Background NNC0109-0012 is a novel human monoclonal IgG4 antibody which binds to and neutralises the activity of IL-20. Phase 1 single-dose results did not raise any safety concerns for NNC0109-0012 in healthy subjects and patients with rheumatoid arthritis (RA). Phase 1 multiple-dose data indicated linear pharmacokinetics (PK) of NNC0109-0012 within the investigated dose range (1.0-3.0 mg/kg) and preliminary signs of reduced disease activity in patients with RA.
Objectives The primary objective of this phase 2a trial was to evaluate the change in disease activity (DAS28-CRP) following once-weekly subcutaneous (s.c.) dosing for 12 weeks with 3 mg/kg NNC0109-0012 or placebo in patients with active RA. Secondary objectives included clinical response, PK, pharmacodynamics (PD), safety, tolerability and immunogenicity.
Methods A total of 67 patients (51 females:16 males) with active RA (1987 ACR classification criteria) were randomised in a multicentre, double-blind, multiple-dose, placebo-controlled trial. Patients were dosed once-weekly for 12 weeks and followed for additional 13 weeks. Patients were 18 to 75 years old with active RA (DAS28-CRP ≥4.5 as well as ≥5 swollen and ≥5 tender joints of the 28 joint count) and on stable MTX treatment (≥7.5 to ≤25 mg/week) for at least 4 weeks prior to randomisation. Patients were randomised in a 2:1 ratio (45 NNC0109-0012: 22 placebo).
Results At 12 weeks, mean changes in DAS28-CRP were significantly greater for NNC0109-0012 compared to placebo (-0.88; p=0.020). Significant reduction of disease activity (-0.5; p=0.011) was observed already after 1 week of treatment and maintained for 5 weeks after end of treatment. The reduction of disease activity was primarily observed in patients who were RF-positive and anti-CCP-positive (p=0.0003) and maintained throughout 25 weeks. NNC0109-0012 also induced a higher proportion of subjects with improved EULAR response compared to placebo after 12 weeks’ treatment (p=0.014). ACR 20/50/70 responses were significantly higher in NNC0109-0012-treated patients being RF-positive and anti-CCP-positive, compared to placebo-treated patients (p=0.027, 0.045 and 0.018 respectively), although the trial was not powered to detect differences in ACR20/50/70 responses. NNC0109-0012 also significantly shortened the time to first ACR20/50/70 responses compared to placebo (p=0.004, 0.029 and 0.047 respectively). No changes in CRP, RF, anti-CCP or MMP-3 levels were observed throughout the trial. NNC0109-0012 did not raise any safety concerns. An increased number of mild and reversible injection-site reactions (in 4 patients) and non-serious infections were observed following NNC0109-0012 treatment. Low titers of antibodies against NNC0109-0012 were detected in 2 subjects after treatment. No deaths, serious adverse events or dose-limiting toxicities were reported. The NNC0109-0012 serum concentrations increased with repeated dosing approaching steady state after administration of the 12th dose.
Conclusions In this trial, NNC0109-0012 (Anti-IL-20 mAb), administered at 3 mg/kg s.c. once-weekly for 12 weeks in combination with MTX significantly reduced disease activity, improved ACR20/50/70 responses in RF- and anti-CCP-positive patients, and showed a favorable safety/tolerability profile as compared to placebo in patients with RA. These results support further clinical development of NNC0109-0012 as a therapy for RA.
Disclosure of Interest L. Šenolt: None Declared, M. Göthberg Employee of: Novo Nordisk A/S, X. Valencia Employee of: Novo Nordisk Inc., E. Dokoupilová: None Declared
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