Clinical and Molecular Effects of Interleukin-17 Pathway Blockade in Psoriasis

February 2020 | Volume 19 | Issue 2 | Original Article | 138 | Copyright © February 2020

Published online January 17, 2020

Lawrence Green , Jeffrey M. Weinberg , Alan Menter , Jennifer Soung , Edward Lain , Abby Jacobson

aGeorge Washington University School of Medicine, Washington, DC bIcahn School of Medicine at Mount Sinai, New York, NY cBaylor Scott & White, Dallas, TX dSouthern California Dermatology, Santa Ana, CA eAustin Institute for Clinical Research, Pflugerville, TX fOrtho Dermatologics, Bridgewater, NJ

Clinical Efficacy of IL-17 Pathway Blockade in Psoriasis

In clinical trials, therapeutic doses of brodalumab, secukinumab, and ixekizumab have all demonstrated substantial skin clearance efficacy following 12 weeks of treatment by psoriasis area and severity index (PASI) and static physician’s global assessment (sPGA) scores (Table 1).26,29,37-40 During the long-term extension phases (range, 52-60 weeks) in many of these trials, efficacy was maintained in large percentages of patients. For example, in AMAGINE-1, among those receiving brodalumab 210 mg every 2 weeks who had PASI 90% improvement response (PASI 90) and PASI 100 at week 12, 78.3% and 67.5% achieved PASI 90 and PASI 100, respectively, at week 52.39 In AMAGINE-2 and AMAGINE-3, PASI 75, PASI 90, and PASI 100 rates at week 52 among those receiving brodalumab 210 mg every 2 weeks were 80%, 75%, and 56%, respectively, in AMAGINE- 2 and 80%, 73%, and 53%, respectively, in AMAGINE-3.38 Maintenance of response to ixekizumab was demonstrated in UNCOVER-3; PASI 75, PASI 90, and PASI 100 rates were 80%, 71%, and 52%, respectively, at week 60.37 The 52-week efficacy rates for secukinumab ranged from approximately 75% to 80% and 60% to 65% for PASI 75 and PASI 90, respectively, and the 52-week efficacy rate for PASI 100 was ~40% in the ERASURE and FIXTURE trials.29

The efficacy results for brodalumab, secukinumab, and ixekizumab, all of which act within the IL-17 pathway cascade (by binding to the IL-17 receptor A [brodalumab] or the IL-17A ligand [secukinumab and ixekizumab]), compare very favorably with those of other biologics that target different pathways in the pathogenesis of psoriasis. For example, among the TNFα- blocking agents, efficacy rates by PASI 75 in phase 3 studies (range, 10-16 weeks) were 49%, 71%, and 80% for etanercept, adalimumab, and infliximab, respectively.41-43 Interestingly, after 50 weeks of therapy in a phase 3 clinical trial of infliximab, the efficacy rate by PASI 75 was reduced to 61%.43 Of note, both secukinumab and ixekizumab were superior to etanercept in terms of sPGA or modified PGA, PASI 75, PASI 90, and PASI 100 in their respective phase 3 trials that included an etanercept arm.29,40 In the AMAGINE-2 and AMAGINE-3 studies, brodalumab 210 mg was superior to ustekinumab, a monoclonal antibody against IL-12 and IL-23, in terms of sPGA score of 0 or 1 response, PASI 75, and PASI 100.38 Furthermore, in a study evaluating time to achieve clinically meaningful outcomes (defined as time for 25% of patients to achieve PASI 75), brodalumab exhibited the most rapid onset of efficacy (2.1 weeks), followed by the other IL-17 inhibitors ixekizumab (2.4 weeks) and secukinumab (3.0 weeks), whereas adalimumab, ustekinumab, and etanercept achieved onset of efficacy at 4.6, 4.6, and 6.6 weeks, respectively.44

Safety Overview of IL-17 Pathway Blockade in Psoriasis
As summarized in the updated 2019 joint American Academy of Dermatology and National Psoriasis Foundation guidelines of care for the management and treatment of psoriasis with biologics, the safety profile of IL-17 inhibitors is well established and understood.45 IL-17 inhibitors are associated with an increased risk of infection and are not recommended in patients with a history of inflammatory bowel disease (IBD) but are not