritis (RA). In susceptible individuals with RA, citrullinated proteins trigger a T cell–mediated cascade that promotes B cell maturation and activation, culminating in the production of pathogenic anti–citrullinated protein antibodies (ACPA). ACPAs are linked to poorer outcomes, frequently leading to more pronounced joint damage and a faster disease trajectory.

AZD1163 has been shown to bind with high affinity to PAD2 and PAD4 and in vitro inhibits all PAD activity1.

To present safety, pharmacokinetics (PK), and target engagement of AZD1163 from an interim analysis of a Phase 1 study in healthy volunteers (NCT06103877) together with the subsequent Phase 2b Study Design of AZD1163 in patients with moderately-to-severely active RA (NCT07276581).

The randomized, double-blind, placebo-controlled Phase I study in healthy volunteers comprised of single-ascending dose (SAD) and multiple ascending-dose (MAD) cohorts. There were nine SAD cohorts, each receiving AZD1163 or placebo: eight cohorts dosed intravenously and one subcutaneously (SC). There were two MAD cohorts dosed twice, two weeks apart (Q2W), with either AZD1163 SC or placebo.

Safety and tolerability of all cohorts were assessed through evaluation of adverse events, clinical chemistry/hematology, ECG, and vital signs. PK characteristics of AZD1163 were evaluated through repeated serum sampling. Inhibition of solid phase bound histone H3 citrullination (% change from baseline) was used to demonstrate ex vivo AZD1163 target engagement.

There were sixty-five healthy volunteers in the nine SAD cohorts and eighteen in the two MAD cohorts. Adverse events were few and mild. AZD1163 was well-tolerated in healthy volunteers, and no trends were evident in vital signs, lab values, or ECGs.

A dose proportional exposure increase was observed for AZD1163 with maximum concentration occurring 10 days following the SC dose and the mean elimination half-life was 38 days2. Dose-dependent inhibition of PAD2/4 activity was observed, with maximum inhibition exceeding 95% confirming target engagement2.

Based on these results, a Phase 2b dose-ranging global study of AZD1163 in patients with moderately-to-severely active RA has commenced. This is a 24-week study consisting of four treatment arms, three receiving AZD1163 and one receiving placebo. This study includes patients with RA receiving csDMARD and/or TNF inhibitor background standard of care therapy.

Results from the Phase 1 first-in-human study confirm that AZD1163 was safe and well tolerated following single and repeated SC dosing, with favorable PK in the dose levels studied, and near total inhibition of PAD activity. These results support further evaluation of AZD1163 in patients with moderately-to-severely RA in the ongoing Phase 2b study.

Reference

1.      Sims DA, Andrews J, Kuriakose T, et al. ‘OP0110 AZD1163 - First-in-class anti-PAD2/4 bi-specific antibody for the treatment of Rheumatoid Arthritis’. Annals of the Rheumatic Diseases 2024; 83:54.

2.      Prothon S, Leander J, Seppälä U, et al. ‘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 Systemic PAD Activity in Healthy Volunteers’. Arthritis Rheumatol. 2025; 77 (suppl 9).