Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial Emma Guttman-Yassky, MD, PhD,a,b PatrickM.Brunner,MD,b Avidan U. Neumann, PhD,c,d,e SaakshiKhattri,MD,a AnaB.Pavel,PhD,a KunalMalik,BA,a Giselle K. Singer, BS,a Danielle Baum,a Patricia Gilleaudeau,b Mary Sullivan-Whalen,b Sharon Rose, MD,a Shelbi Jim On, MD,a Xuan Li, BA,b Judilyn Fuentes-Duculan, MD,b Yeriel Estrada, BS,a Sandra Garcet, PhD,b Claudia Traidl-Hoffmann, MD,c,f James G. Krueger, MD, PhD,b andMarkG.Lebwohl,MDa New York, New York; Augsburg and Berlin, Germany; and Davos, Switzerland Background: Interleukin 22 promotes epidermal hyperplasia and inhibits skin barrier function. Objective: Evaluate interleukin 22 blockade in adults with moderate-to-severe atopic dermatitis (AD). Methods: We performed a randomized, double-blind, placebo-controlled trial with intravenous fezakinu- mab monotherapy every 2 weeks for 10 weeks, with follow-up assessments until 20 weeks. The change in SCOring AD (SCORAD) score from baseline at 12 weeks served as the primary end point. Results: At 12 weeks, the mean declines in SCORAD for the entire study population were 13.8 6 2.7 in the fezakinumab arm and 8.0 6 3.1 in the placebo arm (P = .134). In the severe AD patient subset (with a From the Department of Dermatology, Icahn School of Medicine personal fees from LEO Pharma and Sanofi. Dr at Mount Sinai, New Yorka; Laboratory for Investigative Traidl-Hoffmann has received research support from Danone Dermatology, The Rockefeller University, New Yorkb; Institute Nutricia and personal fees from Novartis and La Roche Posay. of Environmental Medicine, University Center for Health Dr Krueger is an employee of the Rockefeller University and has Sciences at the Klinikum Augsburg, Technical University received research support (grants paid to his institution) and/or Munich and Helmholtz Zentrum Munchen€ - German Research personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Center for Environmental Health, Augsburgc; Swiss Institute of Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, Allergy and Asthma Research, University of Zurich,€ Davosd; BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Berlin-Brandenburg Center for Regenerative Therapies, Charite Paraxel, Xenoport, and Kineta. Dr Lebwohl is an employee of University Hospital Berline; and Christine Kuhne€ e Center for Mount Sinai who receives research funds from Abbvie, Amgen, Allergy Research and Education, Davos.f Boehringer Ingelheim, Celgene, Eli Lilly, Janssen/Johnson & Funding sources: Supported by National Institutes of Health, Johnson, Kadmon, Medimmune/Astra Zeneca, Novartis, Pfizer, National Institute of Arthritis and Musculoskeletal and Skin and ViDac. Dr Lebwohl is also a consultant for Allergan and Disease (grant no. 1UM1AR063917). Dr Brunner was supported Promius. The rest of the authors have no relevant conflicts of in part by grant no. UL1 TR0001866 from the National Center interest to disclose. for Advancing Translational Sciences, National Institutes of Accepted for publication January 9, 2018. Health, Clinical and Translational Science Award program. Reprints not available from the authors. Fezakinumab was provided by Pfizer Inc (New York, NY). Correspondence to: Emma Guttman-Yassky, MD, PhD, Department Conflicts of interest: Dr Guttman-Yassky is an employee of Mount of Dermatology, Icahn School of Medicine at Mount Sinai Sinai and has received research funds (grants paid to the Medical Center, 5 E 98th St, New York, NY 10029. E-mail: Emma. institution) from Abbvie, Celgene, Eli Lilly, Janssen, Medimmu- [email protected]. ne/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Published online January 17, 2018. Galderma, Asana, Innovaderm, Dermira, and UCB. Dr 0190-9622 Guttman-Yassky is also a consultant for Sanofi Aventis, Regen- Ó 2018 by the American Academy of Dermatology, Inc. This is an eron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, open access article under the CC BY-NC-ND license (http:// AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, creativecommons.org/licenses/by-nc-nd/4.0/). Vitae, Leo Pharma, Abbvie, Eli Lilly, Kyowa, Mitsubishi Tanabe, https://doi.org/10.1016/j.jaad.2018.01.016 Asana Biosciences, and Promius. Dr Brunner has received 872 JAM ACAD DERMATOL Guttman-Yassky et al 873 VOLUME 78, NUMBER 5 baseline SCORAD of $50), SCORAD decline was significantly stronger in the drug-treated patients than placebo-treated patients at 12 weeks (21.6 6 3.8 vs 9.6 6 4.2, P = .029) and 20 weeks (27.4 6 3.9 vs 11.5 6 5.1, P = .010). At 12 weeks, improvements in body surface area involvement in the entire population were significantly stronger in the drug-treated than placebo-treated patients (12.4% 6 2.4 vs 6.2% 6 2.7; P = .009), and in the severe AD subset, the decline in Investigator Global Assessment was significantly higher in the drug-treated than placebo-treated patients (0.7 6 0.2 vs 0.3 6 0.1; P = .034). All scores showed progressive improvements after last dosing (10 weeks) until end of study (20 weeks). Common adverse events were upper respiratory tract infections. Limitations: The limited sample size and lack of assessment with Eczema Area and Severity Index and a pruritus numerical rating scale were limiting factors. Significance was primarily obtained in severe AD. Conclusion: Fezakinumab was well-tolerated, with sustained clinical improvements after last drug dosing. ( J Am Acad Dermatol 2018;78:872-81.) Key words: atopic dermatitis; fezakinumab; IL-22; placebo-controlled trial; moderate-to-severe AD. Atopic dermatitis (AD) is keratinocyte differentiation the most common chronic CAPSULE SUMMARY and skin barrier formation, 2 inflammatory skin disease, hallmarks of AD.8-13 High with a prevalence of 7%- d Interleukin (IL) 22 induces epidermal levels of IL-22eproducing T 10% in adults.1 It is charac- hyperplasia and compromises skin cells have also been identified terized by pruritus; increased barrier function in model systems. in psoriasis, particularly in prevalence of allergic mani- children.14 To assess a d This clinical trial demonstrates the festations (asthma, allergic efficacy of IL-22 blockade in humans, possible role for IL-22 as a rhinitis, food allergies); and implying its possible therapeutic role in driver cytokine of AD, similar a predisposition to cuta- to the established pathogenic 2 atopic dermatitis. 6,15,16 neous infections. In patients role of TH2 cytokines, with moderate-to-severe AD d IL-22 and T helper cell 22 targeting we investigated the IL-22 (;20% of adult patients),3 potentially offers a novel alternative for antagonist, fezakinumab the disease often affects large severe atopic dermatitis patients with (ILV-094), in an investigator- body surface areas (BSAs), limited therapeutic options. initiated clinical trial. leading to profound effects on the patients’ quality of life.4 METHODS However, treatment options for moderate-to- Study design and oversight severe AD patients are limited, and topical treatments, We conducted a phase 2a, randomized, double- including emollients, glucocorticosteroids, and calci- blind, placebo-controlled, multicenter clinical trial to neurin and phosphodiesterase-4 inhibitors are often evaluate efficacy and safety of fezakinumab in 60 unsatisfactory.5 Systemic treatments (cyclosporine A, moderate-to-severe AD patients (clinicaltrials.gov, azathioprine, mycophenolate-mofetil, methotrexate) no. NCT01941537) at the Icahn School of Medicine are largely not Food and Drug Administratione at Mount Sinai (n = 40), and The Rockefeller approved for AD, with the exception of the recently University (n = 20), both in New York, New York. approved interleukin (IL) 4Ra monoclonal antibody, Patients were randomly assigned to either intrave- dupilumab, inhibiting both T helper cell 2 (TH2) nous fezakinumab or placebo (2:1) (Fig 1), with a cytokines, IL-4 and IL-13.6,7 While dupilumab loading dose of 600 mg at baseline (day 0), followed successfully treats a large portion of AD patients, a by 300 mg at weeks 2, 4, 6, 8, and 10 (last dose). considerable subset has insufficient responses,6,7 Primary outcome measures were assessed at week necessitating further treatment modalities. 12, with follow-up until week 20. Safety was assessed Key pathogenic features of AD include a disturbed by the incidence of adverse events, vital signs, skin barrier with epidermal hyperplasia and abnormal physical examination, clinical laboratory testing, keratinocyte differentiation, as well as robust activa- and electrocardiography. The study protocol of this tion of the TH2 and TH22 T-cell pathways. In vitro investigator-initiated trial was developed by the research and animal studies suggest that IL-22, the lead investigators and was approved by the local institu- TH22 cytokine, promotes hyperplasia and inhibits tional review boards. 874 Guttman-Yassky et al JAM ACAD DERMATOL MAY 2018 For categorical variables, statistical significance of Abbreviations used: difference between treatment arms was tested by the AD: atopic dermatitis Fisher’s exact test. To test the robustness of the BSA: body surface area BMI: body mass index results we also conducted a per-protocol analysis, in EASI: Eczema Area and Severity Index which only patients who completed 12 weeks of IGA: Investigator Global Assessment treatment were included in the analysis. The thresh- ITT: intention to treat MMRM: