Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial

Abstract

Background: Biologic disease modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis (r-axSpA), otherwise known as ankylosing spondylitis, when conventional therapies fail. We report efficacy and safety results of a Phase 3 study of ixekizumab, a high-affinity monoclonal antibody that selectively targets IL-17A, in bDMARDnaïve patients with r-axSpA. Methods: In this randomized, double-blind, Phase 3 study, adult patients with inadequate response/intolerance to NSAIDs, an established diagnosis of r-axSpA, and with radiographic sacroiliitis centrally defined by modified New York criteria and ≥1 spondyloarthritis feature according to Assessment of Spondyloarthritis International Society (ASAS) criteria were recruited from 84 sites (12 countries) in Europe, Asia, and North America. Patients were randomized 1:1:1:1 using a computer-generated random sequence to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference arm), or placebo. The primary endpoint was the proportion of patients achieving an ASAS40 response at Week 16. Findings: Between June 20, 2016 and August 22, 2017, 341 patients were randomized to placebo (N=87), adalimumab (N=90), ixekizumab Q2W (N=83), or ixekizumab Q4W (N=81). At Week 16, significantly more patients achieved ASAS40 with ixekizumab Q2W (n=43, 51•8%, p<0•0001), ixekizumab Q4W (n=39, 48•1%, p<0•0001), and adalimumab (n=32, 35•6%; p=0•0053) versus placebo (n=16, 18•4%). One serious infection occurred in each of the ixekizumab Q2W (1•2%), ixekizumab Q4W (1•2%), and adalimumab (1•1%) arms; none were reported with placebo. One (1•1%) Candida infection occurred in the adalimumab arm and one (1•2%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn's disease. No opportunistic infections, malignancies, or deaths occurred. Interpretation: Each dosing regimen of ixekizumab was superior to placebo for improving r-axSpA signs and symptoms in bDMARD-naïve patients; the safety profile was consistent with previous studies of ixekizumab. The adalimumab control arm performed as expected. Funding: Eli Lilly and Company Research in context Evidence before this study Pubmed was searched using the terms "ankylosing spondylitis", "axial spondyloarthritis", and "disease-modifying anti-rheumatic drugs", including articles through May 30, 2018. Axial spondyloarthritis (axSpA) is a chronic immune-mediated disease characterized by inflammation of the spine and sacroiliac joint (SIJ), peripheral joint involvement, extra articular manifestations, and a strong genetic association with human leukocyte antigen (HLA)-B27. Radiographic axSpA (r-axSpA) was previously classified as ankylosing spondylitis (AS) in 1984 and updated to r-axSpA as part of the ASAS criteria. Both criteria sets require the same radiographically confirmed structural damage to the sacroiliac joint as well as at least one accompanying clinical element. Recommendations for the management of r-axSpA generally include exercise and physiothera...

Use and Switching of Biologic Therapy in Patients with Non-Radiographic Axial Spondyloarthritis: A Patient and Provider Survey in the United States

“…Currently, certolizumab pegol is the only FDA-approved biologic for nr-axSpA in the US. However, agents directed at the IL-17 pathway, such as ixekizumab [12][13][14] and secukinumab [15][16][17] have also proven to be effective in both AS and nr-axSpA. Patient symptoms often drive the initiation and choice of treatment.…”

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis

“…Key definitions, including ones for active and stable disease, are provided in Table . Clinical trials of ixekizumab became available during the time the manuscript was in preparation, after the voting panel had met . The data from these trials were provided to the voting panel, and revised recommendations that included ixekizumab were reviewed and voted on by the panel.…”

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

“…In the spine, the paradigm was reversed with ustekinumab being reported as ineffective in the treatment of AS, and similarly, selective targeting of IL‐23p19 with risankizumab had no clinical effect for the treatment of established AS . However, inhibition of IL‐17A has shown clinical benefit for the treatment of AS . The fact that IL‐23 inhibition is ineffective in the spine, whereas inhibition of the downstream effector molecule IL‐17A is, strongly suggests an IL‐23–independent mechanism for the production of IL‐17A.…”

“…116,117 However, inhibition of IL-17A has shown clinical benefit for the treatment of AS. 111,118,119 The fact that IL-23 inhibition is ineffective in the spine, whereas inhibition of the downstream effector molecule IL-17A is, strongly suggests an IL-23-independent mechanism for the production of IL-17A. It also suggests potential differences between the role of IL-23 in spinal vs peripheral skeleton enthesitis.…”