Dermatol Ther (Heidelb) (2020) 10:133–150 https://doi.org/10.1007/s13555-019-00340-3 ORIGINAL RESEARCH Safety of Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure April Armstrong . Carle Paul . Luis Puig . Wolf Henning Boehncke . Michael Freeman . Hideshi Torii . Kim Papp . Christopher E. M. Griffiths . Andrew Blauvelt . Kristian Reich . Melinda Gooderham . Tadashi Terui . Lisa Renda . Noah Agada . Wen Xu . Gaia Gallo . Mark G. Lebwohl Received: August 8, 2019 / Published online: November 20, 2019 Ó The Author(s) 2019 ABSTRACT were analyzed for the 12-week induction period in the combined pivotal studies, and for all Introduction: Long-term safety data are critical pooled studies by year(s) of therapy and overall, for evaluating therapies for psoriasis. Ixek- reported as exposure-adjusted incidence rates izumab has demonstrated efficacy and is well (IRs) per 100 patient-years (p-y) and/or tolerated for the treatment of moderate-to-sev- frequencies. ere plaque psoriasis. We examined the safety Results: Total ixekizumab exposure was and tolerability of up to 5 years of ixekizumab 17,003.4 p-y (N = 5898); 2749 patients therapy in patients with psoriasis. had C 4 years of exposure. When compared Methods: Integrated safety data were analyzed across years of exposure, rates for AEs remained from 13 ixekizumab clinical studies. Rates of largely stable or declined, including TEAEs treatment-emergent adverse events (TEAEs), leading to discontinuation (3.8/100 p-y in year serious AEs (SAEs) and AEs of special interest 1, declining to 2.0/100 p-y in year 5); SAEs (range 6.2–7.0/100 p-y); serious infections (range 1.3–1.7/100 p-y); nonmelanoma skin Enhanced Digital Features To view enhanced digital cancer (ranging from 0.5/100 p-y in year 1 to features for this article go to https://doi.org/10.6084/ m9.figshare.10067021. W. H. Boehncke A. Armstrong (&) Department of Pathology and Immunology, Department of Clinical Research, Keck School of University of Geneva, Geneva, Switzerland Medicine of the University of Southern California, Los Angeles, CA, USA M. Freeman e-mail: armstrongpublication@gmail.com The Skin Centre, Benowa, QLD, Australia C. Paul H. Torii Dermatology Department, Toulouse University Division of Dermatology, Tokyo Yamate Medical Hospital (CHU), Paul Sabatier University, Toulouse, Center, Tokyo, Japan France K. Papp L. Puig K Papp Clinical Research and Probity Medical Hospital de la Santa Creu i Sant Pau, Universitat Research, Waterloo, ON, Canada Autònoma de Barcelona, Barcelona, Spain C. E. M. Griffiths W. H. Boehncke Dermatology Centre, Salford Royal Hospital, Division of Dermatology and Venereology, Geneva University of Manchester, NIHR Manchester University Hospitals, Geneva, Switzerland Biomedical Research Centre, Manchester, UK 134 Dermatol Ther (Heidelb) (2020) 10:133–150 0.2/100 p-y in years 4–5); other malignancies (range 0.4–0.6/100 p-y); inflammatory bowel Key Summary Points disease including ulcerative colitis and Crohn’s disease (IR 0.2/100 p-y); and major adverse car- Psoriasis is a chronic disease that requires diovascular events (MACE) (range 0.3–0.7/100 long-term management; thus, long-term p-y). Candidiasis was reported in 327 patients data on the safety and tolerability of (IR 1.9/100 p-y), with the majority identified as psoriasis treatments are essential to mucocutaneous. The rate of injection site reac- inform patient management decisions. tions was 15.5/100 p-y during year 1 and 2.0–2.3/100 p-y by years 3–5. We examined the long-term safety and Conclusions: The decrease in rates of TEAEs tolerability of ixekizumab based on dosing and the stable rates of SAEs, other malignancies of up to 5 years in 13 clinical trials in and MACE during up to 5 years of ixekizumab patients with moderate-to-severe dosing are consistent with previous reports psoriasis. describing a favorable safety profile of ixek- The incidence rates of treatment-emergent izumab following shorter durations of exposure. adverse events, serious adverse events and Funding: Eli Lilly and Company. adverse events of special interest were either stable or decreased with increasing Keywords: Adverse events; Etanercept; IL-17; duration of ixekizumab therapy. Integrated analysis; Ixekizumab; Safety; These findings are consistent with Psoriasis previous reports on ixekizumab and indicate that no new safety findings have emerged following longer durations of dosing. A. Blauvelt INTRODUCTION Oregon Medical Research Center, Portland, OR, USA Moderate-to-severe psoriasis is a chronic K. Reich immune-mediated inflammatory disease asso- Center for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research ciated with substantial comorbidities [1, 2]. At in Dermatology and Nursing, University Medical present, psoriasis requires long-term manage- Center Hamburg–Eppendorf, Hamburg, Germany ment; thus, long-term data on the safety and K. Reich tolerability of treatments are essential to inform SkinflammationÒ Center, Hamburg, Germany patient management decisions. Ixekizumab is a high-affinity monoclonal antibody that selec- M. Gooderham tively targets interleukin (IL)-17A [3] and is Centre for Dermatology and Probity Medical Research, Peterborough, ON, Canada approved for the treatment of moderate-to-sev- ere plaque psoriasis based on the efficacy and T. Terui consistent safety profile shown in the Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan UNCOVER program. IL-17 plays a role in host mucocutaneous defense, and therefore IL-17 L. Renda  N. Agada  W. Xu  G. Gallo inhibition is linked to adverse events (AEs) in Eli Lilly and Company, Indianapolis, IN, USA patients with candidiasis [4–7]. Furthermore, M. G. Lebwohl while the role of IL-17 in inflammatory bowel Department of Dermatology, Icahn School of disease (IBD) and cardiovascular disease is Medicine at Mount Sinai, New York, NY, USA Dermatol Ther (Heidelb) (2020) 10:133–150 135 unclear, IL-17 inhibitors are of special interest The protocols for all studies included in this in treating these events [8–14]. Overall, the analysis were approved by the Institutional safety profile of ixekizumab has demonstrated Review Board or Ethics Committee at each par- comparability to biologic therapies with differ- ticipating site. All studies included in this ent mechanisms of action that are approved analysis were conducted in accordance with the for plaque psoriasis, namely etanercept ethical principles of the Declaration of Helsinki. (UNCOVER-2 and -3 studies) [15] and ustek- All eligible patients provided written informed inumab (IXORA-S study) [16]. consent before undergoing study-related Two previous safety updates have addressed procedures. cumulative data from the ixekizumab develop- ment program. Strober et al. reported safety Safety Assessments data from seven clinical trials (9 April 2015 data lock) [17]. Langley et al. provided an update of The AEs for the September 2018 update were safety data from 11 clinical trials (15 September classified based on the Medical Dictionary for 2016 data lock) [18]. Here we report our results Regulatory Activities version 21.0 (https://www. from an examination of the long-term safety meddra.org/sites/default/files/guidance/file/ and tolerability of ixekizumab based on whatsnew_21_0_english.pdf); data for the pla- 17,003.4 patient-years (p-y) of ixekizumab cebo-controlled period of UNCOVER-1, -2 and exposure from 13 clinical trials (20 September -3 were based on version 17.0 (https://www. 2018 data lock) in patients with psoriasis. meddra.org/sites/default/files/guidance/file/ whatsnew_17_0_english.pdf). A treatment- METHODS emergent AE (TEAE) was an AE that first occur- red or worsened in severity after baseline and The present analysis included the cumulative within the treatment period. The lowest level safety data covering up to 319 weeks of ixek- terms have been used for the TEAE computa- izumab exposure integrated from 13 controlled tion, and preferred terms are presented. Infec- and uncontrolled ixekizumab clinical studies on tions with an onset date B 14 days before or psoriasis, including three phase 3, randomized, after neutrophil count collection were consid- double-blind, controlled pivotal clinical studies ered temporally associated with the corre- (UNCOVER-1, -2 and -3; Fig. 1) [15, 19]. All sponding neutropenia count. Safety topics of patients were C 18 years of age with moderate- special interest included injection site reactions to-severe plaque psoriasis (C 10% body surface (ISRs), serious infections, candidiasis, major area [BSA] involvement, with the exception of adverse cardiovascular events (MACE), non- the IXORA-Q study, in which the cutoff was melanoma skin cancer (NMSC), malignancies C 1% BSA involvement, as the study assessed (excluding NMSC) and IBD (including Crohn’s genital psoriasis for which a lower threshold is disease and ulcerative colitis). The IBD events considered) and had a Static Physician’s Global were adjudicated using the Registre Epidemi- Assessment of C 3 and a Psoriasis Area and ologique des Maladies de l’Appareil Digestif Severity Index C 12 at baseline (excepting those (EPIMAD) criteria [21, 22]. MACE were adjudi- in IXORA-Q). The UNCOVER-1, -2 and -3 and cated by an external adjudication committee for IXORA-Q [15, 19, 20] studies had 12-week, ten of the 13 studies (n = 5697). randomized, placebo-controlled periods, with the UNCOVER-2 and -3 studies having an Statistical Analyses additional etanercept arm up to week 12. The IXORA-S study also had an ustekinumab treat- Data are summarized overall from 13 clinical ment arm; however, the ustekinumab data are studies, and for the induction period (12 weeks) not analyzed herein due to limited patient of three psoriasis clinical studies (UNCOVER-1, numbers (N = 166) and duration of therapy -2 and -3). All randomized patients who (52 weeks) [16]. received C 1 dose of the study drug were 136 Dermatol Ther (Heidelb) (2020) 10:133–150 Fig. 1 Designs and numbers of patients for all studies NCT02718898, respectively; RHBO, NCT02387801; included in the analysis. aPatients receiving IXE received a RHBZ, NCT02634801; RHAJ, NCT01107457; RHBU, 160-mg starting dose of IXE at week 0 prior to receiving NCT02993471. AC active comparator, DB double-blind, EP 80 mg IXE (Q4W or Q2W). bGlobal studies. cPBO optional extension period after Wk 24 during which patients administered to maintain study blind. dStep-up criteria received 80 mg IXE Q4W up to Wk 60, ETN 50 mg determined if dosing increased from 80 mg IXE Q4W to etanercept twice weekly, FAE fumaric acid esters 105-mg 80 mg IXE Q2W based on whether a patient achieved sPGA starting dose followed by 215 mg given orally 1–3 times per C 2 at 2 consecutive visits during Wk 12 through Wk 40. day, IXE ixekizumab, IXE Q2W ixekizumab every 2 weeks, e Dosing increased from IXE Q4W to IXE Q2W based on IXE Q4W ixekizumab every 4 weeks, IXE Q12W ixekizumab investigator opinion from Wk 24 through Wk 40. fWith- every 12 weeks, LTE long-term extension, MTX methotrex- drawal period (Wks 20–32); a patient was eligible for ate 7.5-mg starting dose up to 30 mg given orally once a week, treatment with 80 mg IXE Q4W when improvement in N number of patients, OL open-label, PAC placebo- PASI score from baseline was\75% at any visit between Wks controlled and active comparator, PASI Psoriasis Area 20 and 32. gProtocol amendment-mandated dose regimen. Severity Index, PBO placebo, R randomized, sPGA Static Clinicaltrials.gov numbers: UNCOVER-1, -2, -3, -A and -J, Physician’s Global Assessment, UST 45 mg ustekinumab NCT01474512, NCT01597245, NCT01646177, given as subcutaneous injection for participants B 100 kg NCT01777191 and NCT01624233, respectively; IXORA- and 90 mg subcutaneous injection for participants [ 100 kg P, -S and -Q, NCT02513550, NCT02561806 and at weeks 0, 4, 16, 28 and 40, Wk week Dermatol Ther (Heidelb) (2020) 10:133–150 137 included in the safety analysis population. Fre- quencies or exposure-adjusted incidence rates (IRs) of AEs are summarized overall and for some events of interest by 1-year (365-day) intervals. The IRs are expressed as number of unique patients with a particular category of event per 100 p-y, using the entire duration of exposure during each interval. Multiple AEs that occurred in different intervals were coun- ted multiple times. As long-term control data were not available, previously published data for the placebo and ixekizumab groups from the large phase 3 UNCOVER studies are reported as time-adjusted Fig. 2 Number of patients by treatment duration. N (total IRs; baseline characteristics for the same patient number of patients) = 5898; total exposure = 17,003.4 groups are also presented. patient-years RESULTS tract infection (15.6/100 p-y) for the placebo group. For the induction period of the com- A total of 5898 patients received at least one bined UNCOVER-2 and -3 studies (N = 2562), dose of ixekizumab across the 13 studies (Fig. 1). which included etanercept as an active control, Approximately two-thirds of patients were in the rate of any TEAE for ixekizumab (250.5/100 the large UNCOVER -1, -2 and -3 studies, which p-y) was similar to that for etanercept (235.8/ were ongoing as of the data cutoff for these 100 p-y), and the rates of nasopharyngitis and analyses. Total patient exposure in the pooled ISRs for etanercept were 32.5 and 47.3 per 100 analysis population was 17,003.4 p-y; 3009 p-y, respectively, versus 35.4 and 41.0 per 100 patients had at least 3 years exposure and 2749 p-y, respectively, for the combined ixekizumab had at least 4 years of exposure (Fig. 2). Median arms. Across the UNCOVER studies, for com- duration of exposure was 1176 days, and maxi- mon TEAEs, IRs through 12 weeks were signifi- mum duration of exposure was 2236 days. For cantly higher among patients receiving the overall ixekizumab population at baseline, ixekizumab than among those receiving pla- mean age was 45.8 years, and 67.8% of patients cebo for ISR and injection site erythema. The IR were male (Table 1). Median duration of psori- of AEs leading to study drug discontinuation asis symptoms at baseline was 16.7 years. was 5.0/100 p-y for placebo and 9.2/100 p-y for patients receiving ixekizumab; for discontinua- Placebo-Controlled Period tions due to ISRs, there were no AEs among placebo patients and an IR of 1.1 per 100 p-y (n = 6; 0.3%) for patients receiving ixekizumab. Results for the combined placebo-controlled The IR of serious AEs (SAEs) was 6.7 per 100 p-y periods of the UNCOVER-1, -2 and -3 studies for patients receiving placebo and 8.6 per 100 have been presented previously [19]. When p-y for patients receiving ixekizumab during the adjusted for patient exposure (N = 3119), the IR induction period. During the induction period of any TEAE was higher with ixekizumab of the combined UNCOVER -2 and -3 studies, (255.2/100 p-y) than with placebo (205.5/100 ISRs and injection site erythema were both sig- p-y) (Table 2). The most common TEAE repor- nificantly higher for etanercept than for pla- ted was nasopharyngitis for both placebo- cebo, while the IR of AEs leading to etanercept (IR 38.3/100 p-y) and ixekizumab- (IR 40.2/100 discontinuation was 5.3 per 100 p-y, with three p-y) treated patients; the next most common patients discontinuing due to ISRs (IR 1.8/100 TEAE was ISR (38.5/100 p-y) among ixek- p-y; 0.4%). Similarly, the incidence of SAEs for izumab-treated patients and upper respiratory 138 Dermatol Ther (Heidelb) (2020) 10:133–150 Table 1 Baseline characteristics for the overall patient population Characteristics Placebo Etanercept Ixekizumab Ixekizumab (UNCOVER-1, -2 (UNCOVER-2 (UNCOVER-1, -2 All and -3) and -3) and -3) Patients, N 791 739 2328 5898 Age, mean (SD) years 46.2 (12.8) 45.5 (13.3) 45.2 (13.0) 45.8 (13.1) Male, % (n/N) 70.7 (559/791) 68.2 (504/739) 66.7 (1553/2328) 67.8 (4000/ 5898) Race, % (n/N) Asian 4.3 (34/791) 2.6 (19/735) 3.7 (86/2323) 6.9 (408/ 5892) African American 3.3 (26/791) 3.1 (23/735) 2.1 (48/2323) 2.9 (168/ 5892) White 91.7 (725/791) 92.7 (681/735) 92.9 (2159/2323) 87.8 (5174/ 5892) Others 0.8 (6/791) 1.6 (12/735) 1.3 (30/2323) 2.4 (142/ 5892) Geographic region, % (n/N) Asia 1.6 (13/791) 0 0.9 (20/2328) 3.9 (232/ 5898) North America 50.9 (403/791) 51.8 (383/739) 51.4 (1197/2328) 52.6 (3100/ 5898) Europe 42.4 (335/791) 42.4 (313/739) 42.9 (999/2328) 37.4 (2205/ 5898) Central/South America 1.8 (14/791) 4.1 (30/739) 2.5 (58/2328) 3.0 (174/ 5898) Australia 3.3 (26/791) 1.8 (13/739) 2.3 (54/2328) 2.8 (165/ 5898) BMI, mean kg/m2 (SD) 30.5 (7.2) 31.0 (7.4) 30.5 (7.1) 30.6 (7.3) Prior systemic therapy, % (n/N) Never 35.8 (283/791) 39.6 (293/739) 34.7 (808/2328) 35.7 (2104/ 5898) Nonbiologic only 31.7 (251/791) 42.1 (311/739) 38.4 (894/2328) 33.7 (1986/ 5898) Biologic only 11.6 (92/791) 8.0 (59/739) 9.3 (216/2328) 12.4 (729/ 5898) Biologic and nonbiologic 20.9 (165/791) 10.3 (76/739) 17.6 (410/2328) 18.3 (1079/ 5898) Dermatol Ther (Heidelb) (2020) 10:133–150 139 Table 1 continued Characteristics Placebo Etanercept Ixekizumab Ixekizumab (UNCOVER-1, -2 (UNCOVER-2 (UNCOVER-1, -2 All and -3) and -3) and -3) Prior biologic therapy, % (n/N) Never 67.5 (534/791) 81.7 (604/739) 73.1 (1702/2328) 69.3 (4090/ 5898) 1 19.6 (155/791) 13.7 (101/739) 16.3 (379/2328) 19.4 (1146/ 5898) 2 7.1 (56/791) 3.0 (22/739) 6.2 (144/2328) 6.5 (384/ 5898) C3 5.8 (46/791) 1.6 (12/739) 4.4 (103/2328) 4.7 (278/ 5898) Duration of psoriasis symptoms, 19.1 (12.1) [16.7] 18.5 (12.1) [16.4] 18.8 (12.2) [16.9] 18.7 (12.2) mean years (SD) [median] [16.7] Tobacco use, yes, % (n/N) 39.5 (310/784) 37.1 (274/739) 37.6 (872/2322) 14.8 (874/ 5898) BMI Body mass index, N total patients evaluated, n number of patients in category, SD standard deviation etanercept was 8.3 per 100 p-y during the the induction phase. The rates of AEs leading to induction period. study discontinuation, any SAEs and SAEs by body system generally decreased or remained Combined Periods of Ixekizumab Therapy static when compared between the induction period and the combined ixekizumab treatment Incidence rates for TEAEs for the combined period (Table 2). ixekizumab treatment period were compared To assess the impact of cumulative exposure with either placebo or ixekizumab treatment on rates of important AEs, IRs were compared during the induction period. Exposure-adjusted through 1, 2, 3, 4 and 5 years of treatment IRs for any TEAE were lower in the combined (Fig. 3). The exposure-adjusted IR of ISRs was ixekizumab treatment period (30.0/100 p-y) 15.5 per 100 p-y during the first year of treat- than in placebo-controlled period (placebo ment and declined to a range of 2.0–2.3 per 100 205.5/100 p-y or ixekizumab 255.2/100 p-y; p-y by years 3–5 of treatment. Similarly, allergic Table 2). The same was true for the most com- reactions or hypersensitivities were reported at mon TEAEs of nasopharyngitis/viral upper res- 9.9/100 p-y during the first year of treatment piratory infection (8.9/100 p-y overall vs. 38.3/ and declined from 5.1 to 3.8 per 100 p-y from 100 p-y for placebo or 40.2/100 p-y for ixek- years 2–5. The IR for AEs leading to study dis- izumab through 12 weeks) upper respiratory continuation declined from 3.8/100 p-y in the tract infection (5.4/100 p-y overall vs. 15.6/100 first year of treatment to 2.0 per 100 p-y in the p-y or 18.0/100 p-y); ISR (3.4/100 p-y vs. 5.0/100 fifth year, while the IR for serious infections p-y or 38.5/100 p-y) and headache (3.0/100 p-y remained essentially constant (range 1.3–1.7 vs. 12.8/100 p-y or 18.9/100 p-y), which were per 100 p-y). IRs of overall SAEs were relatively more common among ixekizumab-treated constant for each of the 1-year periods (range patients than placebo-treated patients during 6.2–7.0 per 100 p-y). The IRs of NMSC were Table 2 Summary of the most commonly reported adverse events 140 Follow-up Placebo-controlled perioda Combined Ixe therapy period (N = 5898) Placebo (N = 791) Ixekizumab (N = 2328) Etanercept (N = 739) Mean follow-up (weeks) 11.9 12.0 11.9 150.4 Total follow-up (p-y) 180.0 534.5 169.2 17,003.4 Adverse events IRb N (%) IRb N (%) IRb N (%) IRb N (%) Patients with C 1 TEAE 205.5 370 (46.8) 255.2 1364 (58.6) 235.8 399 (54.0) 30.0 5105 (86.6) Common TEAEs (preferred terms) Nasopharygitis/viral upper resp. tract infection 38.3 69 (8.7) 40.2 215 (9.2) 32.5 55 (7.4) 8.9 1515 (25.7) Upper resp. tract infection 15.6 28 (3.5) 18.0 96 (4.1) 20.1 34 (4.6) 5.4 921 (15.6) Injection site reaction 5.0 9 (1.1) 38.5 206 (8.8) 47.3 80 (10.8) 3.4 573 (9.7) Headache 12.8 23 (2.9) 18.9 101 (4.3) 18.3 31 (4.2) 3.0 508 (8.6) Arthralgia 9.4 17 (2.1) 9.5 51 (2.2) 10.0 17 (2.3) 3.0 506 (8.6) Back pain 5.0 9 (1.1) 5.6 30 (1.3) 4.1 7 (0.9) 2.5 429 (7.3) Bronchitis 3.9 7 (0.9) 5.1 27 (1.2) 5.3 9 (1.2) 2.3 398 (6.7) Hypertension 3.9 7 (0.9) 3.9 21 (0.9) 7.7 13 (1.8) 2.4 403 (6.8) Sinusitis 3.3 6 (0.8) 4.5 24 (1.0) 2.4 4 (0.5) 2.2 369 (6.3) Diarrhoea 4.4 8 (1.0) 8.0 43 (1.8) 4.7 8 (1.1) 2.0 343 (5.8) Urinary tract infection 5.6 10 (1.3) 5.8 31 (1.3) 3.0 5 (0.7) 2.0 333 (5.6) AE leading to D/C 5.0 9 (1.1) 9.2 49 (2.1) 5.3 9 (1.2) 2.8 477 (8.1) SAE by body system 6.7 12 (1.5) 8.6 46 (2.0) 8.3 14 (1.9) 5.5 929 (15.8) Infections and infestations 1.7 3 (0.4) 2.4 13 (0.6) 1.8 3 (0.4) 1.3 223 (3.8) Cardiac disorders 0.6 1 (0.1) 0.6 3 (0.1) 0.6 1 (0.1) 0.7 122 (2.1) Gastrointestinal disorders 0.6 1 (0.1) 1.1 6 (0.3) 0 0 0.6 110 (1.9) Injury, poisoning and procedural complications 0.6 1 (0.1) 0.4 2 (0.1) 0.6 1 (0.1) 0.7 118 (2.0) Dermatol Ther (Heidelb) (2020) 10:133–150 Table 2 continued Adverse events IRb N (%) IRb N (%) IRb N (%) IRb N (%) Neoplasms benign, malignant and 0.6 1 (0.1) 0.2 1 (0.0) 1.8 3 (0.4) 0.6 100 (1.7) unspecified (including cysts and polyps) Musculoskeletal and connective tissue disorders 0 0 0.2 1 (0.1) 0.6 1 (0.1) 0.5 88 (1.5) Nervous system disorders 0 0 0.7 4 (0.2) 0.6 1 (0.1) 0.4 62 (1.1) Respiratory, thoracic, and mediastinal disorders 1.1 2 (0.3) 0.4 2 (0.1) 0 0 0.3 53 (0.9) Hepatobiliary disorders 0.6 1 (0.1) 0.6 3 (0.1) 0 0 0.3 44 (0.7) Dermatol Ther (Heidelb) (2020) 10:133–150 Renal and urinary disorders 0 0 0.4 2 (0.1) 1.8 3 (0.4) 0.2 39 (0.7) Psychiatric disorders 0.6 1 (0.1) 0.6 3 (0.1) 0 0 0.2 36 (0.6) Skin and subcutaneous tissue disorders 1.7 3 (0.4) 0.9 5 (0.2) 0 0 0.2 31 (0.5) Vascular disorders 0 0 0 0 0.6 1 (0.1) 0.2 36 (0.6) Metabolism and nutrition disorders 0 0 0.6 3 (0.1) 0 0 0.2 31 (0.5) General disorders and administrative site conditions 0 0 0 0 0.6 1 (0.1) 0.2 28 (0.5) AE Adverse event, D/C study discontinuation, IR incidence rate, Ixe ixekizumab, N total number of patients, p-y patient-years, resp. respiratory, SAE serious AE, TEAE treatment-emergent AE a Etanercept was an active control in two of the three UNCOVER studies included in the placebo-controlled analysis here; data for placebo and ixekizumab are shown for all three studies b Incidence rates are per 100 patient-years 141 142 Dermatol Ther (Heidelb) (2020) 10:133–150 Table 3 Summary of treatment-emergent adverse events of special interest during combined ixekizumab dosing Treatment-emergent AEs N (%) IRa Patients treated 5898 Injection site reactions 892 (15.1) 5.2 Hypersensitivity/allergic reactions 876 (14.9) 5.2 Serious infections and infestations 223 (3.8) 1.3 Oral candidiasis 140 (2.4) 0.8 Malignancies 131 (2.2) 0.8 NMSC 51 (0.9) 0.3 Other malignancies (excluding 86 (1.5) 0.5 Fig. 3 Treatment-emergent adverse events per 100 NMSC) patient-years by years of treatment. AE Adverse event, Inflammatory bowel disease (narrow 26 (0.4) 0.2 D/C study discontinuation, IBD inflammatory bowel disease, MACE major adverse cardiovascular events, terms) NMSC non-melanoma skin cancer, p-y patient-years, Rx Inflammatory bowel disease 1 (0.0) \ 0.05 reaction, SAE serious adverse event Crohn’s disease 7 (0.1) \ 0.05 highest in the first year (0.5/100 p-y) and Ulcerative colitis 18 (0.3) 0.1 decreased or stayed the same in subsequent MACE, adjudicated (n = 5697) 84 (1.5) 0.5 years (range 0.2–0.4 per 100 p-y), while IRs for other malignancies ranged from 0.4 per 100 p-y Vascular death 20 (0.4) 0.1 in the first year to 0.6 per 100 p-y in the fourth Myocardial infarction, nonfatal 45 (0.8) 0.3 year. MACE occurred in 84/5697 patients, with an overall IR of 0.5 per 100 p-y (Table 3); Stroke, nonfatal 20 (0.4) 0.1 although IRs varied across treatment years, no AE Adverse event; IR incidence rate; MACE major adverse trend was observed for an increase over time. cardiovascular events, N total number of patients, n num- IRs (unadjudicated) of IBD ranged from a high ber of patients in category, NMSC non-melanoma skin of 0.5 in the first year to a low of 0.1 during the cancer third and fourth years of treatment. The IRs of a Incidence rates are per 100 patient-years candidiasis were highest in the first year (3.2/ 100 p-y) and then ranged from 2.1 to 2.3 per 100 p-y in subsequent years. Thirty-four deaths were reported, with 32 Adverse Events of Special Interest deaths occurring during ixekizumab treatment (IR during treatment 0.2/100 p-y; range 0.1–0.3 per 100 p-y by year). For all deaths, causes were As assessed based on years of treatment, IRs were cardiac-related (n = 14), malignancies (n = 4), generally constant or decreasing for ISRs, allergic unknown (n = 5), respiratory causes (n = 3), reactions/hypersensitivity, serious infections, trauma/accident (n = 3), severe hemorrhagic candidiasis, MACE, NMSC, other malignancies cerebral infarction (n = 1), death concomitant and IBD across the treatment periods (Fig. 2). with severe senile dementia (n = 1), ulcerative colitis (n = 1), cholecystolithiasis (n = 1) and Administration Site or Drug Reactions septic shock (n = 1). MACE accounted for most As noted above, the IRs for ISRs, as well as for deaths, and none of the deaths were considered allergic reactions/hypersensitivity, decreased related to the study drug. over time through the 5 years of the study. Dermatol Ther (Heidelb) (2020) 10:133–150 143 One or more ISRs were reported for 15.1% of Table 4 Infections patients (Table 3), with 10.0, 4.5 and 0.6% Category Combined experiencing mild, moderate and severe reac- ixekizumab tions, respectively, at an overall IR of 5.2 per (N = 5898) 100 p-y. The most commonly reported specific terms were ISR (IR 3.4/100 p-y), injection site n (%) IRa erythema (1.1/100 p-y) and injection site pain Patients with C 1 infection 3859 (65.4) 22.7 (0.6/100 p-y). A total of 13 patients discontin- ued the study drug due to injection site–related Nasopharyngitis 1515 (25.7) 8.9 TEAEs (0.1/100 p-y). The most frequently Upper respiratory tract infection 921 (15.6) 5.4 reported allergic events (IR C 0.5) were contact Bronchitis 398 (6.7) 2.3 dermatitis (IR 1.1/100 p-y), eczema (1.0/100 p-y), urticaria (0.6/100 p-y), dermatitis (0.5/100 Sinusitis 369 (6.3) 2.2 p-y), allergic rhinitis (0.5/100 p-y) and rash Urinary tract infection 333 (5.6) 2.0 (0.5/100 p-y). There was one case of worsening eczematous reaction that was considered a Influenza 307 (5.2) 1.8 possible paradoxical reaction, but the patient Pharyngitis 278 (4.7) 1.6 recovered and continued in the study. Four SAEs of pustular psoriasis were reported. One Gastroenteritis 237 (4.0) 1.4 event occurred after an upper respiratory tract Patients with C 1 serious infection/ 223 (3.8) 1.3 infection; the patient recovered and continued infestation in the clinical trial. Of three cases of pustular psoriasis events, two were considered related to Cellulitis 40 (0.7) 0.2 the study drug by the investigator, and the Pneumonia 25 (0.4) 0.1 third case was considered unrelated; all three patients discontinued the study drug. There Appendicitis 11 (0.2) 0.1 were reports of potential anaphylaxis events; Erysipelas 9 (0.2) 0.1 however, upon review, none occurred in tem- poral relationship to the administration of IR incidence rate, N total number of patients, n number of patients in category ixekizumab, and no confirmed cases of ixek- a Incidence rates are per 100 patient-years izumab-related anaphylaxis have been identi- fied in any clinical studies. (n = 25; IR 0.1/100 p-y); appendicitis (n = 11; Infections IR 0.1/100 p-y) and erysipelas (n = 9; IR 0.1/ Infections overall were more common during 100 p-y). the first year of treatment (IR 56.6; 95% con- Latent tuberculosis was reported for 42 fidence interval [CI] 54.6, 58.6/100 p-y) versus patients (IR 0.2/100 p-y), the mycobacterium later years (IR range 35.8 [95% CI 33.7, 38.0] to complex test was positive for 43 patients (IR 41.2 [95% CI 39.1, 43.4]/100 p-y). In addition 0.2/100 p-y) and the tuberculin test was posi- to the upper respiratory tract infections tive for 17 patients (IR 0.1/100 p-y); pulmonary described above, the most common infections tuberculosis or tuberculosis was determined for overall were bronchitis (IR 2.3/100 p-y), one patient (IR \ 0.05/100 p-y) each. These sinusitis (IR 2.2/100 p-y) and urinary tract findings were criteria for discontinuation for infection (IR 2.0/100 p-y; Table 4). Infections some of the studies and led to discontinuation and infestations were largely mild to moderate in 20, 31, 13, 1 and 1 patients, respectively. in severity and seldom led to discontinuation There were no confirmed cases of tuberculosis of the study drug (IR for discontinuation due reactivation; one de novo case of tuberculosis to infection 0.4/100 p-y). The most common was reported in a country with a high tuber- serious infections (IR C 0.1/100 p-y) were cel- culosis burden. lulitis (n = 40; IR 0.2/100 p-y); pneumonia 144 Dermatol Ther (Heidelb) (2020) 10:133–150 Malignancies by 140 patients (IR 0.8/100 p-y) (Table 3); one The most common malignancies were NMSCs case of esophageal candidiasis led to study dis- (keratinocyte cancers)—specifically basal cell continuation; there were no reports of deep carcinoma (n = 42; IR 0.2/100 p-y) and squa- organ or bloodstream Candida infection. mous cell carcinomas (n = 12; IR 0.1/100 p-y) (Table 5). The total number of other malignan- Inflammatory Bowel Disease cies was 86 (IR 0.5/100 p-y), with prostate can- Overall, TEAEs of IBD (narrow terms) were cer being the most common (n = 12, IR in men reported by a total of 26 patients (IR 0.2/100 only 0.1/100 p-y), followed by squamous cell p-y), largely as ulcerative colitis (n = 18; IR 0.1/ carcinoma (n = 6; IR \ 0.05/100 p-y for all n B 100 p-y) and Crohn’s disease (n = 7, IR \ 0.05/ 6), invasive ductal breast carcinoma (n = 5), 100 p-y; Table 3). Of the eight reports of colon cancer (n = 4) and metastatic lung cancer Crohn’s disease from seven patients, four events (n = 3); no other specific malignancies were occurred in the first year and two each were seen in more than two patients. reported in the second and fifth years of treat- ment. As awareness of the role of IL-17 inhibi- Candidiasis tion in IBD evolved after initiation of the Candidiasis overall was reported by 327 patients psoriasis clinical trial program, a protocol (IR 1.9/100 p-y), with oral candidiasis reported amendment was instituted that allowed for post hoc adjudication of IBD in a retrospective Table 5 Malignancies manner. Per adjudication, prespecified specific and nonspecific terms for IBD were identified Category Combined IRa and evaluated as follows: 24 patients had ixekizumab reported IBD confirmed as ulcerative colitis (N = 5898) (n = 16; IR 0.1/100 p-y) and Crohn’s disease Non-melanoma skin 51 (0.9) 0.3 (n = 8; IR \ 0.05/100 p-y). As shown for unad- cancer, n (%) judicated cases (specific terms) in Fig. 3, the IR for adjudicated cases remained relatively con- Basal cell carcinoma, 42 (0.7) 0.2 stant over time (year 1, n = 14, IR 0.3/100 p-y; n (%) year 2, n = 6, IR 0.2/100 p-y; years 3 and 4, n = 1 Squamous cell 12 (0.2) 0.1 each [each IR \ 0.05/100 p-y]; year 5, n = 4, carcinoma, n (%) IR 0.2/100 p-y). Malignancies excluding 86 (1.5) 0.5 Major Adverse Cardiovascular Events NMSC, n (%) Major adverse cardiovascular events occurred in Prostate cancer,b n (%) 12 (0.3) 0.1 84/5697 patients (IR 0.5/100 p-y) in studies with adjudication (total p-y 16,455.6) (Table 3). Squamous cell 6 (0.1) \ 0.05 The most common category of events was carcinoma, n (%) nonfatal myocardial infarction (n = 45; IR 0.3/ Invasive ductal breast 5 (0.1) \ 0.05 100 p-y), followed by vascular death (n = 20; carcinoma, n (%) IR 0.1/100 p-y) and nonfatal stroke (n = 20; IR 0.1/100 p-y). Colon cancer, n (%) 4 (0.1) \ 0.05 Lung cancer metastatic, 3 (0.1) \ 0.05 n (%) DISCUSSION IR incidence rate, N total number of patients, n number of Many factors must be considered when select- patients in category, NMSC non-melanoma skin cancer ing the optimal therapy for psoriasis; important a Incidence rates are per 100 patient-years among these are the association of therapies b Calculated in men only; N = 4000 men with 11,714.2 with AEs, such as infection or malignancy, and patient-years of exposure the impact of therapy on comorbidities [23, 24]. Dermatol Ther (Heidelb) (2020) 10:133–150 145 We assessed safety events up to 5 years of ther- tests led to discontinuation (which was protocol apy with ixekizumab in 5898 patients, for specified for a portion of the studies) for 66 [17,000 total p-y of exposure. IRs of TEAEs patients. However, no cases of tuberculosis generally decreased or remained stable over reactivation have been observed in the ixek- time, and the overall rate of TEAEs was lower izumab clinical development program, includ- with longer duration of therapy compared to ing in patients with latent or previously treated the first 12-week placebo-controlled period. Mycobacterium tuberculosis infection. One case of Most AEs were not serious, and the rate of dis- de novo tuberculosis was reported in a country continuation due to AEs was low, with a with a high tuberculosis burden. ISRs were also decreasing trend over time. The overall rate of one of the most commonly reported AEs, and SAEs was stable across the study period, with no their IRs declined over time, as noted in a pre- trend toward increasing rates of AEs with longer vious analysis that used most of the current duration of exposure. This was also true for rates dataset [28]. Allergic reactions/hypersensitivi- of malignancies, MACE and serious infections, ties were more frequently reported during the which remained comparable to those for pla- first year, then stabilized or decreased moder- cebo or ixekizumab during the 12-week pla- ately in subsequent years. The occurrence of cebo-controlled induction period. These results potential paradoxical reactions, such as pustular support and confirm previous reports describing psoriasis, were rare. SAEs classified as allergic a favorable safety profile following shorter reactions/hypersensitivity events and discon- durations of ixekizumab exposure, and suggest tinuation of ixekizumab due to allergic reac- that increased duration and total exposure to tions/hypersensitivities were uncommon, with ixekizumab were not associated with additional 27 (0.5%) and 28 (0.5%) patients reporting such or unexpected safety concerns [15, 17, 18]. events, respectively. Overall, there was no Previous reports have noted infections as the indication of an increased risk for allergic reac- most frequent AE associated with ixekizumab tions/hypersensitivity events with increasing therapy. In the present report, infections were durations of exposure to ixekizumab. found to be generally mild to moderate in Findings regarding IBD in the present anal- severity and seldom led to study discontinua- ysis were consistent with those of an earlier tion. The IR of severe infections (1.4/100 p-y) report on combined ixekizumab safety data did not increase over time and was comparable collected over 3 years, indicating that Crohn’s to that reported in pooled safety data for up to disease and ulcerative colitis were uncommon 5 years of treatment with the anti-IL-12 and [18]. Annual IRs of patients with TEAEs (specific anti-IL-23 agent ustekinumab (1.1/100 p-y) [25], and broad terms) adjudicated (retrospective and in pooled safety data primarily for 3 years for prospective) per EPIMAD criteria as probable or the tumor necrosis factor (TNF) inhibitor adal- definite Crohn’s disease and ulcerative colitis imumab (1.8/100 p-y) [26] and in data for up to did not increase and remained stable for up to 66 months in a single study of the Janus kinase 5 years of therapy. As noted in a previous report inhibitor tofacitinib (1.2/100 p-y) [27]. There on IBD in patients receiving ixekizumab, which were no reports of Grade 4 (\ 0.5 9 109/L) assessed approximately two-thirds of the neutropenia associated with infections; an patients included herein over shorter periods of infection temporally associated with Grade 3 exposure, such rates are comparable to those (\ 1.0–0.5 9 109/L) neutropenia was reported reported in psoriasis cohort studies, but are for three patients (0.1%; influenza [n = 1], otitis difficult to compare directly to rates reported in externa [n = 1] and nasopharyngitis [n = 1]) and studies of other biologics due to differences in infections associated with Grade 2 neutropenia criteria for reporting events [22]. (\ 1.5–1.0 9 109/L) were reported for 27 (0.5%) Patients with psoriasis are at an increased risk patients. Consistent with the role of IL-17A in of cardiovascular AEs, including a 10-year risk of the suppression of mucocutaneous candidiasis, MACE [29–33]. While a reduction in cardiovas- oral candidiasis was the most frequently repor- cular risk has been suggested for methotrexate ted opportunistic infection. Positive tuberculin or biologics in the treatment of rheumatoid 146 Dermatol Ther (Heidelb) (2020) 10:133–150 arthritis [34–36], reports on cardiovascular risk with that reported for ustekinumab up to reduction with psoriasis treatment have been 5 years (0.22/100 p-y) [25]. Most deaths in this contradictory [37, 38]. Low serum levels of IL-17 study were secondary to cardiovascular disor- have been associated with a risk of repeat ders in patients with background risk factors. myocardial infarction; however, the role of IL- The limitations of the present study include 17 in atherosclerosis is complex, with conflict- the following. First, although overall IRs of AEs ing results reported [14]. In the present study, decreased after the 12-week induction period, the overall incidence of MACE of 0.5/100 p-y some of the decreases in AEs may be due to was comparable to long-term results reported reporting fatigue and differences in recall due to for patients receiving ustekinumab (0.44/100 increased time between visits at later time p-y) [25] and adalimumab (0.36/100 p-y) [39], points. Secondly, the lack of a randomized pla- with no apparent increase in incidence with cebo control group after the induction period longer ixekizumab exposure. Determining limited our ability to directly compare IRs at whether biologics, including specific later time points with a control population. immunomodulators, are associated with Thirdly, the length of follow-up varied between increased, decreased or comparable rates of studies, and the three largest studies, cardiovascular disease relative to rates in UNCOVER-1, -2 and -3, are not all completed; untreated patients with psoriasis or in patients thus, it will be important to revisit these findings receiving other psoriasis treatments will require once all of the UNCOVER studies have been further studies, such as observational studies or completed. Fourthly, certain adverse effects, studies using claims database cohorts, and such as MACE and malignancies, require longer meta-analyses with large numbers of patients observation periods and larger patient exposures receiving various comparator treatments. to ascertain risk. Long-term safety studies, Patients with psoriasis may be at increased including post marketing studies, are ongoing to risk for some lymphoproliferative [40] and continue to evaluate the safety of ixekizumab; NMSC malignancies [41, 42], and there are however, preliminary data up to 27 months concerns about the impact of long-term sys- from the Corrona observational database are temic treatment with anti-TNF therapies [43]. consistent with the present results [46]. The IR of malignancies other than NMSC (0.5/ 100 p-y) for up to 5 years of therapy with ixek- izumab in this study was comparable to that for CONCLUSION long-term ustekinumab (0.6/100 p-y) [25] and the anti-TNF therapies adalimumab (0.8/100 In conclusion, no new safety signals were p-y) [26] and etanercept (estimated 0.55/100 identified with longer-term follow-up with p-y) [44]. The IR of NMSC seen with ixekizumab ixekizumab, nor was any trend observed for an of 0.3/100 p-y in this study was somewhat lower increase in IRs for any AE of special interest than that reported based on long-term safety based on increased duration of therapy through data for ustekinumab (0.52/100 p-y) [25] or with 1–5 years. Thus, the long-term safety profile adalimumab (0.6/100 p-y) [26] or etanercept with ixekizumab up to 5 years was consistent (0.9 per 100 p-y) [44] in psoriasis. The ratio of with the favorable safety profile observed pre- basal cell carcinoma to squamous cell carci- viously following shorter durations of ixek- noma expected in immunocompetent patients izumab exposure. in the general population is 4:1, and is reversed in severely immunocompromised patients, such as transplant recipients [45]; thus, the ratio of ACKNOWLEDGEMENTS 3.5:1 during long-term ixekizumab dosing was consistent with the expectation for immuno- competent patients. There were 34 total deaths Funding. The studies described herein and reported over the 17,003.4 p-y of exposure to the Rapid Service Fee were funded by Eli Lilly ixekizumab; the IR of 0.2/100 p-y is consistent and Company. Dermatol Ther (Heidelb) (2020) 10:133–150 147 Medical Writing Assistance. Thomas Melby a consultant and/or scientific adviser and/or (Syneos Health) assisted as a medical writer in investigator and/or scientific officer and/or the preparation of this manuscript, funded by speaker for Amgen, Anacor, AbbVie, Akros, Eli Lilly and Company. Allergan, Astellas, AstraZeneca, Baxalta, Baxter, BMS, Boehringer Ingelheim, Can-Fite, Celgene, Authorship. All named authors meet the Coherus, Dermira, Dow Pharma, Eli Lilly and International Committee of Medical Journal Company, Forward Pharma, Galderma, Genen- Editors (ICMJE) criteria for authorship for this tech, GSK, Janssen, Kyowa Hakko Kirin, Leo article, take responsibility for the integrity of Pharma, Medimmune, Meiji Seika Pharma, the work as a whole, and have given their Merck (MSD), Merck-Serono, Mitsubishi approval for this version to be published. Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi/Genzyme, Takeda, UCB, and Valeant. Disclosures. April Armstrong has served as a Christopher E.M. Griffiths has received hono- research investigator and/or consultant to raria and/or research grant support (University AbbVie, Janssen, Lilly, Leo, Novartis, UCB, of Manchester) from AbbVie, Almirall, Bristol Ortho Dermatologics, Dermira, Sanofi, Regen- Meyers Squibb, Celgene, Eli Lilly and Company, eron, BMS, Dermavant, and Modernizing Med- GSK, Janssen, LEO Foundation, Novartis, Pfizer, icine. Carle Paul has served as consultant and/or Sandoz, Sun Pharma, and UCB Pharma. Andrew investigator for AbbVie, Amgen, Boehringer, Blauvelt has served as a scientific adviser and/or Celgene, Eli Lilly and Company, Janssen, Leo, clinical study investigator for AbbVie, Aclaris, Novartis, and Pfizer. Luis Puig has received: Akros, Allergan, Almirall, Amgen, Arena, Athe- grants or research support or participated in nex, Boehringer Ingelheim, Bristol-Myers clinical trials (paid to institution) from AbbVie, Squibb, Celgene, Dermavant, Dermira Eli Lilly Almirall, Amgen, Boehringer Ingelheim, Jans- and Company, FLX Bio, Galderma, Genentech/ sen, Leo-Pharma, Eli Lilly and Company, Roche, GlaxoSmithKline, Janssen, Leo, Meiji, Novartis, Pfizer, Regeneron, Roche, Sanofi, and Merck Sharp & Dohme, Novartis, Pfizer, Purdue UCB; honoraria or consultation fees (paid to Pharma, Regeneron, Revance, Sandoz, Sanofi self) from AbbVie, Almirall, Amgen, Baxalta, Genzyme, Sienna Pharmaceuticals, Sun Biogen, Boehringer Ingelheim, Celgene, Gebro, Pharma, UCB Pharma, Valeant, and Vidac, and Janssen, Leo-Pharma, Eli Lilly and Company, as a paid speaker for AbbVie, Regeneron, and Merck-Serono, MSD, Mylan, Novartis, Pfizer, Sanofi Genzyme. Kristian Reich has served as an Regeneron, Roche, Sandoz, Samsung-Bioepis, advisor and/or paid speaker for and/or partici- Sanofi, and UCB; and has been a speaker for pated in clinical trials sponsored by AbbVie, Celgene, Janssen, Eli Lilly and Company, MSD, Affibody, Amgen, Biogen, Boehringer Ingelheim Novartis, and Pfizer. Luis Puig is also a member Celgene, Centocor, Covagen, Forward Pharma, of the journal’s Editorial Board. Wolf-Henning GlaxoSmithKline, Janssen-Cilag, Kyowa Kirin, Boehncke has received honoraria as an advisor Leo, Eli Lilly and Company, Medac, Merck or speaker from the following companies: Abb- Sharp & Dohme, Novartis, Ocean Pharma, Pfi- Vie, Almirall, Celgene, Janssen, Leo, Eli Lilly zer, Regeneron, Sanofi, Takeda, UCB Pharma, and Company, Novartis, Pfizer, and UCB. and Xenoport. Melinda Gooderham has been Michael Freeman has been a scientific adviser an investigator, speaker, advisory board mem- and/or investigator and/or speaker for Amgen, ber or consultant for AbbVie, Amgen, Akros, AbbVie, Allergan, Celgene, Dermira, Eli Lilly Arcutis, Boehringer Ingelheim, Bristol-Myers and Company, Galderma, Janssen, Leo Pharma, Squibb, Celgene, Dermira, Dermavant, Eli Lilly Novartis, Pfizer, Regeneron, Roche, and Sanofi/ and Company, Galderma, GSK, Janssen, Kyowa Genzyme. Hideshi Torii has received consulting Kirin, LEO Pharma, Medimmune, Novartis, Pfi- fees or honoraria from the following compa- zer, Regeneron, Roche, Sun Pharmaceuticals, nies: AbbVie, Eli Lilly and Company, Celgene, UCB, and Valeant. Tadashi Terui has received Janssen, Novartis, Kyowa Hakko Kirin, and research funds from Maruho Co. Ltd. and Mitsubishi Tanabe Pharma. Kim Papp has been honoraria for speaker, consultancy and advisory 148 Dermatol Ther (Heidelb) (2020) 10:133–150 board member from AbbVie, Boehringer Ingel- acceptance, whichever is later. No expiration heim, Celgene, Janssen, Kyowa Hakko Kirin date of data requests is currently set once data Co., Ltd, Leo Pharma, Eli Lilly and Company, are made available. Access is provided after a Mitsubishi Tanabe Pharma Corporation, proposal has been approved by an independent Novartis, TAIHO Phamaceutical Co, and Sanofi. review committee identified for this purpose Mark G. Lebwohl is an employee of Mount Sinai and after receipt of a signed data sharing Hospital, for which he receives research funds agreement. Data and documents, including the from: AbbVie, Amgen, AstraZeneca, Boehringer- study protocol, statistical analysis plan, clinical Ingelheim, Celgene, Eli Lilly and Company, study report and blank or annotated case report Incyte, Janssen/Johnson & Johnson, Kadmon, forms, will be provided in a secure data sharing Leo Pharmaceuticals, Medimmune, Novartis, environment. For details on submitting a Pfizer, Sciderm, UCB, Ortho-dermatologics, and request, see the instructions provided at www. ViDac. Mark G. Lebwohl is also a consultant for vivli.org. Allergan, Almirall, Arcutis, Avotres, Birch biomed, Boehringer-Ingelheim, Bristol Myers Open Access. This article is distributed Squibb, Cara, Castle Biosciences, Dermavant, under the terms of the Creative Commons Encore, Inozyme, LEO Pharma, Meiji, Menlo, Attribution-NonCommercial 4.0 International Mitsubishi Pharma, Neuroderm LTD, Pfizer, License (http://creativecommons.org/licenses/ Promius/Dr. Reddy, Theravance Biopharma, by-nc/4.0/), which permits any noncommer- and Verrica. Mark G. Lebwohl is also a member cial use, distribution, and reproduction in any of the journal’s Editorial Board. Lisa Renda is an medium, provided you give appropriate credit employee and minor shareholder of Eli Lilly and to the original author(s) and the source, provide Company. Noah Agada is an employee and a link to the Creative Commons license, and minor shareholder of Eli Lilly and Company. indicate if changes were made. Wen Xu is an employee and minor shareholder of Eli Lilly and Company. Gaia Gallo is an employee and minor shareholder of Eli Lilly and Company. 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