Efficacy and Safety of Switching to Ixekizumab in Etanercept Non-Responders: A Subanalysis from Two Phase III Randomized Clinical Trials in Moderate-to-Severe Plaque Psoriasis (UNCOVER-2 and -3)

Abstract

Background: Patients with psoriasis who have an inadequate response to one biologic may benefit from switching to a new biologic, such as ixekizumab, a high affinity monoclonal antibody that selectively targets interleukin (IL)-17A.

Objective: Our aim was to assess the response to ixekizumab in patients with moderate-to-severe plaque psoriasis who did not respond adequately to etanercept using a post-hoc analysis in two phase III studies.

Methods: For the subanalyses in two phase III trials (UNCOVER-2 and -3), non-response was defined by either failure to have a static physician global assessment (sPGA) of 0/1 in UNCOVER-2 or failure to have at least 75% improvement in psoriasis area and severity index (PASI 75) in UNCOVER-3 at Week 12 of each study. Non-responders treated with twice-weekly etanercept 50 mg in the first 12 weeks received two injections of placebo at Week 12 (4-week wash-out period), followed by ixekizumab every 4 weeks (Q4W) for Weeks 16-60. Non-responders to placebo in the first 12 weeks were administered ixekizumab 160 mg at Week 12, followed by ixekizumab Q4W for Weeks 16-60.

Results: After switching to ixekizumab Q4W, a substantial proportion of patients with moderate-to-severe psoriasis who did not respond to etanercept experienced rapid and durable improvement in all efficacy evaluations. Among sPGA 0/1 (UNCOVER-2) and PASI 75 (UNCOVER-3) non-responders to etanercept, 73.0% achieved sPGA 0/1 and 78.2% achieved PASI 75, respectively, after 12 weeks of ixekizumab treatment. Safety profiles in patients switched from etanercept to ixekizumab were similar to those in patients switched from placebo to ixekizumab.

Conclusion: Patients who were non-responders to etanercept after 12 weeks, as defined by failure to meet sPGA 0/1 (UNCOVER-2) or PASI 75 (UNCOVER-3), achieved high levels of response 12 weeks after switching to ixekizumab. Studies are registered with ClinicalTrials.gov (NCT01597245 and NCT01646177).

Conflict of interest statement

Funding

NCT01597245 and NCT01646177 and the post hoc analyses of these studies presented in this manuscript were funded by Eli Lilly and Company.

Conflict of interest

Andrew Blauvelt served as a scientific advisor and clinical study investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Genentech, GSK, Janssen, Eli Lilly and Company, Merck, Novartis, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, Sun, UCB, and Valeant, and is a paid speaker for Eli Lilly and Company. Kim A. Papp has served as a consultant for 3 M, Abbott/AbbVie, Akesis, Akros, Alza, Amgen, Astellas, Baxter, Bayer, Boehringer Ingelheim, Celgene, Cipher, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Funxional Therapeutics, Galderma, Genentech, Janssen, J&J, Kyowa Hakko Kirin, Leo, Lypanosys, Medimmune, Meiji Seika Pharma Co., Merck, Mitsubishi Pharma, Mylan, Novartis, Pan GEnetics, Pfizer, Regeneron Pharmaceuticals, Merck-Serono, Stiefel, Sosei, Takeda, UCB, Vertex, Wyeth, and Xoma; he has served as part of a speakers bureau for 3 M, Abbott, AbbVie, Amgen, Astellas, Celgene, Genentech, Merck, Novartis, Pfizer, and Merck-Serono; he has received clinical research grants from Abbott/AbbVie, Allergan, Amgen, Anacor, Astellas, Boehringer Ingelheim, Celgene, Celtic, Cipher, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, GSK, Janssen, Kyowa Hakko Kirin, Leo, Medimmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Merck-Serono, Stiefel, Takeda, UCB, Wyeth, and Xoma; he has received honoraria from Abbott/AbbVie, Akros, Amgen, Baxter, Boehringer Ingelheim, Celgene, Eli Lilly, Forward Pharma, Galderma, Janssen, Kyowa Hakko Kirin, Lypanosys, Meiji Seika Pharma, Merck, Mitsubishi Pharma, Mylan, Novartis, Pfizer, Merck-Serono, Stiefel, Takeda, UCB, and Vertex; he has served as a scientific officer for Abbott/AbbVie and Anacor; he has served on a scientific committee for Celgene, Centocor, Janssen, Novartis, Pfizer, and UCB; he has served on advisory boards for 3 M, Abbott/AbbVie, Allergan, Alza, Amgen, Astellas, Baxter, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, Janssen Biotech (Centocor), Leo, Medimmune, Merck, Mylan, Novartis, Pfizer, Regeneron Pharmaceuticals, Merck-Serono, UCB; and he has served as a coordinating investigator for Astellas, Boehringer Ingelheim, Celgene, Coherus, Dermira, Eli Lilly, Forward Pharma, Isotechnika, Kyowa hakko Kirin, Leo, Merck, Novartis, Pfizer, Merck-Serono, Takeda, and Xoma. Christopher E.M. Griffiths has received research grants and/or has received honoraria from AbbVie, BMS, GSK, Janssen, Leo Pharma, MSD, Pfizer, Novartis, Sandoz, Eli Lilly and Company, and UCB Pharma. Lluis Puig has been a clinical trial investigator for AbbVie, Amgen, GSK, Janssen, Eli Lilly and Company, MSD, Novartis, Pfizer, Regeneron, and VBL; he has also been a paid advisor/speaker for AbbVie, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, GSK, Janssen, Leo-Pharma, Eli Lilly and Company, Merck-Serono, MSD, Novartis, Pfizer, Regeneron, Sandoz, Sanofi, and VBL. Jamie Weisman has served as a clinical study investigator for Amgen, AbbVie, Biogen, Boehringer Ingelheim, Celgene, Glaxo Smith Kline, Janssen, Leo pharmaceuticals, Eli Lilly and Company, Merck, Novartis, Pfizer, Regeneron, Stiefel, and Valeant; she has also served on speaker’s bureaus/advisory boards for AbbVie, Janssen, and Eli Lilly and Company. Yves Dutronc, Lisa Farmer Kerr, Dapo Ilo, and Lotus Mallbris are stockholders and full-time employees of and Eli Lilly and Company. Matthias Augustin has been a scientific consultant for Leo Pharma, Almirall, Abbott Laboratories, Amgen, Biogen Idec, Celgene, Centocor Ortho Biotech, Janssen, Medac Pharma, Merck, Novartis, and Pfizer; he has been a clinical study investigator for Eli Lilly and Company, Leo Pharma, Abbott Laboratories, Amgen, Biogen Idec, Celgene, Centocor Ortho Biotech, Janssen, Merck, Novartis, and Pfizer; and he has received honoraria from Eli Lilly and Company, Leo Pharma, Abbott Laboratories, Amgen, Biogen Idec, Celgene, Centocor Ortho Biotech, Janssen, Almirall, Medac Pharma, Merck, Novartis, and Pfizer.

Ethics Approval and Consent to Participate

This report contains post hoc analyses of previously published studies (Griffiths CE, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386:541-51 and Gordon KB, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:345-56). Study protocols and informed consent forms for NCT01597245 and NCT01646177 were approved by an investigational review board at each site, all patients signed informed consent before undergoing study-related procedures, and the trials were conducted in accordance with the ethical principles of the Declaration of Helsinki.

Figures

Fig. 1

UNCOVER-2: sPGA and PASI response rates through Week 60 in Week 12 sPGA 0/1 non-responders. sPGA 0/1, PASI 75, PASI 90, and PASI 100 response rates among patients in UNCOVER-2 who were switched to ixekizumab Q4W if they were Week 12 sPGA 0/1 non-responders to etanercept (a) or placebo (b). Response rates for all patients treated with etanercept (a) or placebo (b) during the first 12 weeks have been previously reported and are provided for reference [1]. ETN etanercept, ETN-NR/IXEQ4W etanercept Weeks 0–12, placebo at Week 12, and 80 mg ixekizumab every 4 weeks for Weeks 16–60, NR sPGA 0/1 non-responder at Week 12, PASI psoriasis area and severity index, PBO placebo, PBO-NR/IXEQ4W placebo Weeks 0-12 and 80 mg ixekizumab every 4 weeks for Weeks 16–60 after a starting dose of 160 mg at Week 12, sPGA static physician global assessment

Fig. 2

UNCOVER-3: sPGA and PASI response rates through Week 60 in Week 12 PASI 75 non-responders. sPGA 0/1, PASI 75, PASI 90, and PASI 100 response rates among patients in UNCOVER-3 who were switched to ixekizumab Q4W if they were Week 12 PASI 75 non-responders to etanercept (a) or placebo (b). Response rates for all patients treated with etanercept (a) or placebo (b) during the first 12 weeks have been previously reported and are provided for reference [1]. ETN etanercept, ETN-NR/IXEQ4W etanercept Weeks 0–12, placebo at Week 12, and 80 mg ixekizumab every 4 weeks for Weeks 16–60, NR PASI 75 non-responder at Week 12, PASI psoriasis area and severity index, PBO placebo, PBO-NR/IXEQ4W placebo Weeks 0-12 and  80 mg ixekizumab every 4 weeks for Weeks 16–60 after a starting dose of 160 mg at Week 12, sPGA static physician global assessment