PsO: Review of Available Assessment Instruments and Lessons from Trial Results - Part II

1. PsO: Review of AvailableAssessment Instruments and Lessons from Trial Results - Part II Today's Stand In Mark Lebwohl MD Steve Feldman, M.D., Ph.D Professor of Dermatology, Pathology & Public Health Sciences Wake Forest University School of Medicine

2. Part I • Various ways to score psoriasis • Quantitative measures of lesions • PASI • OLA • PGA (static anddynamic via a photo assisted approach) • The Ellis Lattice • NPF Psoriasis Score • Target lesion

3. Part II • Other ways to assess the disease • QOL: Impact on patients’ lives • Biopsies • Photographs • Geneomic approach (DNA, mRNA, proteomics) • Lessons from Trial Results

4. Quality of Life (QOL) • Doesn’t directly measure the impact of drug on the disease • Does measure the impact on the patient’s life • Clearly the overall goal is to improve patient’s lives • But the direct measure of the disease is essential for drug trials

5. 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%

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

7. QOL is Complementary • Want treatments that improve the disease enough to make a difference • QOL tells you if the change in the disease made a difference • Treatments that improve QOL without improving the disease shouldn’t be approved for the disease • Anxiolytics or narcotics might make patients feel better without changing the character of the lesions • They could be approved for the symptom

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

9. 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

10. Psoriasis: Impact on Physical Health–Comparison With Other Diseases 60 55 55 50 47 45 45 44 43 43 45 42 42 41 Physical Component Summary Score of 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.

11. 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.

12. Skindex-16 • 16 items rated on a scale from 1-7 • Total score of 16-102 • Higher score indicating worse QOL • Symptoms • Itching, burning, pain, irritation, appearance, persistence • Emotions • Worry, frustration, annoyance, depression, embarrassment • Social • Being with others, interactions, activities, affection, work

13. QOL Without The Condition • Patients first rate overall QOL with the facial blemish • Then rate what QOL would be without the facial pigmentary disorder • 8 subscales—work, family relationships, social life, sexual relationships, recreation and leisure, physical health, money matters, and emotional well-being • The difference between QOL with and without the facial pigmentary disorder (score range, 0-40)

14. 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.

15. Baseline Week 12 Efalizumab Phase III Results: DLQI Scores at Weeks 0 & 12 14 12 12.0 11.7 11.5 10 9.9 Mean DLQI Score 8 * * 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) 0 = Minimum effect on QOL; 30 = Maximum effect on QOL. *P<0.001 vs placebo. Feldman SR, et al. AAD Annual Meeting 2002; Poster. 15

16. 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.

17. Percent Improvement FromBaseline in DLQI Mean change Median change 100 91* 84* 79* 80 70* % Improvement From Baseline 60 40 16 20 0 0 Placebo Infliximab 3mg/kg Infliximab 5mg/kg *p<0.001 vs placebo Only patients with baseline score >0 included in the analysis Data on file, Centocor, Inc.

18. Responders with 50% reduction in PASI 2 weeks after last dose Nonresponders Percentage Improvement from Baseline in DLQI Scores by Responder Status • PASI 50 Responders Achieved Substantial QOL Improvements Relative to Nonresponders • QOL Benefits Were Maintained 12 Weeks After Last Dose 80 70 56%* 60 Percentage 49%* 50 40 30 19% 19% 20 10 0 2 weeks after last dose 12 weeks after last dose *P<0.001 Alefacept IM Phase 3 Study

19. DLQI in Alefacept 15 mg IM Proportion responding “Very Much” or “A Lot”* 2 Weeks After Last Dose Baseline Embarrassment 64% 27% Impact on daily activities 21% 7% Leisure or social activities 34% 18% Sexual difficulties 21% 15% Problems with partner, 20% 9%relatives, friends *Scale: 1=Very Much; 2= A Lot; 3= A Little; 4=Not At All; 5= Not Relevant

20. Improvement in DLQI Subscales 70 Placebo Etanercept 25 mg QWk § 60 Etanercept 25 mg BiWk § Etanercept 50 mg BiWk 50 § § § § † † * § § 40 § Mean % Change § † * § 30 ‡ ‡ 20 10 0 -10 Symptoms and Feelings Daily Activities Work and School Personal Relationships Leisure Treatment -20 *p<0.01 vs. placebo †p<0.001 vs. placebo ‡p=0.0001 vs. placebo §p<0.0001 vs. placebo Leonardi C et al. International Investigative Dermatology 2003. Poster 409.

21. Timing of Improvement • Mean PASI scores may show statistical significance early in the trial • QOL measures can confirm that these changes are clinically meaningful • Whether there is improvement in QOL

22. Placebo/Etanercept 25 mg BiW Etanercept 25 mg QWk Etanercept 25 mg BiWk Etanercept 50 mg BiWk Mean % Improvement in DLQI 80 74% 70 59% 60 54% 53% 50 Mean % Improvement From Baseline 40 30 20 Placebo group received etanercept 25 mg BiWk after Week 12 10 0 2 0 4 8 12 16 20 24 Weeks p≤0.003 vs. placebo at all time points through Week 12 Leonardi C et al. International Investigative Dermatology 2003. Poster 409.

23. QOL Success • Any statistical improvement • Predetermined degree of improvement

24. Placebo/Etanercept 25 mg BiW Etanercept 25 mg QWk Etanercept 25 mg BiWk Etanercept 50 mg BiWk % With a Zero DLQI or a 5 Point Reduction in DLQI Score 80% 80 68% 70 67% 60 62% 50 Mean % Improvement From Baseline 40 30 Placebo group received etanercept 25mg BiWk after Week 12 20 10 0 2 0 4 8 12 16 20 24 Weeks

25. QOL of Zero • No impact of the disease • Very, very stringent measure of success

26. SPIRIT: Patients With DLQI of 0 at Week 10 45 40* 40 33* 35 30 25 % Patients 20 15 10 5 2 0 Placebo Infliximab 3mg/kg Infliximab 5mg/kg *p<0.001 compared to placebo Data on file, Centocor, Inc.

27. Biopsies • Lab tests are attractive because they are objective • Work great for blood levels, such as glucose, because there is uniformity within the blood • Biopsies can’t assess the severity of psoriasis because one can’t achieve representative sampling • Biopsies are at best nice for assessments of mechanism

28. Photographs • In theory, could be used to confirm real time assessments of severity • Not clear that thickness or even scaliness of lesions can be accurately assessed • Real use is for the marketing department after the study is approved

29. Genomics • Again the problem is finding a representative sample • Perhaps will be useful for • Mechanistic understanding of the disease • Identifying specific subpopulations • For prognostic information • For guiding treatment

30. Summary • Step 1 is to accurately determine the effect of drug on disease • QOL measures supplement lesion measures • Effective quantitative objective measures to assess overall severity (such as based on biopsy of lesions) aren’t available