Gaps in the Treatment of Psoriasis and PsA for Systemic Therapy

Gaps in the Treatment of Psoriasis and PsA for Systemic Therapy Mark Lebwohl, MD Sol and Clara Kest Professor And Chairman Department of Dermatology Icahn School of Medicine at Mount Sinai

Disclosure 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, Valeant and ViDac. Dr. Lebwohl is also a consultant for Allergan, Aqua Leo-pharma,and Promius.

Research gaps in psoriasis: opportunities for future studies Ryan C, Korman NJ, Gelfand JM, Lim HW, Elmets CA, Feldman SR, Gottlieb AB, Koo JY, Lebwohl M, Leonardi CL, Van Voorhees AS, Bhushan R, Menter A. J Am Acad Dermatol. 2014;70:146-67

Psoriasis outcome measures: a report from the GRAPPA 2012 annual meeting Gottlieb AB, Armstrong AW. J Rheumatol. 2013;40:1428-33

Research Gaps Can we predict who ll develop PsA and can we prevent it? Can we predict who ll develop other comorbidities (cardiac, renal, etc) and can we prevent them? Can we predict who ll respond to which therapy?

Can we predict who ll develop PsA? (Can we treat to prevent joint disease?)

Patient perspectives in the management of psoriasis: Results from the populationbased Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. Lebwohl MG, Bachelez H, Barker J, Girolomoni G, Kavanaugh A, Langley RG, Paul CF, Puig L, Reich K, van de Kerkhof PC. J Am Acad Dermatol. 2014 Feb 24. [Epub ahead of print]

139,948 households were screened and 3426 patients prevalence of psoriasis/psa ranged from 1.4% to 3.3% 79% had psoriasis alone and 21% had PsA 27% (psoriasis) and 53% (PsA ± psoriasis) of patients rated it as severe 45% had not seen a physician in a year;

Psoriasis and Psoriatic Arthritis: Timing of Onset 21% Arthritis 1st 7% concurrent 72% Psoriasis 1st Psoriasis 1st Arthritis 1st concurrent

Subclinical Joint Involvement in Patients With Psoriasis Joint structural damage can occur before the appearance of clinical symptoms of PsA In a study by Offidani and colleagues, which used MRI rather than conventional radiography to assess joint involvement, 68% of patients with psoriasis were found to have 1 or more arthritic signs Appeared before patients experienced clinically evident joint symptoms Joint damage was only detected by X-ray imaging in 32% of these patients Source: Offidani A, et al. Acta Derm Venereol (Stockh). 1998;78:463-465.

Sharp score or van der Heijde score measures joint damage on x-ray: narrowing and erosions Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. van der Heijde DM, et al Arthritis Rheum. 1992 Jan;35(1):26-34.

Mean Change in mtss* From Baseline Etanercept for Psoriatic Arthritis: Radiographic Improvement 1.2 1 0.8 0.6 0.4 0.2 0-0.2-0.4-0.6 ** 6 12 18 24 Study Month Etanercept 25 mg biw (n=101) Placebo (n=104) OLE completers originally randomized to etanercept (n=71) OLE completers originally randomized to placebo (n=70) *X-rays of hands and wrists (includes DIP joints); **P =.0001 vs placebo (stratified rank test). Start of OLE. Source: Mease P, et al. Arth Rheum. 2004;50:2264-2272. Lebwohl M, et al. Presented at: 63rd Annual Meeting of AAD; February 18-22, 2005; New Orleans, La. (Abstract P2753).

Mean Change in mtss Adalimumab for Psoriatic Arthritis: Radiographic Results Mean Change in mtss Through Week 48 1.5 Placebo Adalimumab 1.0 0.5 0 0.5 24 Weeks N Baseline 24 Wk Mean Change 48 Wk Mean Change Placebo 152 21.8 0.9 1.0 Adalimumab 144 23.7 0.1* 0.1 *P.001 vs placebo for ranked ANCOVA. Sources: Mease P, et al. Arth Rheum. 2005;52:3279-3289. Mease P, et al. Presented at: EULAR Annual Meeting; June 8-11, 2005; Vienna, Austria. * 48

Total vdh-s Score Total vdh-s Score Mean Change from Baseline at Week 24* 1.0 0.82 p<0.001 0.5 0.0-0.5-1.0 *Median Change in both groups was 0.0-0.70 Placebo (n=100) Infliximab 5 mg/kg (n=100) Van der Heijde D, et al. Ann Rheum Dis. 2005;64 (Supplement III):109.

Treatment of psoriatic arthritis with tumor necrosis factor inhibitors: longerterm outcomes including enthesitis and dactylitis with golimumab treatment in the Long term Extension of a Randomized, Placebo-controlled Study (GO-REVEAL). Kavanaugh A, Mease P. J Rheumatol Suppl. 2012 Jul;89:90-3.

Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA) Mease PJ, Fleischmann R, Deodhar AA, Wollenhaupt J, Khraishi M, Kielar D, Woltering F, Stach C, Hoepken B, Arledge T, van der Heijde D. Ann Rheum Dis. 2014;73:48-55.

% achieving response PALACE 1: Apremilast in PsA (Phase 3) Apremilast, oral phosphodiesterase 4 (PDE4) inhibitor RDBPC trial stratified for DMARD use, N=489, 1:1:1 randomization Major adverse events diarrhea and nausea, resolve over time Week 16 Week 24 45 * Placebo Apremilast 20mg BID Apremilast 30mg BID *P<0.05; P<0.0001 ACR20 ACR20 ACR50 ACR70 Kavanaugh A et al, ACR 2012, Washington, #L13

Mean Change from Baseline Change From Baseline in Modified Total vdhs Score Over Time (ITT) 1.4 1.2 1.0 0.8 0.6 0.4 0.2 USTEKINUMAB PSUMMIT I and II 0.0 Week 0 Week 24 Week 52 Placebo (n=310) UST 45 mg (n=308) Placebo 45 mg at Wk 24 (n=269)* UST 90 mg (n=309) *Patients who did not receive UST are excluded

Mean change in vdh-mtss FUTURE 1: Radiographic progression in PsA patients stratified by MTX use Baseline to Week 24 (full analysis set) Pooled SKB doses PBO SECUKINUMAB 1 0.8 0.6 0.57 0.57 0.58 0.4 0.2 * 366 179 0.08 * 216 114 150 65 344 206 98 0.04 0.13 138 54 0 Overall population MTX: Yes MTX: No *P<0.05 vs PBO Change in mtss >0.5 considered progression of radiographic disease Gottlieb AB, et al. EADV 2015, P0348 Sponsored by Novartis Pharma AG

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. 2017;76:79-87. IXEKIZUMAB

IXEKIZUMAB 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. 2017;76:79-87.

Patients (% ± SE) Patients (% ± SE) Brodalumab Phase 2 PsA study: Clinical response and improvement in psoriasis in subjects with PsA 80 60 40 20 0 2 * * ACR20 response rate at Week 24 PBO (n=55) BRO 140 mg q2w (n=57) BRO 280 mg q2w (n=56) ACR20 * * Open label 4 8 12 16 24 Week Number of subjects PBO 54 52 51 52 49 46 140 mg 56 56 51 53 51 47 280 mg 50 55 53 50 49 45 64.4 51.1 43.5 Indicates time point at which all subjects began receiving BRO 280 mg q2w 80 60 40 20 0 2 ACR50 BRODALUMAB * * Open label 4 8 12 16 24 Week Number of subjects PBO 54 53 51 52 50 46 140 mg 56 56 53 53 51 49 280 mg 50 55 53 51 50 45 33.3 32.7 19.6 Mease P, et al. AAD 2014, P7605

We don t have a serologic marker that predicts psoriatic arthritis or its severity

Risk of myocardial infarction in patients with psoriasis. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. JAMA 2006;296:1735-41

Does treatment of psoriasis reduce the risk of cardiovascular disease? Churton S, Brown L, Shin TM, Korman NJ. Drugs. 2014;74:169-82

Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to antitumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Dixon WG, Watson KD, Lunt M, Hyrich KL; British Society for Rheumatology Biologics Register Control Centre Consortium, Silman AJ, Symmons DP; British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56(9):2905-12.

Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Wu JJ, Poon KY, Channual JC, Shen AY Arch Dermatol. 2012;148:1244-50

Risk of moderate to advanced kidney disease in patients with psoriasis: population based cohort study. Wan J, Wang S, Haynes K, Denburg MR, Shin DB, Gelfand JM. BMJ. 2013;347:f5961

Cost of Biologics: Year 1 Etanercept: ~$79,623 Adalimumab: ~ $69,670 Ustekinumab: ~$52,525-105,015 Infliximab: ~$22,995-80,482 (50-100 kg q4-8w. at 5mg/kg) Secukinumab: ~$75,007 Ixekizumab:~$82,891 Brodalumab:~$31,395 Guselkumab: ~$71,237 www.goodrx.com 1/21/18

Patients (%) ERASURE study results: Secukinumab rapidly improved plaque Ps, and sustained high responses through 52 weeks ERASURE SEK 300 mg (n=245) SEK 150 mg (n=245) Placebo (n=247) b 100 90 80 70 60 50 40 30 20 10 0 PASI 75 Response 87.8% SECUKINUMAB * * 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks *p<0.0001 vs placebo at Wk 12. Grey arrows indicate peak response a IGA score of 0 (clear) or 1 (almost clear) and an improvement of at least 2 points on the IGA scale compared with baseline; b One subject did not sign informed consent before starting study procedures and was excluded from analyses Elewski B, et al. EADV 2013: P1501. Sponsored by Novartis Pharma AG

Patients (%) ERASURE study results: Secukinumab rapidly improved plaque Ps, and sustained high responses through 52 weeks ERASURE SEK 300 mg (n=245) SEK 150 mg (n=245) Placebo (n=247) b PASI 90 Response PASI 100 Response 100 90 80 70 60 50 40 30 20 10 0 * * 0 4 8 12 16 20 24 28 32 36 40 44 48 52 100 90 80 70 60 50 40 30 20 10 0 * * 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks Weeks *p<0.0001 vs placebo at Wk 12 a IGA score of 0 (clear) or 1 (almost clear) and an improvement of at least 2 points on the IGA scale compared with baseline; b One subject did not sign informed consent before starting study procedures and was excluded from analyses Elewski B, et al. EADV 2013: P1501. Sponsored by Novartis Pharma AG

Percent of Responders BRODALUMAB PASI 75 Response Rate (NRI) by Week in the Induction Phase 100% 80 % 60 % 40 % 20 % 0% AMAGINE-2 1 2 4 6 8 10 Visit Week 86.3% 77.0% 70.0% 66.6% 8.09% 12 Placeb o Ustekinumab 140 mg Q2W 210 mg Q2W Weight-Based Data on file, Amgen. 34

Percent of Responders BRODALUMAB PASI 90 Response Rate (NRI) by Week in the Induction Phase 80% 60 % 40 % AMAGINE-2 70.3% 58.7% 49.3% 47.0% 20 % 0% 1 2 4 6 8 10 Visit Week 12 3.24% Placeb o Ustekinumab 140 mg Q2W 210 mg Q2W Weight-Based Data on file, Amgen. 35

Percent of Responders BRODALUMAB PASI 100 Response Rate (NRI) by Week in the Induction Phase 50% 40 % 30 % 20 % 10 % 0% AMAGINE-2 1 2 4 6 8 10 Visit Week 44.4% 33.6% 25.7% 21.7% 0.65% 12 Placeb o Ustekinumab 140 mg Q2W 210 mg Q2W Weight-Based Data on file, Amgen. 36

IXEKIZUMAB

Sensitivity / Specificity IXEKIZUMAB PASI 50 at Wk 4 optimal for predicting PASI 75 at Wk 12 Predictability for PASI 75 at Wk 12 at different percentages of PASI improvement at Wk 4 (combined groups) 1.0 0.8 0.6 Sensitivity Specificity 0.4 0.2 0.0-20 -10 0 Optimal threshold* 10 20 30 40 50 60 70 80 90 100 PASI improvement at Week 4 *Optimal threshold at PASI48; PASI 50 selected for practicality Good overall sensitivity (83%), specificity (87%), positive predictive value (90%), and negative predictive value (77%) Combining results for 75 and 150 mg groups showed similar results PASI 50 responders at Wk 4 were called early responders Zhu B, et al. EADV 2012: P952

% Patients Early responders had significantly higher improvement in PASI 75 and 100 than non-responders *** *** *** * *p<0.05; **p<0.01; ***p<0.001 vs non-responder group ** *** Weeks PASI 75 Weeks PASI 10S0 IXEKIZUMAB Zhu B, et al. EADV 2012: P952

Week 16 Partial Responders (50 PASI < 75) and Nonresponders (25 PASI < 50) That Achieved PASI 50, 75, or 90 at Week 28 UST Combined* 50 PASI < 75 at Week 16 25 PASI < 50 at Week 16 Patients at Week 16, n 98 48 Achieve PASI 50 at Week 28 98% 71% Achieve PASI 75 at Week 28 52% 13% Achieve PASI 90 at Week 28 13% 2% USTEKINUMAB *Combined data for PHOENIX 1 and 2 patients 100kg receiving 45 mg UST and >100kg receiving 90 mg UST. Sobell J, et al. Poster Presentation at FCD 2010.

Successful treatment of recalcitrant palmoplantar psoriasis with etanercept. Weinberg JM. Cutis. 2003;72:396-8.

Successful treatment of hand and foot psoriasis with infliximab. Di Lernia V, Guareschi E. Dermatol Online J. 2010 ;16:8. Severe psoriasis pustulosa palmaris et plantaris (Barber-Königsbeck) treated successfully with soluble tumour necrosis factor receptor fusion protein (etanercept). Kasche A, et al J Eur Acad Dermatol Venereol.2007;21:255-7.

Safety and efficacy of Adalimumab in the treatment of moderate to severe palmo-plantar psoriasis: an open label study. Clin Ter. 2012;163(2):e61-6. Richetta AG, et al 4/11 clear 5/11 50% improvement

Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis of PP pustulosis; results from a randomized controlled trial. Bissonnette R et al. JEADV 2013 DOI: 10.1111/jdv.12272. UST 45mg doesn t work

Investigator-initiated, open-label trial of ustekinumab for the treatment of moderate-tosevere palmoplantar psoriasis. J Dermatolog Treat. 2012 May 8. [Epub ahead of print] Au SC, Goldminz AM, Kim N, Dumont N, Michelon M, Volf E, Hession M, Lizzul PF, Andrews ID, Kerensky T, Wang A, Yaniv S, Gottlieb AB. 7/20 clear (90 mg:6/9; 45mg:1/11) 12/20 >2point PGA approval

An investigator-initiated, open-label study evaluating the efficacy and safety of UST in patients with moderate-tosevere palmar/plantar psoriasis 24 subjects with palmar/plantar psoriasis with PGA 3 treated with FDA-approved dose of UST using weight-based dosing Report of 20/24 subjects, 11 in 45-mg dose, 9 in 90-mg dose. Mean weight of subjects not reported Shimrat Y, et al. AAD 2012: P4733; Study sponsored by Centocor

Apremilast, an oral phosphodiesterase-4 inhibitor, in the treatment of palmoplantar psoriasis: Results of a pooled analysis from phase II PSOR-005 and phase III Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) clinical trials in patients with moderate to severe psoriasis. Bissonnette R, et al. J Am Acad Dermatol. 2016 Mar 24. pii: S0190-9622(16)01400-6. doi: 10.1016/j.jaad.2016.02.1164. [Epub ahead of print]

Patients Achieving PPPGA 0 or 1 (%) PPPGA 0 or 1 Achievement at Week 16 in Patients With Baseline PPPGA 3 80 70 60 50 40 30 20 10 0 20.0 66.7 * PSOR-005 38.6 30.8 31.3 ESTEEM 1 Placebo Apremilast 30 mg BID 65.4 n/m = 2/10 6/ 8/26 22/57 5/16 17/2 9 6 ESTEEM 2 *P<0.05 vs. placebo. Includes patients with Palmoplantar Psoriasis Physician Global Assessment (PPPGA) 3, indicating moderate or severe palmoplantar psoriasis, at baseline; all data are last observation carried forward. n/m=number of patients with response/number of patients with sufficient data for evaluation. *

% Patients Achieving Change from Baseline in ESIF Score of >4.98 Clinical and patient-reported improvements of hand and/or foot psoriasis with ADA 40 mg qow: Subanalysis of REACH Subanalysis of REACH study looking at elements of erythema, scaling, induration and fissuring (ESIF) score along with DLQI 100 90 80 70 60 50 40 30 20 10 0 Patients achieving a change from baseline in ESIF score of >4.98 Week 16 Week 28 PBO ADA Non-responder imputation. ESIF: Erythema, scaling, induration, fissuring. Menter A, et al. AAD 2012: P5061; Study sponsored by Abbott Laboratories

Secukinumab shows significant efficacy in palmoplantar psoriasis: results from GESTURE, a randomized controlled trial. Gottlieb A, Sullivan J, van Doorn M, Kubanov A, You R, Parneix A, Hugot S, Milutinovic M. J Am Acad Dermatol. 2016 Oct (epub ahead of print)

Journal of the American Academy of Dermatology DOI: (10.1016/j.jaad.2016.07.058)

More than Half of All Subjects on Secukinumab 300 mg Achieved Clear/Almost Clear Palms and Soles at 1.5 Years ppiga 0/1 Response Out to 1.5 Years 57.2% pppasi Change Out to 1.5 Years 39.4%** 35.3%*** 52.4%*** 34.9% 23.1%* 1.5% 54.6%*** 69.5% Palmoplantar disease improved by approximately 70% at 1.5 years in subjects receiving secukinumab 300 mg

Patients (%) UNCOVER-3: Ixekizumab in patients with palmoplantar involvement: pppasi 75 response rates Placebo/IXE q4w (n=20) IXE q4w/ixe q4w (n=32) ETN/IXE q4w (n=25) IXE q2w/ixe q4w (n=38) Placebo washout 100 80 60 40 Induction dosing period * * 78.1* 68.4* 44.0 Open label, long term extension period (IXE q4w) 80.0 80.0 71.1 68.8 20 20.0 0 0 2 4 8 12 16 20 24 28 32 Weeks 36 40 44 48 52 56 60 These patients have plaque psoriasis of the hands and feet, this does not address efficacy in pustular disease nor patients with predominantly palmoplantar disease Menter A, et. al. EADV 2016, FC03.08; Sponsored by Eli Lilly and Company