(LY3074828) in the Treatment of Moderate‐To‐Severe Plaque Psoriasis

BJD CLINICAL TRIAL British Journal of Dermatology Efﬁcacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study 1,2 3 4 4 5 6 7 8 K. Reich, P. Rich, C. Maari, R. Bissonnette iD , C. Leonardi, A. Menter, A. Igarashi, P. Klekotka, 8 8 8 8 8 8 9 D. Patel, J. Li, J. Tuttle, M. Morgan-Cox, E. Edson-Heredia iD , S. Friedrich and K. Papp iD on behalf of the AMAF investigators 1Dermatologikum Berlin, Berlin, Germany 2SCIderm Research Institute, Hamburg, Germany 3Dermatology and Clinical Research, Oregon Health Science University, Portland, OR, U.S.A. 4Innovaderm Research, Montreal, QC, Canada 5St Louis University School of Medicine, St Louis, MO, U.S.A. 6Department of Dermatology, Baylor University Medical Center, Dallas, TX, U.S.A. 7NTT Medical Center Tokyo, Tokyo, Japan 8Eli Lilly and Company, Indianapolis, IN, U.S.A. 9Probity Medical Research, Waterloo, ON, Canada

Summary

Correspondence Background Inhibiting interleukin (IL)-23 in patients with psoriasis has demon- Kristian Reich. strated high levels of skin clearance. E-mail: [email protected] Objectives To investigate, in a phase II (AMAF; NCT02899988), multicentre, double-blind trial, the efficacy and safety of three doses of mirikizumab Accepted for publication 6 January 2019 (LY3074828), a p19-directed IL-23 antibody, vs. placebo in patients with moderate-to-severe plaque psoriasis. Funding sources Methods Adult patients were randomized 1 : 1 : 1 : 1 to receive placebo (n = 52), This study was funded in full by Eli Lilly and mirikizumab 30 mg (n = 51), mirikizumab 100 mg (n = 51) or mirikizumab Company, Indianapolis, IN, U.S.A. 300 mg (n = 51) subcutaneously at weeks 0 and 8. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving a 90% Conflicts of interest See Appendix. improvement in the Psoriasis Area and Severity Index (PASI 90) response at week See Appendix S1 for the complete list of AMAF 16. Comparisons were done using logistic regression analysis with treatment, investigators. geographical region and previous biological therapy in the model. Missing data were imputed as nonresponses. DOI 10.1111/bjd.17628 Results Ninety-seven per cent of patients completed the first 16 weeks of the study. The primary end point was met for all mirikizumab dose groups vs. placebo, with PASI 90 response rates at week 16 of 0%, 29% (P = 0Á009), 59% (P < 0Á001) and 67% (P < 0Á001) for patients receiving placebo, and mirikizumab 30 mg, 100 mg and 300 mg, respectively. There were two (1%) serious adverse events in mirikizumab-treated patients vs. one (2%) in a placebo-group patient. Conclusions At week 16, 67% of patients treated with mirikizumab 300 mg at 8-week intervals achieved PASI 90. The percentage of patients reporting at least one treatment-emergent adverse event was similar among patients treated with placebo or mirikizumab.

What’s already known about this topic?

• Interleukin (IL)-23 is a key cytokine in the pathogenesis of psoriasis. • Inhibiting IL-23 has shown great promise for psoriasis therapy in clinical trials.

What does this study add?

• In this phase II trial of mirikizumab – a p19-directed IL-23 antibody – we evaluated three dose regimens of mirikizumab vs. placebo. There was significantly higher efficacy in patients treated with mirikizumab vs. placebo and comparable safety profiles.

The importance of T helper cell 17-related cytokines in the required to treat an adverse event (AE). Lower potency to pathogenesis of psoriasis has become increasingly clear in the upper-mid-strength topical steroids were permitted for use last decade, with therapies targeting interleukin (IL)-17 and limited to the face, axilla and/or genitalia, as needed, except IL-23 resulting in a higher proportion of patients achieving for 24 h prior to study visits. higher efficacy levels than previously described with other This study was approved by the applicable ethical review – biological therapies.1 9 Ustekinumab was one of the first bio- boards. All patients in this study signed informed consent logics to target this pathway. However, as ustekinumab binds forms before undergoing study-related procedures and admin- to the shared p40 subunit, IL-12 is inhibited in addition to istration of the investigational product. This study was con- IL-23.4,6 Gene expression patterns in lesions from patients ducted in accordance with consensus ethics principles derived with psoriasis, as well as studies of mouse models of psoriasis, from international ethical guidelines, including the Declaration point to IL-23, and not IL-12, as being the more critical cyto- of Helsinki and Council for International Organizations of – kine in psoriasis pathogenesis.10 12 Recently, several biological Medical Sciences International Ethical Guidelines, applicable therapies targeting the p19 subunit of IL-23 have resulted in International Council for Harmonisation Good Clinical Practice high Psoriasis Area and Severity Index (PASI) response rates Guidelines and other applicable laws and regulations. This trial – with good safety profiles.5,7 9 was registered with ClinicalTrials.gov (NCT02899988) and Mirikizumab (LY3074828), a humanized IgG4-variant first patient was enrolled in September 2016. monoclonal antibody that binds to the p19 subunit of IL-23 and does not bind IL-12, was previously shown in a phase I Study design study to improve PASI score in patients with plaque psoriasis.13 We evaluated the week-16 efficacy and safety of three This multicentre, phase II trial was conducted at 40 study sites dosing regimens of mirikizumab vs. placebo in a phase II, ran- across five countries (Canada, Germany, Japan, Poland and the domized, multicentre, double-blind trial (AMAF; NCT02899988) U.S.A.; see Appendix S1 for a complete list of study sites). of patients with moderate-to-severe plaque psoriasis. The double-blind, placebo-controlled 16-week treatment period of this trial was designed to establish the efficacy and Patients and methods safety of mirikizumab administered at weeks 0 and 8 (Fig. 1). Patients were randomized at a 1 : 1 : 1 : 1 ratio to receive subcutaneous mirikizumab 30 mg, mirikizumab 100 mg, Patients mirikizumab 300 mg or placebo. Patients were stratified on Inclusion criteria for this study included adult patients (aged the basis of previous exposure to biological therapy for the 18–75 years), with an investigator-confirmed diagnosis of treatment of psoriasis. chronic plaque psoriasis vulgaris for at least 6 months before baseline. Patients must have had ≥ 10% body surface area Randomization and blinding (BSA) involvement, absolute PASI score ≥ 12 and static Physi- cian’s Global Assessment (sPGA) score of ≥ 3 at screening and Assignment to study drug groups was determined by a baseline, and they must have been deemed eligible for biolog- computer-generated random sequence using an interactive ical therapy for psoriasis. Anti-tumour necrosis factor or anti- web-response system. To maintain blinding, the investiga- IL-17 biological use within 8 weeks of baseline was not tional product was prepared at the site by unblinded pharma- allowed. Previous exposure to any biological therapy targeting cists or other trained personnel, and administered at the site IL-23 was also not allowed, with the exception of briak- by blinded nurses or other trained personnel. inumab. Complete lists of inclusion and exclusion criteria are provided in Appendix S2 (see Supporting Information). Per Objectives and assessments protocol, patients were to maintain stable dosages of their usual medication regimens for concomitant conditions or dis- The primary objective of this study was to establish the supe- eases throughout the study unless those medications were riority of mirikizumab 30 mg, 100 mg or 300 mg given at specifically excluded in the protocol, or if a change was weeks 0 and 8 vs. placebo, as measured by the proportion of

Screening Treatment period 205 patients randomized 1:1:1:1 Mirikizumab 300 mg Q8W (n = 51)

R Mirikizumab 100 mg Q8W (n = 51)

Mirikizumab 30 mg Q8W (n = 51)

Placebo (n = 52)

WEEK 0 WEEK 8 WEEK 16

Fig 1. Study design diagram. Patients on mirikizumab received subcutaneous doses at weeks 0 and 8. Q8W, every 8 weeks. patients achieving a 90% improvement in PASI (PASI 90) at Results week 16. Secondary and exploratory objectives reported herein Study population include proportions of patients achieving at least a 75% improvement in PASI (PASI 75), 100% improvement in PASI Of 251 patients screened, 205 were randomized to receive (PASI 100), absolute PASI ≤ 5, absolute PASI ≤ 3, absolute placebo (n = 52), mirikizumab 30 mg every 8 weeks (Q8W; PASI ≤ 1, sPGA 0/1, sPGA 0, BSA ≤ 1%, Dermatology Life n = 51), mirikizumab 100 mg Q8W (n = 51) and mirik- Quality Index (DLQI) 0/1, a Psoriasis Scalp Severity Index izumab 300 mg Q8W (n = 51). Ninety-seven per cent of (PSSI) of 0 and a Psoriasis Symptoms Scale (PSS) Symptoms patients completed the initial 16-week period of this study domain score of 0. The PSS is a new patient-reported measure (Fig. 2). that includes assessment of itch, pain, burning and stinging Generally, patients had similar baseline characteristics across severity. Detailed descriptions of all measures are included in study drug groups (Table 1). On average, patients were 47 Appendix S2 (see Supporting Information). years of age, had a body weight of 89 kg and had been diag- AEs were coded according to the Medical Dictionary for nosed with psoriasis for 19 years. There were more men in all Regulatory Activities Version 19Á1 and summarized by system treatment groups and approximately 41% of patients had pre- organ class, preferred term, severity and relationship to the viously been treated with biological therapy. On average, investigational product. A treatment-emergent AE (TEAE) was patients had a baseline PASI score of 20 with 25% of their defined as an event that first occurred or worsened in severity BSA affected by psoriasis. after baseline. The Columbia–Suicide Severity Rating Scale (Columbia University Medical Center)14 was used to capture the Efficacy occurrence, severity and frequency of suicide-related ideations and behaviours (see Appendix S2 for additional details). At week 16, a statistically significantly higher proportion of patients achieved a PASI 90 response (primary outcome) in = Á < Á Statistical analyses the 30 mg (29%; P 0 009), 100 mg (59%; P 0 001) and 300 mg (67%; P < 0Á001) mirikizumab groups compared Assuming 60% and 3% PASI 90 response rates at 16 weeks for with the placebo (group 0%) (Fig. 3, Table 2). mirikizumab and placebo, respectively, pairwise comparisons Additionally, week 16 PASI 75 and sPGA 0/1 response rates to placebo were determined to have > 99% power using a were, respectively, 52Á9% and 37% in the 30 mg, 78% and two-sided Fisher’s exact test at the 0Á05 significance level, 71% in the 100 mg, and 75% and 69% in the 300 mg with no adjustment for multiple comparisons. mirikizumab dose groups vs. 4% and 2% in the placebo group All randomized patients were analysed according to the (P < 0Á001 for each mirikizumab dose group vs. placebo). dose group to which they were assigned (intent to treat). PASI 100 and sPGA 0 response rates were identical at week Safety analyses were performed for all patients who received 16, with 16% in the 30 mg, 31% in the 100 mg and 31% in at least one dose of the study drug. the 300 mg mirikizumab groups vs. 0% in the placebo group A logistic regression analysis with treatment, geographical (P = 0Á039 for 30 mg vs. placebo; P = 0Á007 for the higher region (U.S.A./outside the U.S.A.) and previous biological dose groups vs. placebo) achieving complete clearance of therapy (yes/no), was used for the comparison of each psoriasis (Fig. 3, Table 2). The proportion of patients with mirikizumab dose regimen (300 mg, 100 mg, 30 mg) and complete clearance of scalp psoriasis, as measured by a PSSI of placebo for categorical binary efficacy and health-outcome 0, was 43% in the 30 mg, 75% in the 100 mg and 51% in variables. the 300 mg mirikizumab groups vs. 6% in the placebo group

Screened n = 251 Not randomized (n = 46) Screen failure n = 41 Subject decision n = 4 Adverse event Randomized n = 1 n = 205

30 mg 100 mg 300 mg Placebo mirikizumab mirikizumab mirikizumab n=52 n = 51 n = 51 n = 51

Discontinued Discontinued treatment treatment Discontinued (n = 2) (n = 2) treatment 1 due to Discontinued 1 due to (n = 2) withdrawal treatment withdrawal 2due to by subject (n = 0) by subject adverse 1 due to 1 patient event physician with suicidal decision ideation

Completed week Completed week Completed week Completed week 16 16 16 16 n = 50 n = 49 n = 51 n = 49

Fig 2. Consort diagram.

(P < 0Á001 for each mirikizumab dose group vs. placebo) Statistically significant differences from placebo were (Table 2). For all week-16 outcomes presented here, the high- observed across the mirikizumab treatment groups, regardless est responses were seen in the mirikizumab 100 mg and 300 of prior exposure to biological treatment (Fig. S1, see Sup- mg treatment groups. porting Information) and body weight at baseline (Fig. S2, Similarly high response rates were observed for absolute see Supporting Information). PASI thresholds. At least 80% of patients treated with mirikizumab 100 mg or 300 mg had PASI scores of ≤ 5 and at least Safety 70% had PASI scores of ≤ 3 at week 16. More than 50% of the patients treated with mirikizumab 300 mg had an absolute Percentages of patients reporting at least one TEAE were com- PASI score of ≤ 1. In addition, > 50% of the patients treated parable across study drug arms during the first 16 weeks of with mirikizumab 100 mg or 300 mg had no more than 1% this study. The specific event of hypertension was reported in of their BSA covered with psoriasis at week 16 (Table 2). the 100-mg (three patients) and 300-mg (two patients) dose At week 16, the proportion of patients reporting no symp- groups, but not the placebo or 30-mg dose groups. All five of toms of itching, pain, burning or stinging (PSS Symptoms these patients had elevated or borderline elevated blood pres- domain score of 0) and no impact of their psoriasis on their sure at screening or baseline; two had pre-existing hyperten- quality of life (DLQI 0/1) was significantly higher for each sion for which they were being treated. None of these events mirikizumab treatment groups vs. the placebo group, with the was serious and none led to discontinuation. The percentage highest response rates noted in the 100 mg and 300 mg treat- of patients reporting infections was also comparable across all ment groups (Table 2). study drug groups (Table 3). The most common AEs [at least

Table 1 Baseline demographics and clinical characteristics

Mirikizumab Mirikizumab Mirikizumab Placebo group 30 mg Q8W 100 mg Q8W 300 mg Q8W (n = 52) (n = 51) (n = 51) (n = 51) Age (years) 46Á0 Æ 12Á4 49Á2 Æ 13Á3 46Á0 Æ 13Á2 47Á5 Æ 13Á2 (23–71) (22–74) (20–70) (20–72) Male 42 (81) 39 (76) 35 (69) 36 (71) Weight (kg) 89Á1 Æ 22Á0 91Á3 Æ 19Á8 86Á4 Æ 15Á0 87Á9 Æ 21Á3 (50–157) (51–153) (55–117) (56–169) ≥ 100 kg 13 (25) 13 (25) 13 (25) 11 (22) À BMI (kg m 2)29Á2 Æ 5Á8 30Á5 Æ 6Á0 29Á3 Æ 4Á9 29Á7 Æ 6Á7 (20–45) (20–47) (20–40) (20–52) Duration of psoriasis (years) 18Á0 Æ 9Á8 20Á4 Æ 13Á5 18Á6 Æ 11Á3 18Á1 Æ 12Á7 (2–40) (1–58) (1–47) (1–57) Previous biological therapy 21 (40) 20 (39) 21 (41) 22 (43) Previous systemic therapy 38 (73) 39 (76) 41 (80) 40 (78) PASI 19Á7 Æ 7Á4 21Á0 Æ 8Á4 20Á3 Æ 8Á0 18Á4 Æ 6Á9 (12–58) (12–46) (12–52) (12–50) sPGA ≥ 4 23 (44) 18 (35) 24 (47) 14 (27) Percentage of BSA involved 26Á4 Æ 17Á5 27Á3 Æ 15Á8 26Á5 Æ 16Á5 21Á3 Æ 10Á3 (10–84) (11–76) (10–90) (10–90) Scalp psoriasis 47 (90) 45 (88) 51 (100) 49 (96) PSSIa 25Á0 Æ 13Á7 22Á6 Æ 12Á8 21Á0 Æ 12Á6 19Á5 Æ 12Á0 (2–60) (3–60) (3–54) (2–48) PSS 50Á4 Æ 19Á3 48Á6 Æ 18Á2 50Á1 Æ 17Á3 47Á4 Æ 18Á0 (8–80) (12–80) (15–80) (16–80) DLQI 14Á1 Æ 7Á2 12Á6 Æ 7Á3 12Á5 Æ 5Á6 12Á7 Æ 6Á6 (2–30) (2–30) (0–26) (3–29)

Data are mean Æ SD (range) or n (%). BMI, body mass index; PASI, Psoriasis Area and Severity Index; sPGA, static Physician’s Global Assess- ment; BSA, body surface area; PSSI, Psoriasis Scalp Severity Index; PSS, Psoriasis Symptom Scale; DLQI, Dermatology Life Quality Index. aIn patients with baseline scalp psoriasis.

three patients (≥ 5%) in any study drug group] included viral have resumed alcohol abuse, and liver enzymes were again upper and other respiratory tract infections, injection-site pain, elevated at a follow-up visit. hypertension and diarrhoea. In the first 16 weeks of the trial, no deaths were reported Discussion and there were no major adverse cardiac events or malignan- cies. Three patients reported serious AEs (SAEs) during the Mirikizumab, given every 8 weeks as 100 mg or 300 mg initial 16-week period of the trial. One patient in a mirik- subcutaneous injections, resulted in the majority of patients izumab group and one patient in the placebo group had an achieving clear or nearly clear skin after 16 weeks of treat- SAE of suicidal ideation. In both cases, each patient had a ment. Response rates for all efficacy outcomes were statistically history of psychiatric conditions. Despite improvement with significantly higher for all mirikizumab treatment arms vs. psychiatric treatment, both patients discontinued the study. placebo, and highest in the mirikizumab 100 mg and 300 mg The third patient who reported an SAE was hospitalized treatment arms. While we did not examine nail or palmoplan- owing to increased alanine aminotransferase and aspartate tar psoriasis specifically in this study, another difficult-to-treat aminotransferase at a study visit. Both test results were >10 region – the scalp – was evaluated. Even though almost all times the upper limit of normal. The patient had a history patients in this trial had scalp psoriasis at baseline, > 50% of of hypercholesterolaemia and alcohol abuse several years patients in the 300 mg group and nearly 75% of patients in before starting the study. Other clinical chemistries were the 100 mg group had no evident scalp psoriasis at week 16. within normal limits (bilirubin and alkaline phosphatase) After 16 weeks of treatment, higher percentages of patients and serology was negative for active or acute hepatitis A, B in the mirikizumab treatment arms vs. placebo reported no or C infection. The patient was completely asymptomatic and negative impact of psoriasis on their quality of life, as denied alcohol use. The patient’s liver enzymes returned to assessed by the DLQI. This is likely related to the greater PASI normal after therapy with oral phospholipids; however, the improvements in these groups. We did not specifically evalu- investigator decided to discontinue the patient from the ate the relationship between PASI and DLQI; however, study. Following discontinuation, the patient was reported to numerous publications have established this association, fully

Fig 3. (a) Ninety per cent improvement in Psoriasis Area and Severity Index (PASI 90), (b) static Physician’s Global Assessment (sPGA) 0/1, (c) 75% improvement in PASI (PASI 75), (d) 100% improvement in PASI (PASI 100) and (e) Dermatology Life Quality Index (DLQI 0/1) response rates through week 16 (nonresponder imputation). CI, conﬁdence interval; Q8W, every 8 weeks.

Table 2 Study outcomes at week 16

Mirikizumab Mirikizumab Mirikizumab Placebo 30 mg Q8W 100 mg Q8W 300 mg Q8W (n = 52) (n = 51) (n = 51) (n = 51) Mean Æ SD PASI score (observed) 19Á5 Æ 8Á46Á0 Æ 5Á6*** 2Á7 Æ 4Á2*** 2Á5 Æ 4Á2*** PASI 100 0 8 (16)* 16 (31)** 16 (31)** PASI 90 0 15 (29)** 30 (59)*** 34 (67)*** PASI 75 2 (4) 27 (53)*** 40 (78)*** 38 (75)*** PASI ≤1 0 8 (16)* 23 (45)** 27 (53)*** PASI ≤3 2 (4) 21 (41)*** 37 (73)*** 36 (71)*** PASI ≤5 2 (4) 28 (55)*** 41 (80)*** 41 (80)*** sPGA 0/1 1 (2) 19 (37)*** 36 (71)*** 35 (69)*** sPGA 0 0 8 (16)* 16 (31)** 16 (31)** BSA ≤1% 1 (2) 10 (20)* 28 (55)*** 30 (59)*** PSSI = 0 3 (6) 22 (43)*** 38 (75)*** 26 (51)*** PSS domain score = 0 0 8 (16)* 14 (27)* 16 (31)** DLQI 0/1 2 (4) 18 (35)*** 25 (49)*** 24 (47)***

Data are nonresponder imputation or n (%) unless otherwise indicated. PASI, Psoriasis Area and Severity Index; PASI 100, 100% improvement in PASI; PASI 90, 90% improvement in PASI; PASI 75, 75% improvement in PASI; sPGA, static Physician’s Global Assessment; BSA, body surface area; PSSI, Psoriasis Scalp Severity Index; PSS, Psoriasis Symptom Scale; DLQI, Dermatology Life Quality Index. *P < 0Á05; **P < 0Á01; ***P < 0Á001 vs. placebo.

recognizing that the DLQI instrument is not specific for This report describes patients evaluated during the first 16 – psoriasis.2,15 17 weeks of Study AMAF. Longer-term results are needed to better inform whether efficacy is maintained or continues to improve

Table 3 Adverse events

Mirikizumab Mirikizumab Mirikizumab Mirikizumab Placebo 30 mg Q8W 100 mg Q8W 300 mg Q8W total n (%) (n = 52) (n = 51) (n = 51) (n = 51) (n = 153) Patients with ≥ 1 TEAE 25 (48) 26 (51) 24 (47) 24 (47) 74 (48) Mild 9 (17) 18 (35) 9 (18) 11 (22) 38 (25) Moderate 15 (29) 7 (14) 14 (27) 11 (22) 32 (21) Severe 1 (2) 1 (2) 1 (2) 2 (4) 4 (3) Death 0 0 0 0 0 SAEs 1 (2) 1 (2) 0 1 (2) 2 (1) Investigator-deﬁned 7 (13) 12 (24) 7 (14) 9 (18) 28 (18) treatment-related AEs Infections 12 (23) 14 (27) 13 (25) 13 (25) 40 (26) Common TEAEsa Viral URTI 5 (10) 5 (10) 7 (14) 7 (14) 19 (12) Other URTI 2 (4) 6 (12) 3 (6) 2 (4) 11 (7) Injection-site pain 1 (2) 3 (6) 2 (4) 2 (4) 7 (5) Hypertension 0 0 3 (6) 2 (4) 5 (3) Diarrhoea 1 (2) 0 1 (2) 3 (6) 4 (3)

Data are n (%). AE, adverse event; TEAE, treatment-emergent adverse event; SAE, serious adverse event; URTI, upper respiratory tract infection. aCommon is defined as at least three (≥ 5%) in any treatment group. with prolonged mirikizumab treatment. As in all phase II trials, 2 Griffiths CE, Reich K, Lebwohl M et al. Comparison of ixekizumab the overall numbers in this trial are small, with larger and longer with etanercept or placebo in moderate-to-severe psoriasis studies needed to better assess overall safety and efficacy profile (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015; 386:541–51. of mirikizumab. Head-to-head studies with active comparators 3 Langley RG, Elewski BE, Lebwohl M et al. Secukinumab in plaque are also needed to compare appropriately the efficacy and safety psoriasis – results of two phase 3 trials. N Engl J Med 2014; of mirikizumab to commercially available treatments. Addition- 371:326–38. ally, clinical trials investigating other biological therapies have 4 Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of often used dosing regimens that were more frequent than every ustekinumab, a human interleukin-12/23 monoclonal antibody, 8 weeks during the induction period. It is unknown what in patients with psoriasis: 76-week results from a randomised, impact a similar approach for mirikizumab would yield regard- double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371:1665–74. ing percentages of patients achieving clear or nearly clear skin. 5 Papp KA, Blauvelt A, Bukhalo M et al. Risankizumab versus ustek- In conclusion, patients with moderate-to-severe plaque pso- inumab for moderate-to-severe plaque psoriasis. N Engl J Med 2017; riasis achieved significantly greater improvements in skin mea- 376:1551–60. sures and patient-reported life quality measures after 16 weeks 6 Papp KA, Langley RG, Lebwohl M et al. Efficacy and safety of when treated every 8 weeks with mirikizumab compared with ustekinumab, a human interleukin-12/23 monoclonal antibody, placebo. The efficacy response was highest in patients treated in patients with psoriasis: 52-week results from a randomised, with the 100 mg or 300 mg mirikizumab. While the number double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371:1675–84. of patients participating in this study was small, the frequen- 7 Reich K, Armstrong AW, Foley P et al. Efficacy and safety of guselku- cies of patients reporting AEs were similar in patients treated mab, an anti-interleukin-23 monoclonal antibody, compared with with mirikizumab and those receiving placebo. adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-con- Acknowledgments trolled VOYAGE 2 trial. J Am Acad Dermatol 2017; 76:418–31. We would like to thank the following Eli Lilly employees: Brid- 8 Reich K, Papp KA, Blauvelt A et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reS- get Charbonneau for providing writing and editorial support; URFACE 2): results from two randomised controlled, phase 3 tri- and Vipin Arora, Nathan Morris, Ying Guo and Huayu Karen als. Lancet 2017; 390:276–88. Liu for providing statistical review and analytical support on this 9 Blauvelt A, Papp KA, Griffiths CE et al. Efficacy and safety of manuscript. guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, dou- References ble-blinded, placebo- and active comparator-controlled VOYAGE 1 – 1 Gordon KB, Blauvelt A, Papp KA et al. Phase 3 trials of ixekizumab trial. J Am Acad Dermatol 2017; 76:405 17. in moderate-to-severe plaque psoriasis. N Engl J Med 2016; 10 Chan JR, Blumenschein W, Murphy E et al. IL-23 stimulates epider- 375:345–56. mal hyperplasia via TNF and IL-20R2-dependent mechanisms with

implications for psoriasis pathogenesis. J Exp Med 2006; 203:2577– Galderma, Leo Pharma, Merck, Novartis and Tribute. R.B. has 87. served as a speaker, advisor, investigator and/or received 11 Kopp T, Lenz P, Bello-Fernandez C et al. IL-23 production by cose- grant/research support from AbbVie, Amgen, BMS, Boehringer cretion of endogenous p19 and transgenic p40 in keratin 14/p40 Ingelheim, Celgene, Eli Lilly and Company, Galderma, GSK transgenic mice: evidence for enhanced cutaneous immunity. J Immunol 2003; 170:5438–44. Steifel, Incyte, Janssen, Leo Pharma, Merck, Novartis, Pfizer and 12 Lee E, Trepicchio WL, Oestreicher JL et al. Increased expression of Kineta. C.L. is in the speakers bureau of AbbVie, Celgene and interleukin 23 p19 and p40 in lesional skin of patients with psori- Leo Pharma; is a consultant for AbbVie, Amgen, Dermira, Eli asis vulgaris. J Exp Med 2004; 199:125–30. Lilly and Company, Janssen, Leo Pharma, Pfizer, Sandoz and 13 Maari C, Bissonette R, Papp K et al. Safety, efficacy, and pharma- UCB Pharma; and has a conflict with AbbVie, Actavis, Amgen, cokinetics of a p19-directed IL-23 antibody in patients with plaque Celgene, Cermira, Coherus, Eli Lilly and Company, Galderma, psoriasis and healthy subjects. Presented at the Euorpean Academy Janssen, Leo Pharma, Merck, Novartis, Pfizer, Sandoz, Stiefel of Dermatology and Venereology, Vienna, Austria, 28 September– 2 October 2016; abstract. and Wyeth. A.M. has served as a speaker, advisor, investigator 14 Posner K, Oquendo MA, Gould M et al. Columbia Classification and/or received honoraria and/or grant/research support from Algorithm of Suicide Assessment (C-CASA): classification of suici- AbbVie, Allergan, Amgen, Boehringer Ingelheim, Celgene, Der- dal events in the FDA’s pediatric suicidal risk analysis of antide- mira, Eli Lilly and Company, Galderma, Janssen Biotech, LEO pressants. Am J Psychiatry 2007; 164:1035–43. Pharma, Merck, Neothetics, Novartis, Pfizer, Regeneron and 15 Takeshita J, Callis Duffin K, Shin DB et al. Patient-reported out- Syntrix. A.I. has received honoraria or fees for serving on advi- comes for psoriasis patients with clear versus almost clear skin in sory boards, as a speaker and as a consultant, and grants for the clinical setting. J Am Acad Dermatol 2014; 71:633–41. 16 Torii H, Sato N, Yoshinari T et al. Dramatic impact of a Psoriasis being an investigator from AbbVie, Celgene, Eli Lilly, Janssen, Area and Severity Index 90 response on the quality of life in Kyowa Hakko Kirin, Maruho and Novartis. P.K., D.P., J.L., J.T., patients with psoriasis: an analysis of Japanese clinical trials of M.M.-C., E.E.-H. and S.F. are current employees and sharehold- infliximab. J Dermatol 2012; 39:253–9. ers of Eli Lilly and Company. K.P. has served as a speaker, advi- 17 Viswanathan HN, Chau D, Milmont CE et al. Total skin clearance sor, investigator and/or received grant/research support from results in improvements in health-related quality of life and AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, Astellas, reduced symptom severity among patients with moderate to severe AstraZeneca, Baxalta, Baxter, Boehringer-Ingelheim, Bristol- psoriasis. J Dermatolog Treat 2015; 26:235–9. 1 Myers Squibb, Can Fite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, GSK, Appendix Janssen, Kyowa Hakko Kirin, Leo, Medimmune, Meiji Seika Pharma, Merch (MSD), Merck-Serono, Mitsubishi Pharma, Conflicts of interest Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, K.R. has served as advisor and/or paid speaker for and/or par- Takeda, UCB and Valeant. ticipated in clinical trials sponsored by AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Covagen, Forward Pharma, Supporting Information GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Lilly, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Takeda, Additional Supporting Information may be found in the online UCB Pharma and Xenoport. P.R. has been a principal investiga- version of this article at the publisher’s website: tor for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Appendix S1. Complete list of AMAF investigators. Lilly and Company, Merck, Novartis, Pfizer and Sandoz; a con- Fig S1. Logistic regression analysis with previous or no bio- sultant for AbbVie, Novartis and Polichem; and an advisory logic therapy as factors at week 16. board participant for AbbVie, Eli Lilly, Novartis and Sandoz. Fig S2. Logistic regression analysis with weight < 100 kg C.M. has been an advisory board member, investigator and/or or weight ≥ 100 kg as factors at week 16. speaker for: AbbVie, Amgen, Celgene, Eli Lilly and Company,