2. PsO: Review of Available Assessment Instruments and Lessons from Trial Results - Part II Steve Feldman, M.D., Ph.D Professor of Dermatology, Pathology & Public Health Sciences Wake Forest University School of Medicine

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

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

5. 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

6. 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%

7. Correlation of Change in DLQI and Change in PASI and PGA PASIPGA Correlation of absolute changes 0.490.46 Correlation of percent changes 0.610.58 Spearman rank correlations Data on file, Centocor, Inc.

8. 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

9. QOL Measures Non-specific –SF-36 –Euro QOL –Utility Skin specific –DLQI –Skindex Psoriasis specific –PDI

10. 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

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

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

13. 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

14. 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)

15. Dermatology Life Quality Index 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 Finlay AY et al. Clin Exp Dermatol. 1994;19:210.

16. 0 = Minimum effect on QOL; 30 = Maximum effect on QOL. *P<0.001 vs placebo. * 11.7 11.5 12.0 9.9 6.1 6.3 0 2 4 6 8 10 12 14 Placebo (n=170) Efalizumab 1.0 mg/kg/wk (n=162) Efalizumab 2.0 mg/kg/wk (n=166) Mean DLQI Score Baseline Week 12 * Feldman SR, et al. AAD Annual Meeting 2002; Poster. 6.16.3 15 Efalizumab Phase III Results: DLQI Scores at Weeks 0 & 12

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

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

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

20. Embarrassment64%27% Impact on daily activities21% 7% Leisure or social activities34%18% Sexual difficulties21%15% Problems with partner, 20% 9% relatives, friends Proportion responding “Very Much” or “A Lot”* *Scale: 1=Very Much; 2= A Lot; 3= A Little; 4=Not At All; 5= Not Relevant DLQI in Alefacept 15 mg IM 2 Weeks After Last Dose Baseline

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

22. 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

23. Mean % Improvement in DLQI 0 10 20 30 40 50 60 70 80 04812162024 Mean % Improvement From Baseline Weeks 2 54% 53% 59% 74% Placebo group received etanercept 25 mg BiWk after Week 12 Placebo/Etanercept 25 mg BiW Etanercept 25 mg QWk Etanercept 25 mg BiWk Etanercept 50 mg BiWk p≤0.003 vs. placebo at all time points through Week 12 Leonardi C et al. International Investigative Dermatology 2003. Poster 409.

24. QOL Success Any statistical improvement Predetermined degree of improvement

25. % With a Zero DLQI or a 5 Point Reduction in DLQI Score Placebo/Etanercept 25 mg BiW Etanercept 25 mg QWk Etanercept 25 mg BiWk Etanercept 50 mg BiWk 0 10 20 30 40 50 60 70 80 0 4812162024 2 62% 68% 67% 80% Placebo group received etanercept 25mg BiWk after Week 12 Mean % Improvement From Baseline Weeks

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

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

28. 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

29. 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

30. 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

31. 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