SAT0254 Safety and Tolerability of the Anti-C5ar Humanised Monoclonal Antibody NNC0151-0000 in Patients with Rheumatoid Arthritis: A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Multiple-Dose Trial
Authors: S. Daniluk, B.K. Skrumsager, P. Leszczynski
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The 1st generation compound NNC0151-0000 is a humanised monoclonal antibody that blocks the complement factor 5a receptor (C5aR). C5aR is mainly expressed on leukocytes and is thought to play an important pathogenic role in rheumatoid arthritis (RA).<sup>1</sup> <h3>Objectives</h3> The primary objective was to investigate the safety and tolerability including immunogenicity, of multiple doses of NNC0151-0000 at increasing dose levels in patients with RA. Clinicaltrials.gov: NCT01223911 <h3>Methods</h3> In a multi-centre, multinational setting, patients with active RA (DAS28-CRP ≥3.2) on stable background methotrexate (MTX) treatment (≥4 weeks) were randomised 3:1 to 4 once-weekly subcutaneous doses of NNC0151-0000 or placebo, respectively. A dose-escalation design was planned, awaiting safety evaluation after each cohort. The treatment period was followed by a 7-week follow-up. Parameters investigated included adverse events (AEs), vital signs, laboratory safety parameters, anti-drug antibodies (ADA), C5aR occupancy, pharmacokinetics, clinical improvement measures (DAS28-CRP, ACR20/50/70 and ACR-N) and Vectra<sup>®</sup> DA scores. <h3>Results</h3> 34 patients (24 female; 10 male) were randomised; DAS28-CRP: 5.5±0.7; age: 57.0±10.7 years; disease duration: 7.4±5.8 years; MTX treatment duration: 2.2±2.9 years; and MTX dose: 16.3±5.2 mg/week [mean ± SD]. Five dose levels were used in the trial: 0.05, 0.1, 0.2, 0.4 and 0.6 mg/kg, with 25 patients receiving NNC0151-0000 and 9 placebo. All patients were analysed. In total, 56 AEs were reported: 48 AEs in 16 (64%) NNC0151-000 patients and 8 AEs in 4 (44%) placebo patients. Most frequently reported were dose-dependent events of lymphopenia, leukopenia and neutropenia (NNC0151-0000=32 AEs; placebo=1 AE); the events were not associated with increased number of infections. No serious AEs were reported. No clinically relevant changes were observed in vital signs or laboratory safety parameters. ADAs were observed in the majority of patients (n=20; 80%) treated with NNC0151-0000, with <i>in vitro</i> neutralising antibodies in 15 patients (60%). C5aR occupancy by NNC0151-0000 on peripheral blood neutrophils and monocytes increased in a dose-dependent manner. The observed NNC0151-0000 exposure showed nonlinear disposition kinetics, with no or limited systemic accumulation 48 hours after last dosing. No statistically significant difference was seen between increasing doses in any of the clinical improvement measures. The trial was terminated after the fifth dose level. <h3>Conclusions</h3> The trial was terminated due to the pronounced reduction in leukocyte, neutrophil and lymphocyte numbers observed even at moderate receptor occupancy of NNC0151-0000, as well as the apparent immunogenicity. NNC0151-0000 is no longer in clinical development and a 2nd generation humanised antibody (NNC0215-0384) has been developed with reduced potential of inducing Fc-mediated depletion of C5aR-expressing cells and with less immunogenicity potential. A phase 1 trial in patients with RA has confirmed the improved profile.<sup>2</sup> <h3>References</h3> Jose et al. Ann Rheum Dis 1990; 49(10):747-752 Clinicaltrials.gov: NCT01611688 <h3>Disclosure of Interest</h3> S. Daniluk: None declared, B. Skrumsager Shareholder of: Novo Nordisk A/S, Employee of: Novo Nordisk A/S, P. Leszczynski Grant/research support: NovoNordisk, GSK, Pfizer, Amgen, Samsung, Jansen – Cilag, UCB, Novartis,Lilly, Roche, BMS, Consultant for: Samsung, Speakers bureau: Pfizer, Amgen, Samsung, UCB, Novartis, Roche <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3239