Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study

Abstract

Objectives: To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS).

Methods: A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug.

Results: At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was -2.5% (95% CI -21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups.

Conclusions: Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS.

Trial registration number: NCT02047110; Pre-results.

Keywords: DMARDs (biologic); ankylosing spondylitis; treatment.

Figure 1

Overview of study design and patient disposition. Overview of treatment and observation periods including escape and open-label extension phases (panel A); patients were randomised 1:1:1:1 to one of three regimens of risankizumab (18 mg single dose, 90 mg or 180 mg at  day 1 and weeks 8, 16 and 24) or placebo; patients without ASAS20 response at week 12 received escape treatment; patients with a flare of disease activity within 24 weeks of the last double-blind treatment entered the open-label extension. Arrows represent treatment administration. *Patients received 18 mg single dose at day 1 followed by placebo at weeks 8, 16 and 24. Trial profile (panel B). AE, adverse event; ASAS20, 20% improvement in Assessment in SpondyloArthritis International Society; DB, double blind; FU, follow-up; OLE, open-label extension; PV, protocol violation.

Figure 2

Response rates for ASAS40, ASAS20, ASAS 5/6 and ASAS partial remission during double-blind and escape treatment and follow-up periods. Clinical response rates over time for double-blind and escape treatment periods. ASAS40 (panel A), ASAS20 (panel B), ASAS 5/6 (panel C)  and partial remission (panel D). NRI was used for missing data. Number of patients entering the double-blind treatment were: placebo: n=40; 18 mg risankizumab: n=40; 90 mg risankizumab: n=39; and 180 mg risankizumab: n=40. Patients entering escape treatment received 180 mg risankizumab; responses shown for the escape period are by the original randomised treatment (placebo: n=26; 18 mg risankizumab: n=21; 90 mg risankizumab: n=23; 180 mg risankizumab: n=26). Values for all data points are provided in online supplementary tables S1–S4. ASAS, Assessment in SpondyloArthritis International Society; NRI, non-responder imputation.

Figure 3

Change from baseline in ASDAS-CRP, CRP and BASDAI over time to week 12. Change from baseline in ASDAS-CRP (panel A), CRP (mg/L) (panel B) and BASDAI (panel C) over time to week 12. Median (IQR) changes are shown (observed). The values under each plot are the number of patients per treatment arm with a valid measurement at the specified time point. *P=0.0229 and p=0.0101 for median change in ASDAS-CRP for 18 mg and 180 mg risankizumab, respectively, versus placebo at week 12. Values for all data points are provided in online supplementary  tables S5–S7. ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score-CRP; BASDAI, Bath Ankylosing Spondylitis Disease Activity Score; CRP, C reactive protein.