Psoriasis OMERACT 2004 Methods to assess disease activity in clinical trials

1. Psoriasis OMERACT 2004 Methods to assess disease activity in clinical trials Gerald G Krueger MD Professor, Cumming Presidential Endowed Chair Dept of Dermatology University of Utah 5/2004

2. The challenge 1 4 6p 16 17

3. Qualities for Assessment of psoriasis • Investigators want • Quick and easy to perform • Clear definitions, reproducible • FDA seeks • “Static” ratings — indicating severity at the time the patient is seen • Results in steps (segmented).e.g. clear, mild, moderate, severe • Results that have clinical relevance to patient

4. Tools to quantitate clinical improvement in psoriasis • Clinical Assessments - Subjective • PASI • PGA: Dynamic + / - assisted recall; Static • OLA • National Psoriasis Foundation Psoriasis Score (NPF-PS) • Lattice System-Global Psoriasis Score (LS-GPS) • Target lesions: + / - BSA • QOL (SF36, DLQI, others) • Clinical Assessments - Objective • Biopsy -- thickness, biomarkers (real time PCR, EGIR, etc) • Photographs

5. PASI • E = Erythema • I = Infiltration (induration; thickness; elevation) • D = Desquamation (scale; scaling) • A = Score for % involvement in each body area Fredriksson & Pettersson, Dermatologica 1978; 157:238

6. Placebo (n=479) Efalizumab 1 mg/kg/wk (n=763) Improvement in PASI score vs time 60 * * 50 * * 40 Mean Percentage Improvement in PASI Score From Baseline 30 * 20 * 10 0 0 2 12 4 6 8 10 Week *P=0.0001 vs placebo. Gordon KB, et al. 9th IPS 2003; Poster 29.

7. 70 PASI 75 PASI 50 PASI 75/ PASI 50 60 57%* 55%* 50 40 Percentage of Patients 28%* 28%* 30 20 15% 10 4% 0 Placebo (n=479) Efalizumab 1 mg/kg/wk (n=763) Efalizumab 2 mg/kg/wk (n=409) Improvement in PASI 50 and 75 *P<0.001 vs placebo. Gordon KB, et al. 9th IPS 2003; Poster 29.

8. Alefacept 7.5 mg/week x 12 PASI < 75 is clinically meaningful Baseline 2 Weeks After Last Dose (PASI = 9.5) 33% PASI Reduction 3 Months After Last Dose (PASI = 4.8) 66% PASI Reduction (PASI = 14.2)

9. PASI problems • Plaque qualities (e.g., induration) not defined • Area is non-linear, uses a 1-6 scale (1 = <10% BSA, 2 = 10-<30% BSA, 3 = 30-<50% BSA, 4 = 50-<70% BSA, 5 = 70-<90% BSA, and 6 = 90-100% BSA) • Erythema, infiltration, scaling all weighted equally • Plaque elevation may be more important(FDA and investigator consensus) • Small amount of disease = less reduction than appreciated clinically • Continuous, not in steps, PASI 50 and PASI 75 arbitrary endpoints

10. PASI problems, cont’d • Not intuitive to physicians or patients • PASI = 28 -- what does it mean? • 50% or 75% reduction in PASI -- what does this mean when recognized that score is non-linear? • Clear/almost clear not defined • What scores = clear to almost clear? • FDA interested in percent of patients who achieve clear or almost clear

11. The NPF Psoriasis Score:Development and Use of a New Psoriasis Scoring System

12. The NPF Score

13. 0.0 mm 0.25 mm Psoriasis Score 0.50 mm 0.75 mm 1.00 mm 1.25 mm Target Lesion Assessment • Induration = most heavily weighted score • Felt to be most important of EIS system • Possible to improve inter-observer reliability via NPF Reference Card embossed with elevations that increase at 0.25 mm intervals • Score 0 to 5

14. Body Surface Area % Current X 100 BSA = % Baseline 0 = 0% BSA remaining with psoriasis (complete clearing except residual discoloration) 1 = 1-20% BSA remaining 2 = 21-40% BSA remaining 3 = 41-60% BSA remaining 4 = 61-80% BSA remaining 5 = 81-100% BSA remaining • Percent relative to baseline, therefore able to make cross-study comparison • Uses 1%=palm to PIP joint system • Does not account for worsening of disease

15. Physician’s Global Assessment 0 = cleared except residual discoloration 1=majority of lesions have individual scores for I, E, S that average 1 2 = majority of lesions have individual scores for I, E, S that average 2 3 = majority of lesions have individual scores for I, E, S that average 3 4 = majority of lesions have individual scores for I, E, S that average 4 5 = majority of lesions have individual scores for I, E, S that average 5 • Felt to be most important score, but not very dynamic alone • EIS scores are used by physician to assist in making a single PGA score

16. Patient’s Global Assessment Rank severity of psoriasis, 0 = no psoriasis, 5 = worst psoriasis has been: 0 = no psoriasis 1 = 20% as bad as my psoriasis has ever been 2 = 40% as bad as my psoriasis has ever been 3 = 60% as bad as my psoriasis has ever been 4 = 80% as bad as my psoriasis has ever been 5 = the worst my psoriasis has ever been • Dynamic assessment that relies on “set point” of individual rather than baseline

17. Patient’s Assessment of Itch 0 = No itching 1=Mild; only aware of itching at times, only present when relaxing, not present when focused on other activities 2 = Intermediate between 1 and 3 3 = Moderate; often aware of itching, annoying; sometimes disturbs sleep and daytime activities 4 = Intermediate between 3 and 5. 5 = Severe; constant itching, distressing, frequent sleep disturbance, interferes with activities • Static Assessment • Averaged over past 24 hours • Felt to be significant indicator of improvement

18. P A S I N P F 3 0 . 0 2 5 . 0 2 0 . 0 Score 1 5 . 0 1 0 . 0 5 . 0 0 . 0 1 2 3 4 V i s i t # Average score -- all patients NPF vs. PASI Example (Patient #6) P A S I N P F 3 0 2 5 2 0 Score Prospective Trial of Acitretin and Commercial Tanning 1 5 1 0 5 0 1 2 3 4 5 6 7 V i s i t #

19. National Psoriasis Foundation Psoriasis Score as a tool to assess efficacy of efalizumab (anti-CD11a) in treatment of moderate to severe plaque psoriasis G G Krueger, Alan Menter, Stephen Tyring, David Harvey, Wolfgang Dummer, Dan Henderson, Alice B Gottlieb

20. Responders @ 12 Weeks Partial responders @ 12 Weeks

21. NPF PS Induration score during extended treatment in subjects who were responders @ 12 weeks

22. Target lesion assessment +/- BSA • Chose two or more target lesions • Representative of all lesions • Representative of therapeutic target, e.g. lichenified, intertriginous, knees, scalp, palms, soles, etc • Assess chosen physical parameters, (E, I, S and area) using definitions of each • No standard definitions • No standard scale, 0 to 3, 0 to 4, 0 to 5, 0 to 6 • BSA baseline, 1 palm = 1%

23. Conclusions re: Assessment of response to therapeutic intervention • Many ways to assess response to Rx • None have met the non-existent definition of what is “clinically meaningful” • PASI strengths: Widespread use, will distinguish active from placebo • PASI weaknesses: “Steps” (PASI 75, PASI 50) are artificial and do not correspond with 75% and 50% improvement, correlate poorly with QOL, unless trained - scores are disparate, not effective for topical studies, not effective for systemic studies if PASI is low, FDA dislikes it and clinicians do not use it nor understand it

24. Conclusions re: Assessment of response to therapeutic intervention, cont’d • NPF-PS strengths: • Correlates well to PASI, better than PASI to QOL • Works with low BSA (topical agents, PsA) • Has patient input • Dynamic patient global (recall to worst ever been) • Quantification of pruritus (most troublesome symptom), • Has defined physician global (static), • The major element -- induration of 2 target lesions -- early change = strong predictor of response useful to assess subtle change, easy and consistent assessment with validated induration tool

25. Conclusions re: Assessment of response to therapeutic intervention, cont’d • NPF-PS weaknesses: • Not in widespread use • “Not validated” • “Steps” remain to be defined • Approval agencies, e.g., FDA has not “blessed” it • Clinicians have not been exposed to it • Unknown = more or less acceptable than a simple PGA

26. Quality of Life (QOL) • Doesn’t directly measure the impact of drug on the disease • Does measure the impact on the patient’s life • The overall goal of therpeutic intervention is to improve patient’s lives • However direct measure of disease activity is the usual primary endpoint

27. QOL vs Disease Severity • Some patients have lots of lesions but aren’t bothered by them • Some have very few lesions and are very bothered by them • QOL correlates to a degree with skin lesions, but certainly not 100%

28. QOL Measures • Non-specific • SF-36 • Euro QOL • Utility • Skin specific • DLQI • Skindex • Psoriasis specific • PDI

29. Short Form-36 • General health, health change, physical functioning, limitations due to physical health/emotional health, social functioning, pain, energy, emotional well-being • Walking, climbing stairs, working • Physical and mental dimensions

30. Psoriasis: Impact on Physical Health–Comparison With Other Diseases 60 55 55 50 47 45 45 44 43 43 45 42 42 Physical Component Summary Score of SF-36 41 40 35 35 30 Cancer Arthritis Psoriasis Dermatitis Depression Hypertension Healthy adults Type 2 diabetes Myocardial infarction Chronic lung disease Congestive heart failure Rapp SR et al. J Am Acad Dermatol. 1999;41:401.

31. Psoriasis: Impact on Mental Health–Comparison With Other Diseases 55 53 52 52 52 50 49 49 50 46 46 45 45 Mental Component Summary Score of the SF-36 40 35 35 30 Cancer Arthritis Psoriasis Dermatitis Depression Hypertension Healthy adults Type 2 diabetes Myocardial infarction Chronic lung disease Congestive heart failure Rapp SR et al. J Am Acad Dermatol. 1999;41:401.

32. Consists of 10 questions covering 6 domains Symptoms and feelings Daily activities Leisure Work and school Personal relationships Bother with psoriasis treatment Response options Very much: scored 3 A lot: scored 2 A little: scored 1 Not at all: scored 0 Range 0-30 Lower scores = Better QOL Dermatology Life Quality Index Finlay AY et al. Clin Exp Dermatol. 1994;19:210.

33. Correlation of Change in DLQI and Change in PASI and PGA Data on file, Centocor, Inc. Spearman rank correlations

34. 14 12 12.0 11.7 11.5 10 9.9 Mean DLQI Score 8 Baseline * * Week 12 6 6.1 6.3 6.3 6.1 4 2 0 Placebo(n=170) Efalizumab 1.0 mg/kg/wk(n=162) Efalizumab 2.0 mg/kg/wk(n=166) Efalizumab Phase III Results: DLQI Scores at Weeks 0 & 12 0 = Minimum effect on QOL; 30 = Maximum effect on QOL. *P<0.001 vs placebo. Feldman SR, et al. AAD Annual Meeting 2002; Poster. 34

35. Improvement From Baseline in DLQI at Week 10 Mean change Median change 12 10.3* 10* 10 8.8* 8* 8 Improvement From Baseline In DLQI 6 4 2.6 2 0 0 Placebo Infliximab 3mg/kg Infliximab 5mg/kg *p<0.001 vs placebo Data on file, Centocor, Inc.

36. Summary • QOL measures supplement lesion measures