1. FDA AAC: Discussion of SLE Concept Paper State of the Art: HRQOL, Fatigue and Function FDA AAC: Discussion of SLE Concept Paper State of the Art: HRQOL, Fatigue and Function Vibeke Strand, MD Biopharmaceutical Consultant Adjunct Clinical Professor, Division of Immunology, Stanford University Vibeke Strand, MD Biopharmaceutical Consultant Adjunct Clinical Professor, Division of Immunology, Stanford University

2. Disclosures Abbott Alexion Amgen Corporation Aventis Pharmaceuticals Celltech Centocor Genelabs Genentech Genzyme Hoffman LaRoche IDEC Incyte La Jolla Pharmaceuticals Novartis Pfizer Procter and Gamble Scios SKK Sumitomo Xoma Corporation Abbott Alexion Amgen Corporation Aventis Pharmaceuticals Celltech Centocor Genelabs Genentech Genzyme Hoffman LaRoche IDEC Incyte La Jolla Pharmaceuticals Novartis Pfizer Procter and Gamble Scios SKK Sumitomo Xoma Corporation Abgenix Affymax Alza Corporation Astra Zeneca Becton Dickinson Biogen Boeringher Ingelheim Entelos Geron, Inc. Glaxo SmithKline Immune Response Corp RWJohnson PRI Eli Lilly and Co Medarex Organon Otsuka Schering Plough Targeted Genetics Abgenix Affymax Alza Corporation Astra Zeneca Becton Dickinson Biogen Boeringher Ingelheim Entelos Geron, Inc. Glaxo SmithKline Immune Response Corp RWJohnson PRI Eli Lilly and Co Medarex Organon Otsuka Schering Plough Targeted Genetics Current ClientsPrevious Clients

3. Lessons Learned: It is Difficult to Assess Outcome in SLE RCTs Disease Activity Indices do NOT necessarily reflect OUTCOME Disease activity ≠ Disease severity Variability in weighting different organ manifestations Variability in scoring and scoring items [eg, fatigue] Only BILAG designed to reflect need for change in treatment Few have been used / validated in RCTs Poor correlation between patient and physician assessments of disease activity Responder analyses do NOT function well if they are proposed in absence of data from RCTs Changes in medical practice may confound treatment effects Disease Activity Indices do NOT necessarily reflect OUTCOME Disease activity ≠ Disease severity Variability in weighting different organ manifestations Variability in scoring and scoring items [eg, fatigue] Only BILAG designed to reflect need for change in treatment Few have been used / validated in RCTs Poor correlation between patient and physician assessments of disease activity Responder analyses do NOT function well if they are proposed in absence of data from RCTs Changes in medical practice may confound treatment effects

4. OMERACT 4 SLE Module 1998 Goal To develop consensus on required outcome domains to be assessed in clinical trials in SLE: Randomized Controlled Trials [RCTs] and/or Longitudinal Observational Studies [LOS] Organizing Committee: D. Gladman D. Isenberg M. Petri J. Smolen V. Strand To develop consensus on required outcome domains to be assessed in clinical trials in SLE: Randomized Controlled Trials [RCTs] and/or Longitudinal Observational Studies [LOS] Organizing Committee: D. Gladman D. Isenberg M. Petri J. Smolen V. Strand Strand et al: J Rheum 1999; 26: 490-497 Smolen et al: J Rheum 1999; 26: 504-507

5. Outcome Domains Recommended by OMERACT 4 Strand et al: J Rheum 1999; 26: 490-497 Smolen et al: J Rheum 1999; 26: 504-507 Disease activity: Damage: HRQOL: Should also include: Adverse events Economic costs including health utilities Disease activity: Damage: HRQOL: Should also include: Adverse events Economic costs including health utilities

6. What is Health Related Quality of Life? NOT the economy… NOT the geopolitical situation… NOT status or access to resources… “In all the ways your disease affects you, how are you doing today?” SLE affects all domains of health related quality of life Patients complain of fatigue, inability to plan ahead, and changes in appearance NOT the economy… NOT the geopolitical situation… NOT status or access to resources… “In all the ways your disease affects you, how are you doing today?” SLE affects all domains of health related quality of life Patients complain of fatigue, inability to plan ahead, and changes in appearance

7. SF-36: Short Form 36 Health Survey Validated, widely used generic measure of HRQOL 8 Domains: Scored 0 - 100; age, gender adjusted norms 2 Summary Scores: Normative based scoring Mean: 50, SD: 10 Physical Component: PCS Measures how decrements in physical function affect day to day activities Impact of physical impairment / disability on HRQOL Mental Component: MCS Impact of mental affect, symptoms of pain on HRQOL Facilitates comparison with other disease states Validated, widely used generic measure of HRQOL 8 Domains: Scored 0 - 100; age, gender adjusted norms 2 Summary Scores: Normative based scoring Mean: 50, SD: 10 Physical Component: PCS Measures how decrements in physical function affect day to day activities Impact of physical impairment / disability on HRQOL Mental Component: MCS Impact of mental affect, symptoms of pain on HRQOL Facilitates comparison with other disease states

8. Physical component Mental component Physical function Role physical Bodily pain General health Vitality Social function Role emotion Mental health SF-36 Domains and Summary Scores

9. SLE Impacts all Domains of HRQOL Coping mechanisms most consistently associated with HRQOL, but not morbidity – Ethnicity and socioeconomic status are important – Variable Social support consistently associated with reported mental health Organ damage less associated with reported HRQOL than disease activity Data in patients receiving care from rheumatologists: In cohort studies or enrolled in RCTs May underestimate influences of access to care and treatment adherence Sutcliffe et al: Rheumatol 1999; 38:1130-7 Ward: Arth Rheum 2001; 44:2711-4

10. Disability in SLE Encompasses all Domains of HRQOL Fatigue and Depression important — and are quantifiable Disease activity, damage ± health related quality of life Disability ± Impairment in physical function: 106 SLE pts in Baltimore: mean HAQ DI = 0.66 > 25% had HAQ DI scores of 0 <10% required assistance or assistive aids 120 SLE pts in Cleveland: mean HAQ DI = 0.83 125 in Canada: mean HAQ DI = 0.61 Hochberg et al JRheum 1988; 15:959-964 Milligan et al JRheum 1993: 20:972-6 Gladman et al: Lupus 1996; 5:190-5

11. HRQOL in SLE compared with RA RA and SLE patients complain of: loss of energy, unpredictable course of disease SLE patients complain of fatigue; ‘inability to plan ahead’ SLE patients have more dissatisfaction with perceived control of their bodies, and body image SLE patients dissatisfied with understanding about their condition on the part of MDs and other individuals «Handicap invisible to others» Burckhardt et al JRheum 1993; 20:997-81 Archenholtz et al: Qual Life Res 1999; 8:411-6

12. HRQOL in SLE Compared with RA Prospective study of 82 patients with RA, 82 with SLE matched for age, gender, disease duration and 74 age and gender controls Both diseases impact all dimensions of health status Less disability in RA, and lower VAS pain scores – but no difference in bodily pain domain scores SF-36 correlated best with: patient global assessment accumulated damage index Gilboe et al JRheum 1999; 26:1694-700

13. SF-36: Short Form 36 Health Survey Baseline domain scores low in SLE – v. age/gender norms for Canada, Norway, UK, US – v. serious medical problems (IDDM, CAD) In cohort studies reflects changes in disease activity (SLAM, BILAG, SLEDAI): –  disease activity  in PF, BP, GHP –  disease activity  SF-36 domain scores, esp. PF –  damage  in PF, GHP Baseline domain scores low in SLE – v. age/gender norms for Canada, Norway, UK, US – v. serious medical problems (IDDM, CAD) In cohort studies reflects changes in disease activity (SLAM, BILAG, SLEDAI): –  disease activity  in PF, BP, GHP –  disease activity  SF-36 domain scores, esp. PF –  damage  in PF, GHP Gladman et al: J Rheum 1995; 23:1953-5 Gordon et al: A+R 1997; 40:487 Gladman et al: Clin Exp Rheum 1995; 14:305-8 Stoll et al: J Rheum 1997; 24:309-13 and 1608-14 Fortin et al: Lupus 1998; 7:101-7 Sutcliffe et al: J Rheum 1999; 26:2352-6 Wang et al: J Rheum 2001; 28: 525-32

14. SF-36 is Sensitive to Change in SLE Demonstrated valid and sensitive to change in RCTs and LOS in SLE Decrements in multiple domains correlate with increases in disease activity and damage – although generally weak correlations Immunosuppressive use Reflect ESRD Demonstrated valid and sensitive to change in RCTs and LOS in SLE Decrements in multiple domains correlate with increases in disease activity and damage – although generally weak correlations Immunosuppressive use Reflect ESRD Abu-Shakra et al J Rheum 1999; 26:306-9 Thumboo et al J Rheum 1999; 26:97-102 Thumboo et al J Rheum 2000; 27:1414-20 Wang et al J Rheum 2001; 28:525-32 Stoll et al: J Rheum 1997; 24: 309-13 and 1608-14 Fortin et al: Lupus 1998; 7:101-7 Sutcliffe et al: J Rheum 1999; 26:2352-6 Strand et al: J Rheum 1999; 26:495-503 Thumboo et al: J Rheum 2000; 27:1414-1420 Wang et al: J Rheum 2001; 28: 525-32 Rood et al J Rheum 2000; 27:2057-9 Vu, Escalante J Rheum 1999; 26:2595-2601

15. SF-36 is Sensitive to Change in SLE Changes in domain scores in general best correlated with changes in disease activity, higher glucocorticoid doses, use of cytotoxic agents Greatest variability in Role Physical and Role Emotional domains Taking the mean of the 4 physical domains = PHS and 4 mental domains = MHS PHS negatively correlated with ↑ steroid doses ↑ BILAG score MHS negatively correlated with ↑ steroid doses use of cytotoxics ↑ BILAG scores Changes in domain scores in general best correlated with changes in disease activity, higher glucocorticoid doses, use of cytotoxic agents Greatest variability in Role Physical and Role Emotional domains Taking the mean of the 4 physical domains = PHS and 4 mental domains = MHS PHS negatively correlated with ↑ steroid doses ↑ BILAG score MHS negatively correlated with ↑ steroid doses use of cytotoxics ↑ BILAG scores Thumboo et al J Rheum 1999; 26:97-102 Thumboo et al J Rheum 2000; 27:1414-20

16. Minimum Clinically Important Differences [MCID] Degree of improvement in various outcome measures Perceptible to patients Considered clinically important / meaningful Defined by patient query, delphi technique HAQ DI: 0.22 improvement Confirmed by statistical correlations with clinical responses in placebo RCTs, using patient global assessments When group median (and mean) changes well exceed MCID, it can be expected that a majority of patients will attain clinically meaningful improvement Degree of improvement in various outcome measures Perceptible to patients Considered clinically important / meaningful Defined by patient query, delphi technique HAQ DI: 0.22 improvement Confirmed by statistical correlations with clinical responses in placebo RCTs, using patient global assessments When group median (and mean) changes well exceed MCID, it can be expected that a majority of patients will attain clinically meaningful improvement

17. 1.Redelmeier et al. Arch Intern Med. 1993; 153:1337-42 2.Wells et al. J Rheumatol. 1993; 20:557-60 3.Guzman et al. Arth Rheum. 1996; 39:5208 4.Kosinski et al. Arth Rheum. 2000; 43:1478-87 5.Samsa et al. Pharmacoeconomics. 1999; 15:141-155 6.Thumboo et al. J Rheumatol. 1999; 26:97-102. 7.Zhao et al: Pharmacotherapy 1999; 19:1269-78 8.Angst et al: Arth Care Res 2001; 45:384-91 Minimum Clinically Important Differences [MCID] HAQ DI 1-4 0 - 3 –0.22 SF-36 2, 4-8 0 - 100 +5 - 10 points PCS/MCS mean 50 ± 10 +2.5 - 5 points HAQ DI 1-4 0 - 3 –0.22 SF-36 2, 4-8 0 - 100 +5 - 10 points PCS/MCS mean 50 ± 10 +2.5 - 5 points ScoreDirectionMCID Range of Scoring ScoreDirectionMCID Range of Scoring

18. Other Points: Confounding Issue of Fatigue 2° to active SLE or fibromyalgia? Associated fibromyalgia in cohort series: Petri: 25 - 30% Gladman:20% Gordon, Isenberg:<10% Capable of treatment independent of SLE? Significantly impacts SF-36, Other patient reported measures? Fatigue assessed by MD included in SLAM; SLAM-R Krupp Fatigue Severity Score reflects alterations NOT 2° to psychological stress Different than reported in other ds states, eg MS 2° to active SLE or fibromyalgia? Associated fibromyalgia in cohort series: Petri: 25 - 30% Gladman:20% Gordon, Isenberg:<10% Capable of treatment independent of SLE? Significantly impacts SF-36, Other patient reported measures? Fatigue assessed by MD included in SLAM; SLAM-R Krupp Fatigue Severity Score reflects alterations NOT 2° to psychological stress Different than reported in other ds states, eg MS Gladman et al J Rheum 1997; 24:2145-8 Taylor et al A+R 1998: 41: 1797-85 Krupp et al Arch Neurol 1989: 46: 1121-3

19. Αnti dsDNA Ab levels Predict Disease Flares Swaak: in 143 SLE patients followed for up to 6 years: 2x ↑ αdsDNA Ab levels within 10 weeks predicted 33 major ‘exacerbations’: 21 renal; 12 non-renal 80% renal ‘flares’ predicted by ↓ C4 levels Ter Borg: in 17/72 SLE patients followed over mean 18.5 months 24/33 ‘exacerbations’ predicted by ↑ αdsDNA Ab levels 13 renal; 20 non-renal flares Bootsma: 156 patients; αdsDNA Ab levels measured monthly When ↑↑: randomized to conventional Rx or addn 30 mg prednisone In 46: relapses in 20/24 v 2/22 p<0.001 Bijl: in 36 patients: αdsDNA Ab levels measured monthly When ↑↑ in 10: MMF 2000 QD → no clinical relapses in 6 months Swaak: in 143 SLE patients followed for up to 6 years: 2x ↑ αdsDNA Ab levels within 10 weeks predicted 33 major ‘exacerbations’: 21 renal; 12 non-renal 80% renal ‘flares’ predicted by ↓ C4 levels Ter Borg: in 17/72 SLE patients followed over mean 18.5 months 24/33 ‘exacerbations’ predicted by ↑ αdsDNA Ab levels 13 renal; 20 non-renal flares Bootsma: 156 patients; αdsDNA Ab levels measured monthly When ↑↑: randomized to conventional Rx or addn 30 mg prednisone In 46: relapses in 20/24 v 2/22 p<0.001 Bijl: in 36 patients: αdsDNA Ab levels measured monthly When ↑↑ in 10: MMF 2000 QD → no clinical relapses in 6 months TerBorg et al: A+R 1990; 33:634-43 Bootsma et al: Lancet 1995; 345:1595-9 Swaak et al: Ann Rh Ds 1986; 45:359-66 Bijl et al: Ann Rh Ds 2003: 62:534-9

20. LJP 394 Placebo anti-dsDNAC3 % change % change in C3 100 mg50 mg50 mg 01020304050 01020304050 Changes in  dsDNA Ab; Complement 3 Levels Study week

21. HRQOL Analysis All patients enrolled in LJP 394 phase 2/3 clinical trial who completed one baseline and follow-up SF-36 Mean scores at endpoint and change scores in SF-36 domains; PCS and MCS summary scores compared between active and placebo End of Induction [week 16] vs baseline (BL): ITT [n=179] and ‘high affinity’ populations [n=157] Post vs Pre documented renal flare values; +/- patients receiving high dose steroids and/or cytotoxics [HDCC] prior to flare [n=37; n=30] All patients enrolled in LJP 394 phase 2/3 clinical trial who completed one baseline and follow-up SF-36 Mean scores at endpoint and change scores in SF-36 domains; PCS and MCS summary scores compared between active and placebo End of Induction [week 16] vs baseline (BL): ITT [n=179] and ‘high affinity’ populations [n=157] Post vs Pre documented renal flare values; +/- patients receiving high dose steroids and/or cytotoxics [HDCC] prior to flare [n=37; n=30] Strand et al: Lupus 2003; 12:677-86

22. SF-36 Scores at Baseline Compared with Age, Gender Matched US Norms Strand et al: Lupus 2003; 12:677-86

23. Mean Changes in SF-36 Domain Scores from Baseline to 16 Weeks [ITT] Strand et al: Lupus 2003; 12:677-86

24. Mean Changes in SF-36 Domain Scores Pre and Post Renal Flare Strand et al: Lupus 2003; 12:677-86

25. Conclusions Patients with clinically stable SLE reported impaired HRQOL compared with age and gender matched US norms. During induction [16 weeks], SF-36 scores improved with active treatment, despite stable disease activity. Following a renal flare, patients receiving active treatment reported maintenance or improvement in HRQOL compared with deterioration in placebo; omitting patients who received HDCC prior to flare did not alter results. Differences in change scores in Role Emotional between treatment groups were replicated in all populations analyzed; are clinically meaningful, and may reflect changes in anti-dsDNA Ab levels. Patients with clinically stable SLE reported impaired HRQOL compared with age and gender matched US norms. During induction [16 weeks], SF-36 scores improved with active treatment, despite stable disease activity. Following a renal flare, patients receiving active treatment reported maintenance or improvement in HRQOL compared with deterioration in placebo; omitting patients who received HDCC prior to flare did not alter results. Differences in change scores in Role Emotional between treatment groups were replicated in all populations analyzed; are clinically meaningful, and may reflect changes in anti-dsDNA Ab levels. Strand et al: Lupus 2003; 12:677-86

26. Longitudinal Changes in anti dsDNA Abs in 2 RCTs, Regardless of Treatment Group Responder: ≥10% reduction in anti-dsDNA antibodies in ≥2/3 of all determinations Non - responder 30%20%10%0-10%-20%-30% % change from BL Responder Time (months)

27. HRQOL Scores at Month 4 in «Responders» in 230 Patients with SLE PFI ROLP PAIN GHP VITAL SOC ROLE MHI Mean change scores

28. HRQOL Scores at Month 6 in «Responders» in 298 Patients with SLE Mean change scores PFI ROLP PAIN GHP VITAL SOC ROLE MHI

29. HRQOL Scores at Month 12 in «Responders» in 298 Patients with SLE Mean change scores PFI ROLP PAIN GHP VITAL SOC ROLE MHI

30. HRQOL Scores at Months 6 and 12 in «Responders» in 298 Patients with SLE Excluding 14 patients with renal flares ≤ 6 months do not change these results Excluding 41 patients with renal flares ≤ 12 months do not change these results Excludes use of high dose glucocorticoids and/or cyclophosphamide Are they clinically meaningful? → Analysis of “minimally clinically important differences” Excluding 14 patients with renal flares ≤ 6 months do not change these results Excluding 41 patients with renal flares ≤ 12 months do not change these results Excludes use of high dose glucocorticoids and/or cyclophosphamide Are they clinically meaningful? → Analysis of “minimally clinically important differences”

31. Mean Changes From Baseline in Patient Global VAS Week Mean change +/-SEM

32. MCID in SF-36 Domains, PCS and MCS Correlation of change in 15 point scale by Guyatt et al: “In the past 3 months, has there been any change in your overall quality of life related to your lupus?” “a little better” = 6 on 15 point scale “a little worse” = 10 Improvements → mean change scores Domains of SF-36: 6.7 – 11.4 PCS and MCS: 3.4 – 3.9 Worsening → mean change scores Domains of SF-36: +1.7 – -14.7 PCS and MCS: -0.8 – -2.0 Correlation of change in 15 point scale by Guyatt et al: “In the past 3 months, has there been any change in your overall quality of life related to your lupus?” “a little better” = 6 on 15 point scale “a little worse” = 10 Improvements → mean change scores Domains of SF-36: 6.7 – 11.4 PCS and MCS: 3.4 – 3.9 Worsening → mean change scores Domains of SF-36: +1.7 – -14.7 PCS and MCS: -0.8 – -2.0

33. Conclusions: Yes, it IS difficult to assess Outcomes in SLE Limited data derived from RCTs ― Yet to result in an ‘approved therapy’ ― Over a broad variety of promising interventions Patient Reported HRQOL is an IMPORTANT OUTCOME Reflects improvements in disease activity Deterioration due to use of high dose glucocorticoids and/or immunosuppressives Has correlated with longer term clinical outcomes May improve w/ sustained reductions in α dsDNA Abs Which are clinically meaningful Yes, it IS difficult to assess Outcomes in SLE Limited data derived from RCTs ― Yet to result in an ‘approved therapy’ ― Over a broad variety of promising interventions Patient Reported HRQOL is an IMPORTANT OUTCOME Reflects improvements in disease activity Deterioration due to use of high dose glucocorticoids and/or immunosuppressives Has correlated with longer term clinical outcomes May improve w/ sustained reductions in α dsDNA Abs Which are clinically meaningful