Background/Purpose

A phase 2, randomised, double-blind, placebo-controlled, parallel-group trial was conducted to evaluate the efficacy and safety of NNC0114-0006 in patients with active rheumatoid arthritis (RA) on background methotrexate (MTX) therapy.

Methods

Patients (N=62; 82% female) with RA (mean duration 6.9 years; 77% RF positive; 82% anti-CCP positive; mean DAS28-CRP 5.7) and on MTX (mean duration 3.9 years; mean dose 14.3 mg/week) were enrolled. Patients were randomised to i.v. NNC0114-0006 (12 mg/kg; n=41) or placebo (n=21); two doses given 6 weeks apart. The primary endpoint was change in DAS28-CRP from baseline to Week 12. ACR 20/50/70 and EULAR response at Week 12, adverse events (AEs), changes in laboratory safety measurements, antibodies against NNC0114-0006 (ADAs) and pharmacodynamic (PD) parameters were also evaluated.

Results

There were no significant differences between treatment groups with respect to baseline. Four patients in the NNC0114-0006 group withdrew (3 withdrew informed consent, 1 was lost to follow-up). A significant improvement in mean DAS28-CRP was observed with NNC0114-0006 versus placebo at Week 12 (–0.65, p=0.04; Fig. 1), due largely to reductions in swollen and tender joint counts. The reduction in DAS28-CRP at week 12 was supported by improved disease activity in terms of ACR20/50/70 and EULAR response, although these endpoints did not reach statistical significance. An expected increase in total (both free and antibody-bound) IL-21 levels after treatment with NNC0114-0006 was observed. While no change in absolute B cell numbers was observed at Week 1, about one third of patients treated with NNC0114-0006 had increased percentages of plasma cells, plasmablasts and short-lived plasmablasts, with decreased percentages of naïve B cells. They also showed increased transcript levels of Ig-Lambda light chain (IGLV7-43) and other plasma-cell signature genes in whole blood analysis. However, the DAS28-CRP response in these patients was comparable to placebo and those who did not exhibit this B cell alteration. Nevertheless, following treatment, DAS28-CRP and ACR-N outcomes appear to be related to baseline CTX-I – a marker of bone resporption – but not baseline DAS28-CRP. In NNC0114-0006-treated patients, 43 AEs were observed in 22/41 (54%) patients, while 24 AEs occurred in 11/21 (52%) placebo patients. Four serious AEs occurred in 3 placebo patients. A higher number of patients reported infections (24% vs 10%) and skin disorders (12% vs 5%) in the NNC0114-0006 group versus placebo. No treatment-related ADAs were detected. No clinically significant changes were observed in laboratory safety parameters.

Conclusion

Treatment with NNC0114-0006 significantly improved DAS28-CRP versus placebo at Week 12. Changes in B cell subsets detected at Week 1 may be due to altered distribution of homing of plasma cells/plasmablasts. No safety concerns were identified.