Background Ixekizumab is an anti-IL-17 monoclonal antibody currently being investigated for treatment of rheumatoid arthritis (RA). Ixekizumab has previously been shown to reduce the signs and symptoms of RA in patients naïve to biologic therapy and those who were inadequate responders to TNF inhibitors (TNF-IR)1.
Objectives To evaluate the association between early clinical improvements and the likelihood of achieving subsequent clinical responses at Week 12 in a Phase 2 study of ixekizumab in TNF-IR RA patients.
Methods In the phase 2 study, placebo or ixekizumab was administered subcutaneously to 188 TNF-IR RA patients (80 or 180 mg) at Weeks 0, 1, 2, 4, 6, 8, and 10 with concomitant conventional DMARD therapy. These analyses were conducted post-hoc for pooled ixekizumab dose groups. The association between early clinical improvements at Week 4 (assessed by DAS28-CRP, DAS28-ESR, and Clinical Disease Activity Index [CDAI]) and ACR20 response at Week 12 was evaluated using receiver operating characteristic (ROC) curves. The optimum cut-point for predictability of a Week 4 clinical response was evaluated based on the Youden Index, a combination of sensitivity and specificity measures.
Results All clinical measures of disease activity (DAS28-CRP, DAS28-ESR, CDAI) studied at Week 4 had a similarly strong association with an ACR20 response at Week 12 as represented by the area under the ROC curves (range: 0.7-0.8). However, serum CRP decreases at Week 4 were non-predictive of ACR20 responses at Week 12. An improvement in DAS28-CRP or DAS28-ESR of 0.7 at Week 4 was identified as the optimum cut-point for predicting an ACR20 response at Week 12 with corresponding negative predictive values of 0.87 and 0.88, and positive predictive values of 0.59 and 0.6, respectively. Similar predictability was observed using CDAI improvement at Week 4 to predict ACR20 response at Week 12.
Conclusions In this small post-hoc analysis of a Phase 2 trial of ixekizumab, TNF-IR patients achieving improvements in DAS28-ESR and DAS28-CRP <0.7 at Week 4 had very low likelihood of achieving an ACR20 response at Week 12. In addition, patients achieving greater levels of improvement had a reasonable probability of achieving an ACR20 response at Week 12. Understanding the relationship between early clinical improvements and longer term clinical responses may help physicians determine the potential benefit and risk of continued treatment with ixekizumab in TNF-IR RA patients. Larger datasets from Phase 3 trials will help refine our understanding of this relationship.
Genovese et al Ann Rheum Dis 2012;71(Suppl3):59
Disclosure of Interest L. Xie Shareholder of: Eli Lilly, Employee of: Eli Lilly, M. Genovese Grant/research support from: Eli Lilly, Consultant for: Eli Lilly, B. Zhu Shareholder of: Eli Lilly, Employee of: Eli Lilly, E. Edson-Heredia Shareholder of: Eli Lilly, Employee of: Eli Lilly, S. Banerjee Shareholder of: Eli Lilly, Employee of: Eli Lilly