Background/Purpose: Interleukin-21 (IL-21), a cytokine produced by activated T cells (especially T₁₇ and T_FH cells), has a proinflammatory and pleiotropic nature, and drives mainly activation and differentiation of adaptive immune cells. Both IL-21 and the IL-21 receptor (IL-21R) have been shown to be upregulated in patients with rheumatoid arthritis (RA). NNC0114-0005 is a human recombinant monoclonal immunoglobulin G1 (IgG1) antibody that binds to and neutralizes IL-21. It is currently in development for the treatment of RA. The primary objective of this trial was to assess safety and tolerability of single intravenous (i.v.) and subcutaneous (s.c.) doses of NNC0114-0005 in healthy subjects (HS) and patients with RA.

Methods: A phase 1, randomized, single-center, placebo-controlled, double-blind, single-dose, dose-escalation trial was conducted in male HS (n=44) aged 18-60 and patients with RA (n=20) aged 18-75 on stable methotrexate treatment (7-25 mg/wk for ≥4 wks) with a DAS28-CRP score >3.2. HS were randomized (3:1 active to placebo) to 8 increasing i.v. dose levels (range: 0.0025-25 mg/kg) and 3 s.c. dose levels (0.1, 1 and 4 mg/kg). Patients with RA were randomized (3:1) to 3 i.v. dose levels (0.25, 4 and 25 mg/kg). Key safety parameters included adverse events (AEs), injection-site reactions and detection of neutralizing antibodies against NNC0114-0005. Pharmacokinetic (PK), pharmacodynamic and efficacy parameters were also assessed.

Results: In total, 55 AEs were reported in 31/64 (48%) subjects: 32 AEs in 16/32 HS on i.v. treatment; 16 AEs in 10/20 RA patients on i.v. treatment; and 7 AEs in 5/12 HS on s.c. treatment. The most commonly reported AEs were headache (22%) and nasopharyngitis (16%). No dose dependency was detected for AEs. One serious AE (eczema) was reported 91 days post-dosing for a patient with RA exposed to 4 mg/kg NNC0114-0005; it was evaluated as unlikely related to the trial product by the investigator. No injection-site reactions or clinically significant antibodies against NNC0114-0005 were detected. No clinically relevant changes in laboratory parameters, vital signs or ECG were observed. Pharmacokinetic dose proportionality of the area under the curve (AUC) was shown after i.v. and s.c. dosing in HS and patients with RA. The mean terminal elimination half-life of NNC0114-0005 was ~3 weeks. Overall, no clinically relevant changes in lymphocyte subsets, B-cell subsets or total IL-21R expression on lymphocyte subsets were observed after NNC0114-0005 treatment. The reduction in DAS28-CRP was numerically favorable (but not statistically significant) for patients with RA treated with 25 mg/kg NNC0114-0005 compared to placebo.

Conclusion: NNC0114-0005 was safe and well tolerated in HS and patients with RA and did not raise any safety concerns during the trial. Linear PK of NNC0114-0005 was demonstrated in HS and patients with RA and the PK properties were similar for both populations. The improvements in DAS28-CRP for patients with RA at the highest dose level may suggest biologic and clinical activity of NNC0114-0005.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/first-in-human-study-with-recombinant-anti-il-21-monoclonal-antibody-in-healthy-subjects-and-patients-with-rheumatoid-arthritis/