Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
A phase 1, randomised, double-blind, placebo-controlled, dose-escalation trial was conducted to assess the safety and tolerability of the anti-IL-21-antibody NNC0114-0006, in patients with active moderate-to-severe rheumatoid arthritis (RA) on background methotrexate (MTX) monotherapy.
Methods
Patients (N=32; 84% female) with RA (mean duration 8.9 years; 72% RF positive; 63% anti-CCP positive; mean DAS28-CRP 5.4), who were on MTX (mean duration 4.7 years; mean dose 13 mg/week) were enrolled. Patients were randomised to NNC0114-0006 or placebo (3:1) for s.c. dosing every other week for 6 weeks (a total of four doses) at 0.05, 0.25, 1 or 4 mg/kg. Dose levels of NNC0114-0006 were escalated when 6 of 8 patients in a cohort completed the third dose. The primary endpoint was incidence of adverse events (AEs) from first administration until trial completion, 26 weeks later. Secondary endpoints were changes in laboratory measurements, antibodies against NNC0114-0006, and pharmacokinetic (PK) and pharmacodynamic (PD) parameters.
Results
There were no significant differences between the treatment groups with respect to baseline data. One patient in the 1 mg/kg NNC0114-0006 group withdrew informed consent after the second dose due to intensification of joint pain considered possibly related to the use of the trial product. Overall, 42 AEs were reported in 18 of 24 (75%) NNC0114-0006 patients, while 20 AEs were reported in 6 of 8 (75%) placebo patients. Two patients receiving 4 mg/kg NNC0114-0006 experienced serious adverse events, which were considered unlikely related to the use of the trial product. No severe or life-threatening events, or fatalities were observed. Two patients at the highest dose reported AEs related to infections, compared with only one patient in each of the other treatment groups, including placebo. No treatment-related anti-drug antibodies were detected during the course of the trial. No clinically significant changes from baseline levels were observed in laboratory safety parameters. From PK measurements, systemic exposure to NNC0114-0006 increased with increasing dose levels, as expected with a mean half-life of approximately 2.5 weeks. PD assessments demonstrated an expected increase in circulating levels of total (both free and antibody-bound) IL-21 after treatment with NNC0114-0006; however, large interpatient variability was observed. No significant changes were observed in RF, CRP and ESR, IL-21R expression on selected lymphocyte subsets, B cells, or gene expression by microarray from whole blood or fractionated blood.
Conclusion
No safety or tolerability concerns were identified following multiple-dose administration of up to 4 mg/kg NNC0114-0006, and no anti-drug antibodies were detected. NNC0114-0006 has a long terminal half-life (2–3 weeks) and s.c. bioavailability similar to that of other monoclonal antibodies. An increase in circulating levels of total IL-21 after treatment with NNC0114-0006 was observed, as expected. No changes in other PD parameters were observed with increasing doses of NNC0114-0006 compared with placebo.
Disclosure:
F. Wagner,
Novo Nordisk,
5;
B. Skrumsager,
Novo Nordisk,
3;
S. Fitilev,
Novo Nordisk,
5.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-and-tolerability-of-nnc0114%c2%ad0006-an-anti-il-21-monoclonal-antibody-at-multiple-s-c-dose-levels-in-patients-with-rheumatoid-arthritis/