What s New in the Treatment of Psoriasis

Transcription

1 What s New in the Treatment of Psoriasis Mark Lebwohl, MD Waldman Professor And Chairman Kimberly and Eric J. Waldman Department of Dermatology Icahn School of Medicine at Mount Sinai

2 Mark Lebwohl is an employee of Mount Sinai which receives research funds from: Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen / Johnson & Johnson, Kadmon, Medimmune/Astra Zeneca, Novartis, Pfizer and ViDac. Dr. Lebwohl is also a consultant for Allergan, Leopharma, and Promius.

3 Tildrakizumab Guselkumab Tremfya Brodalumab Siliq Ixekizumab Taltz Secukinumab Cosentyx Ustekinumab Stelara Adalimumab Humira Etanercept Enbrel Apremilast Otezla Certolizumab - Cimzia Tofacitinib Xeljanz Bimekizumab Risankizumab/Mirikizumab

4 Responders (%) Responders (%) PASI 75 Response Over Time resurface 1 resurface TIL 1 mg TIL 2 mg Placebo TIL 1 mg Placebo TIL 2 mg TIL1 64% TIL2 62% TIL 1: 64% * TIL 2: 62% * PBO/TIL2 86% TIL1 82% PBO/TIL 2: 86% TIL 2: 82% 1: 8% * PBO/TIL TIL2 1: 8% 77% PBO/TIL1 77% TIL 1 mg TIL 2 mg Placebo TIL 1 mg Placebo TIL 2 mg ETN TIL 2: 66% * TIL 1: 61% * ETN: 48% TIL 1: 74 PBO/TIL 2: 74% TIL 2: 74 PBO/TIL 1: 58% ETN: 56% PBO 3% PBO: 6% Weeks Weeks *P<.1 vs PBO; P<.5 vs ETN; P<.1 vs ETN; P-values unadjusted for multiplicity. P-values were calculated using the Cochran-Mantel-Haenszel (CMH) test stratified by body weight ( 9kg, >9kg) and prior exposure to biologic therapy for psoriasis. Modified intention-to-treat population (ie, all randomized patients who received 1 dose of study medication). The figure represents observed data only; data shown for Week 12 are based on missing data being imputed as non-responders. PBO=placebo; TIL=tildrakizumab; ETN=etanercept.

5 Patients (%) resurface 1 and 2: Overall efficacy after 2 years of treatment resurface 1 w.64 resurface 2 w TIL 1 mg (n=219) TIL 2 mg (n=255) FAS (full analysis set; subjects with 1 dose of extension treatment based on assigned treatment); as observed data Patients entering OLE after 64 weeks (resurface 1) or 52 weeks (resurface 2) were at least partial responders (PASI 5). For resurface 1, patients had to have received active drug within 12 weeks of end of base study TIL 1 mg (n=355) TIL 2 (n=333) PASI 75 PASI 9 PASI 1 PGA (/1) Papp K, et al. EADV 217, D3T1.1H Sponsored by Merck & Co., Inc.

6 Percentage of Patients Voyage 1 Guselkumab PASI 75 Responders: 1 Week 16 P<.1 vs. ADA 91.2 Week 24 P<.1 vs. ADA 91.2 Week 48 P<.1 vs. ADA Weeks Guselkumab (n=329) Placebo Guselkumab (n=174) Adalimumab (n=334) 7 A. Blauvelt, et al. FCD 216.

7 Patients (%) Patients (%) VOYAGE1: PASI 9 & PASI 1 response with guselkumab through 2 years GUS Placebo ADA PASI 9 PASI 1 GUS GUS NRI= Weeks n= n= n= GUS Placebo ADA GUS GUS NRI= Weeks n= n= n= Griffiths CEM, et al. EADV 217, D3T1.I Sponsored by Janssen Research and Development LLC

8 RESULTS % of Patients ACR 2/5/7 Responses at Week 24 1 Primary Endpoint 8 6 p< p=.2 p=.23 (post hoc) ACR2 ACR5 ACR7 Placebo (n=49) Guselkumab (n=1) Gottlieb A, et al. AAD 217. P4454.

9 % of Patients RESULTS Percent of Patients with Resolution of Enthesitis at Week 24 in Patients with Enthesitis at Baseline p= Placebo (n=31) Guselkumab (n=76) Enthesitis assessed by Leeds Enthesitis Index (LEI) Median % improvement in LEI at Week 24: 1% in guselkumab vs 33.3% in placebo (p=.9) Gottlieb A, et al. AAD 217. P4454.

10 % of Patients RESULTS Percent of Patients with Resolution of Dactylitis at Week 24 in Patients with Dactylitis at Baseline p= Placebo (n=23) Guselkumab (n=58) Presence and severity of dactylitis in hands/feet assessed by investigators using a -3 scale (none [], mild [1], moderate [2], severe [3]) Median % improvement in dactylitis at Week 24: 1% in guselkumab vs 33.3% in placebo (p<.1) Gottlieb A, et al. AAD 217. P4454.

11 Efficacy of brodalumab for moderate to severe psoriasis through 5 years Patients (%) Mean improvement (%) Week spga /1 response 84.8 spga spga Pts off treatment a n= Week Improvement in PASI score and % BSA PASI BSA Pts off treatment a n= a At week 264, patients had been off treatment for 6 weeks Papp K, et al. EADV 217, P1798 Sponsored by LEO Pharma

12 Patients (%) PASI responses with brodalumab over 5 years 1 Patients off treatment a 8 6 PASI 75 PASI 9 PASI Week n= As observed data Amendment (at Week 59): 65% of patients (118/181) had dose decreased from 21 to 14 mg Efficacy is maintained for up to 5 years a At week 264, patients had been off treatment for 6 weeks. Error bars represent 95% CI Papp K, et al. EADV 217, P1798 Sponsored by LEO Pharma Amendment (at Week 123): 17% of patients (3/181) had dose increased back to 21 mg due to inadequate response

13 IXORA-P: Efficacy and safety of continuous 2-weekly dosing of ixekizumab over 52 weeks in patients with moderate to severe psoriasis Patients (%) Patients (%) Screening R IXORA-P: study design Blinded treatment dosing period Week N=1227 2:1:1 IXE q2w (n=611) IXE q2w IXE q4w/ixe q2w (n=36) Dose adjustment per protocol a IXE q4w (n=31) IXE q2w is better at Week 52 *P<.5; P<.1; P<.1 vs IXE q4w a Dose adjustment based on achievement of spga 2 at 2 consecutive visits during Week 12 through Week 4; investigators were blinded to the predefined criteria and timing Langley RG, et al. EADV 217, OP4.3 Sponsored by Eli Lilly and Company Followup spga (/1) and PASI 75 responses at Week 52 (NRI) IXE q4w (n=31) IXE q4w/ixe q2w (n=36) spga (/1) PASI 75 IXE q2w (n=611) PASI 9 and PASI 1 responses at Week 52 (NRI) * PASI 9 PASI

14 Ixekizumab, an interleukin-17a specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Mease PJ, et al Ann Rheum Dis. 217;76:79-87.

15 Ixekizumab, an interleukin-17a specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Mease PJ, et al; Ann Rheum Dis. 217;76:79-87.

16 Response (%) spga of Genitalia (,1) NRI, Blinded Treatment Period, ITT Population 7 out of 1 ixekizumab-treated patients achieved clear or almost clear genital skin at Week 12 Percentage of patients achieving clear or almost clear genital skin was significantly greater for ixekizumab as early as Week 1 1 PBO (N=74) IXE Q2W (N=75) * Week * p<.1 vs. PBO; p<.1 vs. PBO ITT=Intent-to-Treat; IXE Q2W=8 mg ixekizumab every 2 weeks; NRI=non-responder imputation; PBO=placebo; spga=static Physician s Global Assessment

17 Response (%) Gen-Itch NRS a NRI, Blinded Treatment Period, ITT Population With Baseline Gen-Itch NRS 3 6 out of 1 ixekizumab-treated patients had clinically meaningful improvements a in genital itch at Week 12 Percentage of patients achieving clinically meaningful improvement in genital itch was significantly greater for ixekizumab as early as Week 2 1 PBO (N=6) IXE Q2W (N=62) Week p<.1 vs. PBO a 3 point improvement in gen-itch NRS gen-itch NRS=genital itch numeric rating scale; ITT=Intent-to-Treat; IXE Q2W=8 mg ixekizumab every 2 weeks; NRI=non-responder imputation; PBO=placebo

18 Impact on frequency of sex! SFQ= Sexual Frequency Questionnaire Proportion of patients achieving overall spga (,1) Proportion of patients achieving a 3-point improvement in genital itch numeric rating scale (gen-itch NRS) Among patients with a baseline score of 3 Proportion of patients whose frequency of sexual activity was never or rarely limited by genital psoriasis (SFQ Item 2 score or 1) Among patients with a baseline score 2 SFQ Item 2 In the past week, how often did your genital psoriasis limit the frequency of your sexual activity? Never Rarely 1 Sometimes 2 Often 3 Always 4 gen-itch NRS=genital itch numeric rating scale; SFQ=Sexual Frequency Questionnaire; spga=static Physician s Global Assessment

19 Response (%) SFQ Item 2 Score (,1) Response Rate NRI, Blinded Treatment Period, ITT Population With Baseline SFQ Item 2 Score 2 Approximately 8 out of 1 ixekizumab-treated patients were no longer or rarely limited by the impact of genital psoriasis on frequency of sexual activity at Week 12 Percentage of patients who were no longer or rarely limited by the impact of genital psoriasis on frequency of sexual activity was significantly greater for ixekizumab as early as Week PBO (N=42) IXE Q2W (N=37) 78 6 * Week p<.5 vs. PBO; * p<.1 vs. PBO; p<.1 vs. PBO ITT=Intent-to-Treat; IXE Q2W=8 mg ixekizumab every 2 weeks; NRI=non-responder imputation; PBO=placebo; SFQ=Sexual Frequency Questionnaire

20 Patients (%) SCULPTURE: Long-term skin improvement responses with secukinumab 3 mg fixed interval (q4w) through 5 years Year 1 (n=162) PASI 75 (%) PASI 9 (%) PASI 1 (%) AO MI LOCF AO MI LOCF AO MI LOCF Year Year As observed (AO) Multiple imputation (MI, n=168 at each time point) LOCF (n=168 at each time point) Year 2 (n=152) Year 3 (n=139) Year 4 (n=132) Year 5 (n=122) PASI 75 Δ=~8% PASI 9 Δ=~7% PASI 1 Δ=~5% Bissonnette R, et al. EADV 217, P2223 Sponsored by Novartis Pharma AG

21 ERASURE/FIXTURE extension study: Patients without relapse after withdrawal of secukinumab treatment Patients (%) Proportion of patients without relapse a after withdrawal of SKB 1 8 SKB 15 mg/placebo (n=1) SKB 3 mg/placebo (n=12) No relapse 12 months after SKB discontinuation 6 1 No relapse in 24 months after SKB discontinuation a Relapse: >5% loss of previous gain in PASI reduction Lebwohl M, et al. EADV 217, OP4.6 Sponsored by Novartis Pharma AG

22 Patients (%) FUTURE 2: Resolution of dactylitis and enthesitis through 2 years Resolution of dactylitis and enthesitis 1 SKB 15 mg/placebo (n=1) SKB 3 mg/placebo (n=1) Similar responses with 3 mg and 15 mg, but 3 mg better in TNF inhibitor-refractory patients 4 Efficacy of the two doses should also be compared in obese patients Week 52 Week 14 Week 52 Week 14 Dactylitis Enthesitis Gottlieb AB, et al. EADV 217, P375 Sponsored by Novartis Pharma AG

23 Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: results of the randomized phase 3 CADMUS study. Landells I, et al. J Am Acad Dermatol. 215;73(4):

24 Ustekinumab package insert 25 Business Use Only

25 Ustekinumab as therapy for psoriasis in a 2-year-old girl. Min MS, et al. J Eur Acad Dermatol Venereol. 216;3(11):e19-1.

26 Adalimumab for nail psoriasis: Efficacy and safety from the first 26 weeks of a phase 3, randomized, placebo-controlled trial. Elewski BE, Okun MM, Papp K, Baker CS, Crowley JJ, Guillet G, Sundaram M, Poulin Y, Gu Y, Geng Z, Williams DA, Rich PA. J Am Acad Dermatol. 218 Jan;78(1):9-99.

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28 Long-term safety/efficacy of ADA for pediatric patients with chronic plaque psoriasis Percentage achieving PASI MTX PerA, n=37 ADA.8 PerD, n=36 ADA.8 PerA, n=39 ADA.8 PerD, n=36 ADA.4 PerA, n=38 ADA.4 PerD, n= Week 16A D 1D 4D 8D 11D 16D 2D 28D 4D 52D 1 Percentage achieving PASI Week 16A D 1D 4D 8D 11D 16D 2D 28D 4D 52D Week Papp KA, et al. EADV 215, FC2.4 Sponsored by AbbVie Inc.

29 Etanercept treatment for children and adolescents with plaque psoriasis. Paller AS, Siegfried EC, Langley RG, Gottlieb AB, Pariser D, Landells I,Hebert AA, Eichenfield LF, Patel V, Creamer K, Jahreis A; Etanercept PediatricPsoriasis Study Group. N Engl J Med. 28;358: Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. Paller AS, Siegfried EC, Pariser DM, Rice KC, Trivedi M, Iles J, Collier DH, Kricorian G, Langley RG J Am Acad Dermatol. 216;74:28-7.

30 5-year efficacy of ETN in children and adolescents with plaque psoriasis PASI responses (as observed) PASI 75 responses by BMI category (as observed) Paller AS, et al. EADV 215, FC2.5 Largest and longest pediatric study with biologics in psoriasis reported to date

31 UNVEIL: 52-week efficacy and safety of apremilast in systemic- and biologic-naïve patients with moderate plaque psoriasis 5 Screening Placebo-controlled phase Week APR 3 mg bid (n=148) R 1:2 Placebo (n=73) Primary end point: Mean % change in PGA BSA at Week 16 Open-label treatment phase APR 3 mg bid (n=64) BSA involvement of 5% to 1%, naïve to systemic and biologic therapy Safety observation spga of 3 (moderate) based on a to 5 scale Placebo (n=73) Apremilast (n=148) Age (years) 51.1 ± ±15.4 Male 41 (56.2) 74 (5.) BMI (kg/m 2 ) 3.8 ± ±7.4 Duration of psoriasis (years) 13.9 ± ±13.9 PGA BSA score 21.6 ± ±5.3 % BSA 7.1 ± ±1.6 PASI score ( 72) 8. ± ±4. DLQI total score 11.1 ± ±6.5 Prior topical therapy 59 (8.8) 122 (82.4) Data are mean ±SD or n (%) At baseline, >8% of patients had received topical therapy before enrollment Strober B, et al. EADV 217, FC2.8 Sponsored by Celgene Corporation

32 UNVEIL: PGA BSA-75 and spga /1 response at Week 52 with apremilast in patients with moderate psoriasis Patients (%) Patients (%) 1 PGA BSA-75 response at Week 52 (LOCF) Placeb o n= * APR Placebo/AP n=147 R Week 16 n=64 Week 52 APR/APR n= spga /1 response (LOCF) 9.6 Placebo n=73 * APR Placebo/AP n=148 R Week 16 n=64 Week 52 APR/APR n=148 *P=.1 vs placebo from 2-sided Cochran-Mantel-Haenszel test stratified by site; LOCF was used to impute missing values. Error bars represent 95% CI Strober B, et al. EADV 217, FC2.8 Sponsored by Celgene Corporation

33 UNVEIL: Improvement in nails and scalp with apremilast at Week 52 in patients with moderate psoriasis Mean change from baseline (%) Characteristic Scalp psoriasis a (n=167) Nail psoriasis a (n=83) Placebo (n=55) APR (n=112) Placebo (n=27) Mild nail diseases used target nail NAPSI difficult to compare with other studies Caveat scalp ScPGA had successes already in the baseline Increased attention to the moderate population is necessary as DLQI in some subsets is rather high Jackson JM, et al. EADV 217, P1946 Sponsored by Celgene Corporation APR (n=56) % BSA 7.2 ± ± ± ±1.6 spga score=3 (moderate) b 53 (96.4) 11 (98.2) 26 (96.3) 55 (98.2) PASI score ( 72) 8.1 ± ± ± ±2.9 DLQI total score 1.9 ± ± ± ±5.9 ScPGA score (clear) 1 (minimal) 2 (mild) 3 (moderate) 4 (severe) 5 (very severe) 8 (14.5) 17 (3.9) 24 (43.6) 6 (1.9) 6 (5.4) 38 (33.9) 61 (54.5) 7 (6.3) 1 (3.7) 3 (11.1) 9 (33.3) 9 (33.3) 1 (3.7) 2 (3.6) 16 (28.6) 23 (41.1) 2 (3.6) NAPSI total score 4.8 ± ± ± ±2. Data are mean ±SD or n (%) a 65 patients had both scalp and nail psoriasis (22 placebo, 43 APR); b 4 patients with spga=4 enrolled in error Patients (%) d Placebo (n=27) Placebo (n=55) NAPSI score c Week 16 Week 52 APR (n=56) Placebo/APR (n=23) ScPGA /1 response P=.178 APR (n=112) APR/APR (n=48) Placebo/APR (n=49) Week 16 Week 52 c Includes patients with baseline NAPSI score or ScPGA 1 d Includes patients with baseline ScPGA score 1 Error bars represent 95% CIs APR/APR (n=88)

34 Patients (%) Patients(%) CIMPASI-1 and CIMPASI-2: Maintenance of response with certolizumab pegol during 32-week rerandomized maintenance period PASI 75 (baseline to Week 48) PGA /1 (baseline to Week 48) PASI 9 (baseline to Week 48) CIMPASI-1 Placebo (n=51) CZP 2 mg q2w (n=95) CZP 4 mg q2w (n=88) * * * * 75.8% 66.5% 6.5% % 67.2% % * * * * 47.% * 4.2% % 52.7% % * * 35.8%.4% % 42.8% 48 CIMPASI-2 Placebo (n=49) CZP 2 mg q2w (n=91) CZP 4 mg q2w (n=87) * * 82.6% 81.4% 11.6% Week 81.3% 78.7% * * 71.6% 66.8% 2.% Week 72.6% 66.6% % * * 52.6% * 4.5% Week 62.% 59.6% 48 *P<.5, P<.1 vs placebo, based on logistic regression model with factors for treatment, region and prior biologic exposure (yes/no). Week 16 PASI 5 nonresponders were imputed as nonresponders throughout maintenance period; all other missing data were imputed via multiple imputation (Markov chain Monte Carlo [MCMC] method). CZP 2 mg q2w patients received loading dose of 4 mg at Weeks, 2 and 4 Reich K, et al. EADV 217, P1973 Sponsored by Dermira Inc. in collaboration with UCB Pharma

35 CIMPACT: Maintenance of response with certolizumab pegol during 32-week rerandomized maintenance period Patients (%) Patients (%) Patients (%) CZP 2 mg q2w CZP 4 mg q2w PASI % 46% Placebo q2w (n=22) CZP 2 mg q2w (n=44) CZP 4 mg q4w (n=44) Placebo q2w (n=25) CZP 2 mg q2w (n=5) CZP 4 mg q2w (n=49) 89% % 8% 36% PGA /1 PASI % 61% 14% % 61% % 64% 12% 48 88% 6% Week Week % Week Week 48 12% Missing data were imputed using NRI Augustin M, et al. EADV 217, P1969 Sponsored by Dermira Inc. in collaboration with UCB Pharma

36 CRIB: Maternal and infant plasma and umbilical cord levels of certolizumab pegol CZP concentration ( g/ml) CZP concentration ( g/ml) 1 Plasma CZP levels (n=14 mother infant pairs a ) Mothers Infants 1 Plasma CZP levels in umbilical cord (n=15 c ) Mothers Infants Umbilical cord infant had minimal CZP level of.42 μg/ml, mother s level was 49.4 μg/ml (infant/mother ratio:.9) 1 The infant with a CZP level at birth of.42 μg/ml had a CZP level of.4 μg/ml in the umbilical cord.1.1 LLOQ =.32 g/ml LLOQ =.32 g/ml BLQ Delivery Week 4 Week 8 (±24 hours) (±7 days) b (±7 days) BLQ Delivery Umbilical (±24 hours) cords d a 2/16 infant samples excluded from per protocol analysis set (1 missing data at birth, 1 due to implausible PK data [ie, data not consistent with pediatric CZP PK model, based on expected range of clearance, volume of distribution, and subsequent elimination t ½ ]); b 2 samples not collected; c 1 umbilical cord excluded due to missing data; d Umbilical cords were collected within 1 h of delivery. BLQ, below limits of quantitation of the assay; LLOQ, lower limit of quantitation Kimball A, et al. EADV 217, FC4.3 Sponsored by UCB Pharma

37 Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis. Mease P, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila-Zapata F, Cieślak D, Graham D, Wang C, Menon S, Hendrikx T, Kanik KS. N Engl J Med ;377:

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39 First-in-human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL-17A and IL-17F, in mild psoriasis. Glatt S, Helmer E, Haier B, Strimenopoulou F, Price G, Vajjah P, Harari OA, Lambert J, Shaw S. Br J Clin Pharmacol. 217;83(5):

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44 P456 Safety, efficacy and PK of a p19-directed IL-23 antibody (LY374828) in patients with plaque psoriasis and healthy subjects MIRIKIZUMAB Phase 1, placebo-controlled, 4 patients, 5 healthy volunteers, 12 weeks; 4% BSA, PASI 6.6 Another a p19-directed IL-23 antibody effective in phase 1 Tuttle J, et al. EADV 216, P456 Sponsored by Eli Lilly and Company 45