FDA Arthritis Advisory Committee March 5, 2003

1
FDA Arthritis Advisory CommitteeMarch 5, 2003

• ARAVA (Leflunomide)
• Aventis Pharmaceuticals

2
Leflunomide Presentation Agenda

• Introduction Michael Rozycki, PhD US Regulatory
  Affairs Aventis Pharmaceuticals
• Patient-Reported Outcomes Joseph Doyle, RPh, MBA
• Physical Function Efficacy Data Karen Simpson,
  MD
• Conclusions Michael Rozycki, PhD

3
Improvement in Physical Function

• Does the term physical function or disability
  better capture clinically relevant information
  ascertained in the HAQ? Are more recent
  derivatives appropriate and validated endpoints /
  substitutes?
• What duration of superiority study is needed to
  robustly identify improvement for disability /
  physical function?
• What type of data are needed to assess durability
  of effect beyond an initial superiority study
  period?
• Are data on leflunomide adequately robust to
  support labeling for improvement in physical
  function?

4
Treatment Goals of Arthritis Therapy

• Improvement in signs and symptoms of the disease
• Reduction of structural damage, evidenced by
  radiographic evaluation of erosions and joint
  space narrowing
• Improvement in physical function, as measured
  through health-related quality of life
  instruments
• Specific measure (e.g. Health Assessment
  Questionnaire) for use as primary endpoint
• General measure such as Short Form 36 to capture
  full effect of RA on the patient

5
Pivotal Data

• NDA for leflunomide submitted March 1998
• Six- or twelve-month pivotal data from three
  randomized, controlled trials (RCTs)
• Arthritis Advisory Committee (August 1998)
  discussion of claim for physical function
• Decision not to officially vote, due to draft FDA
  guidance recommendation for 2- to 5-year data
• Leflunomide NDA approved September 1998
• Indication treatment of active RA to reduce
  signs and symptoms and to retard structural damage

6
Maintenance of Effect Data
Blinded, 24-month data in support of physical
function indication was provided by 3 RCTs,
according to the 1999 FDA guidance

• Study US301 24-month study, with pre-specified
  data analyses at 12 and 24 months
• Supporting data
• MN301/303/305 6-month initial study, 6- and
  12-month extensions, respectively
• MN302/304 12-month initial study, 12-month
  extension

7
Requested Labeling
ARAVA is indicated in adults for the treatment
of active RA

1. to reduce signs and symptoms
2. to retard structural damage as evidenced by x-ray
   erosions and joint space narrowing
3. and to improve physical function

8
Aventis Expert Consultants

• Hepatology
• Dominique Larrey, MD Montpelier Hepatology and
  Transplant Unit, School of Medicine, Montpelier,
  France
• Willis Maddrey, MD Univ. of Texas Southwestern
  School of Medicine, Dallas, TX
• Steven Schenker, MD Univ. of Texas Health
  Science Center, San Antonio, TX
• Paul Watkins, MD Univ. of North Carolina School
  of Medicine, Chapel Hill, NC
• Rheumatology
• Stanley Cohen, MD St. Paul Medical Center,
  Dallas, TX
• Mark Hochberg, MD, MPH Univ. of Maryland,
  Baltimore, MD
• Harold Paulus, MD Univ. of California Los
  Angeles, Los Angeles, CA
• Michael Schiff, MD Denver Arthritis Clinic,
  Denver, CO
• John Sharp, MD Independent Consultant
• Vibeke Strand, MD Biopharmaceutical Consultant,
  Division of Immunology and Rheumatology,
  Stanford University, Palo Alto, CA
• Fred Wolfe, MD Arthritis Research Foundation,
  Wichita, KS

9
Aventis Expert Consultants

• Epidemiology
• Gerald Faich, MD, MPH Pharmaceutical Safety
  Assessments
• Judith Jones, MD, PhD The Degge Group Ltd.,
  Arlington, VA
• Robert Nelson, PhD RCN Associates, Annapolis, MD
• Sammy Suissa, PhD McGill Univ., Montreal,
  Quebec, Canada
• Pathology
• Emanuel Rubin, MD Thomas Jefferson Univ. School
  of Medicine, Philadelphia, PA
• Teratology
• Robert Brent, MD Nemours Organization, Sarasota,
  FL
• Tina Chambers, PhD UCSD Medical Center, San
  Diego, CA
• Nephrology
• Andrew Whelton, MD Universal Clinical Research
  Center, Inc, Hunt Valley, MD

10
Aventis Expert Consultants

• Biostatistics
• Bruce Crawford, MA, MPH Mapi Values, Boston, MA
• Kit Dorrier, MS HD Consulting, LLC, Washington,
  DC
• Frank Hurley, PhD RRD Consulting International,
  Inc., Rockville, MD
• Gary Koch, PhD Statistical Consultant, Univ. of
  North Carolina, Chapel Hill, NC
• Christine Oed, MS Covidence GmbH, Frankfurt,
  Germany
• John Ware, MD Quality Metric, Lincoln, RI
• Clinical Development
• Wilhelm Horn, MD Covidence GmbH, Frankfurt,
  Germany

11
Leflunomide Presentation Agenda

• Introduction Michael Rozycki, PhD
• Patient-Reported Outcomes Joseph Doyle, RPh,
  MBA Health Economics and Outcomes
  Research Aventis Pharmaceuticals
• Clinical Efficacy Physical Function Karen
  Simpson, MD
• Conclusions Michael Rozycki, PhD

12
Overview

• Impact of RA on Physical Function
• Review of Physical Function and Health-Related
  Quality of Life Patient-Reported Outcomes (PROs)
• HAQ
• SF-36
• PET Top 5
• Physical Function and Standard of Care
• Correlation of HAQ with SF-36
• Review of Terminology
• MCID
• NNT

13
Physical Function in Rheumatoid Arthritis

• Impairment in performance of physical activities
  due to active RA has significant effects on
  day-to-day function and health-related quality of
  life
• Inability to perform activities of daily living
  can occur early in disease1
• 50 of patients cannot gainfully work within 10
  years of onset2
• Measures of physical function predict work
  disability, joint replacement and premature
  mortality3,4

1 Fries et al. AR. 199639616-622. 2
Gremillion et al. RA. 19881032103-123. 3
Wolfe et al. J Rheumatol. 1991181290-1297. 4
Wolfe F. Am J of Managed Care. 19995S852-859.
14
Patient-Reported Outcomes (PROs)

• Symptom improvement, as reported by the patient,
  has frequently been the only means of detecting
  treatment effect (e.g. pain)
• Patient-reported measures have always been
  fundamental part of the drug development process
• Recently PROs including health-related quality of
  life and physical function have become a focus of
  drug development

15
Health Assessment Questionnaire (HAQ)

• Accepted, validated instrument to assess physical
  function widely used in RA
• Gold Standard OMERACT/FDA Guidance
• 20 questions covering 8 subscales
• HAQ Disability Index (HAQ DI)
• Scores the worst items within each of the eight
  scales based on use of aids and devices
• Included in all three Phase III trials

16
Physical Function and Annual Costs
14000
12000
10000
8000
Annual Direct Costs ()
6000
4000
2000
0
0 - 0.5
0.5 - 1.0
1.0 - 1.5
2.5 - 3.0
1.5 - 2.0
2.0 - 2.5
HAQ Disability Index
Singh et al. Arthritis Rheum. 199639(suppl)S318.
17
Disability in RA with Standard Care
70
60
50
Wolfe et al
40
Lassere et al
Percent Maximum Disability
Sherrer et al
30
Scott et al
20
10
0
7
12
18
Disease Duration (years)
Scott DL et al. Rheumatol. 200039122-132.
18
Progression of HAQ DIwith Standard Care
1993 Gardiner 0.03 points/year1 1996 Fries 0.017
points/year2 1998 Monroe 0.119
points/year3 2000 Uhlig Stabilized4 2000 Young St
abilized5
1Gardiner et al. Br J Rheumatol. 199332724-728.
2Fries et al. Arth Rheum. 199639616-622. 3Monr
oe et al. Ann Rheum Dis. 19985788-93. 4Uhlig
et al. Rheumatol. 200039732-741. 5Young et al.
Rheumatol. 200039603-611.
19
Infliximab Mean HAQ DI Over Time ATTRACT
Year-2 Patients 0 to 24 Months
All Infliximab MTX
PBO MTX
ITT (n340) (n86) Completed 54
weeks (n296) (n50)
Improved
Kavanaugh et al AR. 200043S147.
20
Etanercept Mean HAQ DI Over Time ERA Year-2
Patients 0 to 24 Months
Etanercept 25mg(n 177)
Improved
Genovese et al AR. 2002461443-50.
21
Leflunomide Mean Improvement in HAQ DI Over
TimeYear-2 Cohorts - 0 to 24 Months
MN301/3/5 (n51)
MN302/4(n248)
US301(n97)
Improved
22
Problem Elicitation Technique(PET Top 5)

• Self-administered questionnaire to assess
• Individual patients difficulty in performing
  specific physical activities
• Importance of these physical activities to that
  patient
• Score difficulty x importance (0-49)
• Higher scores indicate a higher degree of
  perceived difficulty on activities

23
Short Form-36 (SF-36)

• Validated, widely used, self-administered generic
  measure of health-related quality of life
• 8 Domains (0-100) 2 Summary Scores
• Physical Component Summary Score (PCS)
• Mental Component Summary Score (MCS)
• Incorporated in US301 as part of OMERACT
  recommendation, prior to FDA draft Guidance
  document
• Not included in European studies (initiated 1994)
  
• Validated translations not available

24
Baseline SF-36 Scores US Norms vs US301 Study
Population
RA Study Population
US Norms (A/G Adjusted)
100
90
80
70
60
50
40
30
20
10
0
PhysicalFunction
RolePhysical
BodilyPain
GeneralHealthPerception
Vitality
Social Function
RoleEmotion
MentalHealth
25
SF-36 Two-Component Summary Scores
PhysicalComponent (PCS)
PhysicalFunction
RolePhysical
BodilyPain
GeneralHealth
SocialFunction
RoleEmotion
MentalHealth
Vitality
MentalComponent (MCS)
26
Physical Activities AssessedHAQ vs SF-36
Physical Function Domain
Activities Assessed HAQ SF-36
Walking x xClimbing Steps x xReaching xGetting
in and out of a car xArising xReaching over
head xGripping xEating x xSelf care
ADLs Hygiene x Dressing, grooming x xInstrument
al Activities xDiscretionary Activities Walking
gt 1 mile x Climbing several sets of
stairs x Moderate activities x Vigorous
activities x
27
Correlation Between HAQ and SF-36
Reference Study Scales Correlation Ruta1 PCS -0.
77 Talamo2 PF -0.72 Kavanaugh3
Infliximab/ATTRACT PCS -0.51 PF -0.54 Kosinski4
Etanercept/ERA PCS -0.60 PF -0.61 Lubeck5 Etane
rcept/RAPOLO PCS -0.79 PF -0.82 Strand6 Leflunom
ide/US301 PCS -0.60 PF -0.74
1Ruta et al. Br J Rheum. 199837425-436.2Talamo
et al. Br J Rheum. 199736463-469.3Kavanaugh et
al. AR. 200043S147.4Kosinski et al. Medical
Care. 199937MS23-39.5Lubeck et al. Value in
Health. 20014MS2,163.6Strand et al. AR.
200144S187.
28
Minimum Clinically Important Differences (MCID)

• Reflect degree of improvement in various outcome
  measures in rheumatoid arthritis
• Perceptible to patients
• Considered clinically important/meaningful
• Developed by statistical correlations with
  clinical and patient-reported outcomes measures
• When group median (and mean) changes well exceed
  MCID, it can be expected that a majority of
  patients will attain clinically meaningful
  improvement

29
Minimum Clinically Important Differences (MCID)
Score Direction of Range Improvement MCID
HAQ DI1-4 0-3 ? -0.22 PET Top 51,4 0-49 ? -5
points SF-36 Domains2,5-7 0-100 ? 5 to 10
points SF-36 PCS/MCS 5010 ? 2.5 to 5 points
mean
1 Guzman et al. AR. 1996395208. 2 Kosinski et
al. AR. 2000431478-87. 3 Redelmeier et al.
Arch Intern Med. 19931531337-42. 4 Wells et
al. J Rheumatol. 199320557-60. 5 Kosinski et
al. AR. 200043S140. 6 Samsa et al.
Pharmacoeconomics. 199915(2)141-155. 7 Thumboo
et al. J Rheumatol. 199926(1)97-102.
30
Number Needed to Treat (NNT)

• NNT refers to the number of patients who need to
  be treated to obtain one additional benefit
  beyond what would have been experienced on the
  alternative therapy
• Formally introduced by Laupacis, Sackett and
  Roberts, NEJM. 1988
• Conveys amount of effort needed to gain a
  positive response
• NNT 1/Net Benefit
• Important in interpretation of results

31
Importance of Physical Function in Rheumatoid
Arthritis

• A major treatment goal is improving signs and
  symptoms
• Another clinically meaningful goal is
  patient-reported improvement in physical function
  and health-related quality of life
• Improvement in physical function is reflected by
  improvement in HRQOL as evidenced by correlations
  demonstrated in randomized controlled trials of
  new therapies in RA including leflunomide

32
Leflunomide Presentation Agenda

• Introduction Michael Rozycki, PhD
• Patient-Reported Outcomes Joseph Doyle, RPh, MBA
• Clinical Efficacy Physical Function Karen
  Simpson, MD US Medical Affairs Aventis
  Pharmaceuticals
• Conclusions Michael Rozycki, PhD

33
Clinical Efficacy Physical Function and
Health-Related Quality of Life

• Pivotal Studies
• Study Designs
• Patient Populations and Disposition
• Results
• Efficacy Summary

34
Phase III LeflunomideRandomized Controlled Trials
6 months
24 months
12 months
US301
LEF MTX PBO
MN301
MN303
MN305
LEF SSZ PBO
MN304
MN302
LEF MTX
LEFleflunomide MTXmethotrexate
SSZsulfasalazine PBOplacebo
35
Phase III Study Cohorts
ITT Cohort
Year-2 Cohort
ACR?20
ACR?20
ACR?20
X-ray
X-ray
X-ray (MN301)
Physical FunctionHRQOL (US301)
Physical FunctionHRQOL (US301)
Physical Function
6 months
24 months
12 months
US301
MN301
MN303
MN305
MN304
MN302
36
Phase III Study Cohorts
ITT Cohort
Year-2 Cohort
BENEFIT
MAINTENANCE
6 months
24 months
12 months
US301
MN301
MN303
MN305
MN304
MN302
37
Phase III LeflunomideRandomized Controlled Trials
US301 N 508 Control Placebo MTX 7.5 ?
20mg/wk MTX Mean 11.7 Yr-1 12.6 Yr-2 MTX
Median 15 Yr-1 15 Yr-2 Duration 24
mos Initiated 1995 Countries US Canada
38
Phase III LeflunomideRandomized Controlled Trials
US301 MN301/3/5 N 508 358 Control Placebo Plac
ebo MTX 7.5 ? 20mg/wk SSZ 0.5 ? 2gm/d MTX
Mean 11.7 Yr-1 12.6 Yr-2 MTX Median 15 Yr-1
15 Yr-2 Duration 24 mos 6?12?24
mos Initiated 1995 1994 Countries US Europe Ca
nada South Africa Australia
39
Phase III LeflunomideRandomized Controlled Trials
US301 MN301/3/5 MN302/4 N 508 358 999 Control Pl
acebo Placebo MTX 7.5 ? 20mg/wk SSZ 0.5 ?
2gm/d MTX 7.5 ? 15 mg/wk MTX Mean 11.7 Yr-1
12.6 Yr-2 11.9 Yr-1 12.2 Yr-2 MTX Median 15
Yr-1 15 Yr-2 10 Yr-1 10 Yr-2 Duration 24
mos 6?12?24 mos 12?24 mos Initiated 1995 1994 1994
Countries US Europe Europe Canada South
Africa South Africa Australia
40
Clinical Efficacy Physical Function and
Health-Related Quality of Life

• Pivotal Studies
• Study Designs
• Patient Populations and Disposition
• Results
• Efficacy Summary

41
US301 Study Completion Rates
LEF PBO MTX
n () n () n () ITT patients
enrolled 190 (100) 128 (100) 190 (100) Completed
12 mo (Y2C) 98 (52) 36 (28) 101 (53) Completed
24 mo 83 (44) 27 (21) 80 (42)
(85 of Y2C)
(75 of Y2C)
(79 of Y2C)
Y2C Year-2 Cohort
42
US301 Study Completion Rates
LEF PBO MTX
n () n () n () ITT patients
enrolled 190 (100) 128 (100) 190 (100) Completed
12 mo (Y2C) 98 (52) 36 (28) 101 (53) Completed
24 mo 83 (44) 27 (21) 80 (42)
(85 of Y2C)
(75 of Y2C)
(79 of Y2C)
Withdrew prior to 12 mo 92 (48) 92 (72) 89 (47) E
ntered Alternate Tx 25 (13) 56 (44) 35 (18) Compl
eted Alternate Tx 16 (8) 34 (27) 17 (9)
Total Completing Protocol 99 (52) 61 (48) 97 (51)
Y2C Year-2 Cohort
43
US301 Discontinuation Due to Lack of
EfficacyITT Cohort
MTX
PBO
LEF
100
90
80
70
60
Percent
50
40
30
20
10
0
0
3
6
9
12
15
18
21
24
Months
44
MN301/3/5 Study Completion Rates
LEF PBO SSZ
n () n () n () ITT patients enrolled in
MN301 133 (100) 92 (100) 133 (100) Completed 6
mo 96 (72) 51 (55) 83 (62) Enrolled in
MN303 80 (60) 76 (57) Completed 12
mo 71 (53) 68 (51) Enrolled in MN305
(Y2C) 60 (45) 60 (45) Completed 24
mo 53 (40) 47 (35)
41 to SSZ
(88 of Y2C)
(78 of Y2C)
Y2C Year-2 Cohort
45
MN302/4 Study Completion Rates
LEF MTX
n () n () ITT patients enrolled in
MN302 501 (100) 498 (100) Completed 12
mo 349 (70) 387 (78) Enrolled in MN304
(Y2C) 292 (58) 320 (64) Completed 24
mo 256 (51) 277 (56)
(87 of Y2C)
(88 of Y2C)
Y2C Year-2 Cohort
46
Baseline CharacteristicsITT Cohorts

• US301 MN301 MN302 (508) (358) (999)
• Mean Age (years) 54 59 58
• Mean DiseaseDuration (years) 6.7 7.0 3.7
• ?2 Years () 38 41 43
• ?10 Years () 22 28 3
• Mean DMARDs 0.9 0.9 1.1
• No PriorDMARD () 42 47 33
• HAQ DI 1.3 1.6 1.5

47
Baseline CharacteristicsYear-2 Cohort

• US301 MN301/3/5 MN302/4 (235) (120) (612)
• Mean Age (years) 54 58 57
• Mean DiseaseDuration (years) 6.9 6.2 3.7
• ?2 Years () 39 43 45
• ?10 Years () 25 25 3
• Mean DMARDs 0.9 0.8 1.1
• No PriorDMARD () 44 47 34
• HAQ DI 1.2 1.6 1.5

48
Clinical Efficacy Physical Function and
Health-Related Quality of Life

• Pivotal Studies
• Study Designs
• Patient Populations and Disposition
• Results
• Efficacy Summary

49
US301 ACR20 Responders Over Time ITT Cohort
0-12 Months (LOCF)
LEF
MTX
PBO
90
ITT (n186) (n188) (n128)
80
70
60

Responders
52
50
44
40
30
26
20
10
0
3
6
9
12
18
24
1
Months
LEF vs PBO p?0.0001LEF vs MTX pNS
50
US301 ACR20 Responders Over Time ITT Cohort
0-24 Months
LEF
MTX
PBO
90
ITT (n186) (n188) (n128)
80
70
60
53
Responders
50
48
40
30
20
10
0
3
6
9
12
18
24
1
Months
LEF vs MTX pNS
51
Results

• Patient-reported outcomes
• ITT Cohort improvement at 6 or 12 month
  primary study endpoints
• Year-2 Cohort maintenance of benefit from
  month 12 to month 24

52
HAQ DI Improvement Across Studies ITT Cohort at
6 or 12 Month Endpoint
LEF
MTX
PBO
12 MonthsUS301
(166) 1.3
(101) 1.3
(169) 1.3
BL
0
-0.03
Mean Change from Baseline
-0.22
-0.26
-0.45
-0.5

Improved
LEF vs PBO plt0.001LEF vs MTX plt0.01
-1
53
HAQ DI Improvement Across Studies ITT Cohort at
6 or 12 Month Endpoint
LEF
MTX
PBO
SSZ
12 MonthsUS301
6 MonthsMN301
(113) 1.7
(81) 1.6
(111) 1.5
(166) 1.3
(101) 1.3
(169) 1.3
BL
0
-0.03
-0.08
Mean Change from Baseline
-0.22
-0.26
-0.37
-0.45
-0.5

-0.56
Improved

LEF vs PBO plt0.001LEF vs SSZ plt0.05
LEF vs PBO plt0.001LEF vs MTX plt0.01
-1
54
HAQ DI Improvement Across Studies ITT Cohort at
6 or 12 Month Endpoint
LEF
MTX
PBO
SSZ
12 MonthsUS301
12 MonthsMN302
6 MonthsMN301
(464) 1.5
(463) 1.5
(113) 1.7
(81) 1.6
(111) 1.5
(166) 1.3
(101) 1.3
(169) 1.3
BL
0
-0.03
-0.08
Mean Change from Baseline
-0.22
-0.26
-0.37
-0.44
-0.45
-0.5

-0.54
-0.56
Improved


LEF vs PBO plt0.001LEF vs SSZ plt0.05
LEF vs PBO plt0.001LEF vs MTX plt0.01
MTX vs LEF plt0.05
-1
55
US301 Improvement in HAQ Subscales ITT Cohort
at 12 Months
PBO
LEF
MTX
0.25
HAQ DI BL 1.3 BL 1.3 BL 1.3 n 166 n
169 n 101
0
-0.22
Mean Change from Baseline




-0.5




Arising
Eating
Hygiene
Dressing
Walking
Gripping
Reaching
Activities
Improved
LEF vs PBO plt0.05 LEF vs MTX plt0.05
-1
56
Mean HAQ DI Over Time US301 Year-2 Cohort
Baseline
Month 6
Month 12
Month 18
Month 24
2
achieving MCID LEF 71 MTX 59
LEF (n97)
MTX (n101)
1.5
1.2
1.2
1
0.9
0.8
0.8
31
Improved
50
0.7
0.5
0.6
0.6

LEF vs MTX plt0.01
0
57
Mean HAQ DI Over TimeMN301/3/5 Year-2 Cohort
Baseline
Month 6
Month 12
Month 18
Month 24
2
achieving MCID LEF 80 SSZ 71
1.6
LEF (n51)
SSZ (n46)
1.5
1.5
37
1
0.9
0.9
0.9
46
0.9
0.9
Improved
0.8
0.5
0
58
Mean HAQ DI Over Time MN302/4 Year-2 Cohort
Baseline
Month 6
Month 12
Month 18
Month 24
2
achieving MCID LEF 67 MTX 73
LEF (n248)
MTX (n273)
1.5
1.5
1.1
1.0
32
0.9
1
1.0
37
0.9
0.9
Improved
0.5
0
59
HAQ DI Improvement Across Studies Year-2 Cohort
at 24 Months
LEF
MTX
US301
(97) 1.2
(101) 1.2
BL
0
-0.22
Mean Change from Baseline
-0.37
-0.5
Improved
-0.6

LEF vs MTX p0.005
-1
60
HAQ DI Improvement Across Studies Year-2 Cohort
at 24 Months
LEF
MTX
SSZ
US301
MN301/3/5
(51) 1.6
(46) 1.5
(97) 1.2
(101) 1.2
BL
0
-0.22
Mean Change from Baseline
-0.37
-0.5
Improved
-0.6
-0.56

-0.73
LEF vs MTX p0.005
-1
61
HAQ DI Improvement Across Studies Year-2 Cohort
at 24 Months
LEF
MTX
SSZ
US301
MN302/4
MN301/3/5
(248) 1.5
(273) 1.5
(51) 1.6
(46) 1.5
(97) 1.2
(101) 1.2
BL
0
-0.22
Mean Change from Baseline
-0.37
-0.5
-0.48
Improved
-0.6
-0.56
-0.56

-0.73
LEF vs MTX p0.005
-1
62
HAQ Disability Index Summary

• Leflunomide significantly improved physical
  function
• Placebo-controlled 6 month trial
• Placebo-controlled 12 month trial
• Non-placebo controlled 12 month trial confirming
  a consistent degree of improvement
• Improvement was maintained in patients continuing
  for a second year of blinded treatment

63
Baseline SF-36 Scores US Norms vs US301
Population
RA Study Population
US Norms (A/G Adjusted)
100
90
80
70
60
50
40
30
20
10
0
PhysicalFunction
RolePhysical
BodilyPain
GeneralHealthPerception
Vitality
Social Function
RoleEmotion
MentalHealth
64
US301 Improvement in SF-36 Domains ITT Cohort
at 12 Months
PBO (n101)
LEF (n157)
MTX (n162)
24


20
Improved
16



12

Mean Change from Baseline
8

4
0
Physical Role Bodily General Vitality Social Role
MentalFunction Physical Pain Health Function Emo
tion Health Perception
-4
LEF vs PBO plt0.05LEF vs MTX plt0.05
65
US301 SF-36 Domain Scores Year-2 Cohort at 24
Months Leflunomide and Methotrexate
US Norms (A/G Adjusted)
Baseline Year-2 Cohort
90
80
Improved
70
60
Mean Scores
50
40
30
20
10
0
Physical Role Bodily General Vitality Social Role
Mental Function Physical Pain Health Function E
motion Health Perception
66
US301 SF-36 Domain Scores Year-2 Cohort at 24
Months Leflunomide and Methotrexate
US Norms (A/G Adjusted)
LEF 24 Months (n 93)
Baseline Year-2 Cohort
MTX 24 Months (n 89)
90
80
Improved
70
60
Mean Scores
50
40
30
20
10
0
Physical Role Bodily General Vitality Social Role
Mental Function Physical Pain Health Function E
motion Health Perception
67
US301 SF-36 Domain Scores Leflunomide Year-2
Cohort at Months 12 and 24
US Norms (A/G Adjusted)
LEF Baseline Year-2 Cohort
90
80
Improved
70
60
Mean Scores
50
40
30
20
10
0
Physical Role Bodily General Vitality Social Role
Mental Function Physical Pain Health Function Em
otion Health Perception
68
US301 SF-36 Domain Scores Leflunomide Year-2
Cohort at Months 12 and 24
US Norms (A/G Adjusted)
12 Months (n 93)
LEF Baseline Year-2 Cohort
24 Months (n 93)
90
80
Improved
70
60
Mean Scores
50
40
30
20
10
0
Physical Role Bodily General Vitality Social Role
Mental Function Physical Pain Health Function Em
otion Health Perception
69
US301 Improvement in PCS Scores Leflunomide and
Methotrexate Year-2 Cohort
60
US Norm
Improved
50
42.7
41.7
38.6
38.8
40
2 SDs below US Norm
30.9
30.2
Mean Scores
30
20
10
0
BL
12 M
24 M
BL
12 M
24 M
LEF (n97)
MTX (n101)
PCS
70
Number Needed to Treat to Achieve MCID at 12
Months in US301

• LEF vs. PBO MTX vs. PBO
• HAQ DI 3 6 MCID -0.22
• SF-36 PCS 5 17 MCID 5.0

Strand et al. AR. 200144S187.
71
Patient-Reported Improvements

• SF-36 Health Transition Question (US301)
• Compared to one year ago, how would you rate
  your health in general now?
• HAQ DI MCID - LEF patients
• 91 who achieved MCID stated they improved
• Of those who said they improved,75 achieved
  MCID
• SF-36 PCS MCID - LEF patients
• 89 who achieved MCID stated they improved
• Of those who said they improved,64 achieved MCID

72
Correlation of HAQ DI with SF-36 PCS US301
Leflunomide ITT
1
SF-36 PCS
0.5
-20
-10
10
20
30
40
-0.5
-1
-1.5
R - 0.60
-2
-2.5
HAQ DI
73
Year-2 Cohorts at 24 MonthsResponses in HAQ DI
LEF (n400)
MTX (n380)
SSZ (n46)
84
17
US301
31
69
14
86
MN301/3/5
18
82
26
74
MN302/4
22
78
Worsened
Same/Improved
100
100
0
Any worsening from baseline to month 24
74
Responses in Patient-Reported Outcomes US301
Year-2 Cohort at 24 Months
LEF (n 97)
MTX (n101)
100
100
0
Worsened
Same/Improved
Any worsening from baseline to month 24
75
Clinical Efficacy Physical Function and
Health-Related Quality of Life

• Pivotal Studies
• Study Designs
• Patient Populations and Disposition
• Results
• Efficacy Summary

76
Conclusions

• Leflunomide therapy has demonstrated efficacy by
  ACR criteria and X-ray progression as reflected
  in the product labeling
• Leflunomide improves physical function
• Maintained in second year of treatment
• Reflected in improvements in health-related
  quality of life
• Clinically meaningful to patients
• Consistent across 3 studies with 2 year
  double-blind data sets

77
Leflunomide Presentation Agenda

• Introduction Michael Rozycki, PhD
• Patient-Reported Outcomes Joseph Doyle, RPh, MBA
• Clinical Efficacy Physical Function Karen
  Simpson, MD
• Conclusions Michael Rozycki, PhD US Regulatory
  Affairs Aventis Pharmaceuticals

78
Physical Function Summary

• Aventis believes that Improvement in Physical
  Function is the appropriate term for claims for
  physical function
• Aventis believes 12 months of data is adequate to
  establish a claim for improvement in physical
  function
• Clinical improvement is observed as early as 6
  weeks after initiating treatment with
  leflunomide
• Statistically significant improvement is observed
  at 6 or 12 months
• Benefits are maintained at 24 months in the vast
  majority of patients who continue therapy

79
Physical Function Summary

• Data indicate that placebo-controlled trials are
  not necessary or appropriate for demonstration of
  maintenance of effect
• Results for patient-reported outcome measures
  were consistent across 3 studies involving a
  total of 824 patients, of whom 450 entered a
  second year of treatment
• In study US301, which used multiple
  patient-reported outcome measures, efficacy
  results were consistent across measures

80
FDA Arthritis Advisory CommitteeMarch 5, 2003

• ARAVA (Leflunomide)
• Aventis Pharmaceuticals

81
Leflunomide Presentation Agenda

• Introduction Michael Rozycki, PhD US Regulatory
  Affairs Aventis Pharmaceuticals
• Epidemiology Overview William Holden, PhD
• Benefit-Risk Synopsis Vibeke Strand, MD
• Conclusions Michael Rozycki, PhD

82
Leflunomide Benefit-Risk

• Leflunomide is an effective and unique treatment
  for RA
• unique mechanism of action
• indicated to treat signs and symptoms, retard
  radiographic progression and improve physical
  function
• critical therapeutic option for patients with RA
• Leflunomide safety profile is well established
• Benefit risk profile for leflunomide and other
  DMARDs is comparable and justifies continued use
  for treatment of RA

83
Leflunomide Presentation Agenda

• Introduction Michael Rozycki, PhD
• Epidemiology Overview William Holden,
  PhD Aventis Pharmaceuticals
• Benefit-Risk Synopsis Vibeke Strand, MD
• Conclusions Michael Rozycki, PhD

84
Pharmacovigilance and Epidemiology Overview

• Pooled analysis of clinical trials
• Reporting rate analysis/liver transplant data
• Aetna cohort study
• Nested case-control study

85
Pharmacovigilance and Epidemiology Overview

• Pooled analysis of clinical trials
• Reporting rate analysis/liver transplant data
• Aetna cohort study
• Nested case-control study

86
Pooled Analysis Data Sources

• Phase II
• YU201/202 n 23
• YU203 n 402
• YU204 n 54
• YU206 n 49
• US201 n 23
• LEF pts 449
• All pts 551

• Phase III
• US301 n 508
• MN301 n 358
• MN302 n 999
• 3006 n 39
• 3012 n 402
• LEF pts 1244
• All pts 2306

Total LEF 1693 pts, 2533 PY
Grand total 2857 pts, 4262 PY
PY Patient years
87
Serious Adverse EventsCumulative Rates Per 100
PY - 6 Months
6
5
Infection
4
3
CV/TE
MTX
Pulmonary
2
Malignancy
Hepatic AEs
1
Cutaneous
Hypertension
0
0
1
2
3
4
5
6
LEF
88
Serious Adverse EventsCumulative Rates Per 100
PY - 12 Months
6
5
Infection
4
CV/TE
3
MTX
2
Pulmonary
Malignancy
Hepatic AEs
1
Hypertension
Cutaneous
0
0
1
2
3
4
5
6
LEF
89
Serious Adverse EventsCumulative Rates Per 100
PY - 24 Months
6
5
Infection
4
3
CV/TE
MTX
Pulmonary
2
Malignancy
Hepatic AEs
1
Cutaneous
Hypertension
0
0
1
2
3
4
5
LEF
90
Hepatic Adverse EventsCumulative Rates Per 100
PY - 6 Months
30
Hepatic AEs
25
AST/ALT gt 3x ULN
20
15
MTX
AST/ALT gt 5x ULN
10
5
AST/ALT gt 10x ULN
0
0
5
10
15
20
25
30
LEF
91
Hepatic Adverse EventsCumulative Rates Per 100
PY - 12 Months
25
Hepatic AEs
20
AST/ALT gt 3x ULN
15
MTX
10
AST/ALT gt 5x ULN
5
AST/ALT gt 10x ULN
0
0
5
10
15
20
25
LEF
92
Hepatic Adverse EventsCumulative Rates Per 100
PY - 24 Months
18
Hepatic AEs
15
AST/ALT gt 3x ULN
12
9
MTX
AST/ALT gt 5x ULN
6
3
AST/ALT gt 10x ULN
0
0
3
6
9
12
15
18
LEF
93
Serious Adverse EventsCumulative Rates Per 100
PY - 6 Months
8
Pulmonary
7
Infection
6
5
Hepatic AEs
4
SSZ
CV/TE
3
Malignancy
2
Hypertension
1
Cutaneous
0
0
2
4
6
8
LEF
94
Serious Adverse EventsCumulative Rates Per 100
PY - 12 Months
6
Pulmonary
5
4
Infection
HepaticAEs
3
SSZ
CV/TE
Malignancy
2
Hypertension
1
Cutaneous
0
0
1
2
3
4
5
6
LEF
95
Serious Adverse EventsCumulative Rates Per 100
PY - 24 Months
5
Pulmonary
4
Infection
3
SSZ
Malignancy
2
HepaticAEs
CV/TE
Hypertension
1
Cutaneous
0
0
1
2
3
4
5
LEF
96
Hepatic Adverse EventsCumulative Rates Per 100
PY - 6 Months
12
10
AST/ALT gt 3x ULN
Hepatic AEs
8
6
AST/ALT gt 5x ULN
SSZ
4
AST/ALT gt 10x ULN
2
0
0
2
4
6
8
10
12
LEF
97
Hepatic Adverse EventsCumulative Rates Per 100
PY - 12 Months
10
Hepatic AEs
8
AST/ALT gt 3x ULN
6
SSZ
AST/ALTgt 5x ULN
4
2
AST/ALT gt 10x ULN
0
0
2
4
6
8
10
LEF
98
Hepatic Adverse EventsCumulative Rates Per 100
PY - 24 Months
6
Hepatic AEs
AST/ALT gt 3x ULN
SSZ
3
AST/ALT gt 5x ULN
AST/ALT gt 10x ULN
0
0
3
6
LEF
99
Pooled AnalysisConclusions

• Relative to MTX, leflunomide had comparable
  serious hepatic events (more hypertension and
  cutaneous), fewer transaminase elevations
• Relative to SSZ, leflunomide had generally fewer
  serious AEs (more cutaneous infection),
  comparable hepatic events, fewer elevated
  transaminases
• No clear evidence of increased risk

100
Pharmacovigilance and Epidemiology Overview

• Pooled analysis of clinical trials
• Reporting rate analysis/liver transplant data
• Aetna cohort study
• Nested case-control study

101
Spontaneous ReportsLimitations And Biases

• AE may be related to the disease being treated
• Reporting rates are measures of reporting
  intensity
• Factors affecting reporting rates
• Time since launch
• Severity of AE
• Health care provider inclination to report
• Under-reporting

102
Spontaneous Reports

• Prioritize safety reviews
• Events evaluated in detail
• Standardized questionnaires for follow-up
• Aid in identification of signals arising in
  specific reporting periods
• Facilitate discussions with regulatory agencies
  worldwide
• Focus endpoints for epidemiologic evaluation

103
Global US Leflunomide UseEstimated Person-year
(PY) Exposure, IMS Data
90,000
80,000
US
70,000
ROW
60,000
50,000
40,000
30,000
20,000
10,000
0
Q4 98-
Q2 99-
Q4 99-
Q2 00-
Q4 00-
Q2 01-
Q4 01-
Q2 02-
Q1 99
Q3 99
Q1 00
Q3 00
Q1 01
Q3 01
Q1 02
Q3 02
Cumulative through Sept 2002 405,000
PY Cumulative through Dec 2002 450,000 PY
104
Reporting RatesHepatic Failure (FDA IMS Data)

• Cumulative rates per 100,000 PY (95 CI) through
  June 2002
• LEF 8.2 (5-11)
• INFLIX 7.9 (4-11)
• ETAN 7.0 (3-11)
• MTX 0.5

Hepatic Failure Reports/100,000 PY
105
Reported Cases of Hepatic FailureFDA AERS
Database
12
LEF
MTX
10
ETAN
8
INFLIX
6
4
2
0
4Q98-
2Q99-
4Q99-
2Q00-
4Q00-
2Q01-
4Q01-
2Q02
1Q99
3Q99
1Q00
3Q00
1Q01
3Q01
1Q02
106
UNOS DataLiver Transplant Etiology
LEF
10
MTX
9
8
7
6
Number of Transplants
5
4
3
2
1
0
1998
1999
2000
2001
2002
2 transplant cases 1 US, 1 Italy
107
Pharmacovigilance and Epidemiology Overview

• Pooled analysis of clinical trials
• Reporting rate analysis/liver transplant data
• Aetna cohort study
• Nested case-control study

108
Study Design

• Retrospective cohort study
• Aetna-US Healthcare claims database
• 6.5 million covered lives
• Over 5,000 leflunomide patients
• All outpatient and hospital claims captured
• All dispensed prescriptions captured
• Time of follow-up
• September 1998 through December 2000
• RA and diagnoses identified through ICD-9-CM
  codes

109
Study Design

• Cohort
• Patients diagnosed with RA who received
  leflunomide, methotrexate or another DMARD,
  including biologic DMARDs
• Patients 18 years or older at entry
• Date of DMARD Rx after September 1, 1998
• Patients with hepatic endpoints of interest in
  the 3 months prior to entry were excluded
• Endpoints
• Primary hepatic events (hepatic necrosis,
  hepatic coma, non-infectious hepatitis,
  hepatocellular jaundice, cirrhosis, elevated
  enzymes, non-specific liver disease)
• Secondary severe cutaneous (SJS/TEN),
  hypertension, respiratory (bronchitis,
  influenza), hematologic (aplastic anemia,
  pancytopenia), pancreatitis

110
Study Design

• Exposure measurement
• Identified through dispensed prescription data
• Leflunomide monotherapy
• Methotrexate monotherapy
• Other DMARD monotherapy
• Leflunomide combinations
• Methotrexate combinations
• Other DMARDs
• biologics etanercept, infliximab
• others sulfasalazine, hydroxychloroquine,
  penicillamine, gold, minocycline,
  cyclophosphamide, cyclosporine

111
Study Design

• Covariates
• Age
• Gender
• Comorbidities
• Analysis
• Description of the cohort
• Age, gender, person-time
• Poisson regression to estimate incidence rates

112
Aetna Cohort Study Limitations

• Lack of indicators for disease severity
• No direct measure of joint counts, HAQ scores,
  acute phase reactants or erosion scores
• Limited clinical detail
• No data on use of OTC medications
• No detailed clinical history of RA, prior
  treatment and hospitalization
• Inability to distinguish biologic DMARD use from
  other DMARD use
• Limited access to raw data
• Used third party

113
Aetna Cohort StudyResults

• 40,594 RA patients identified
• Crude RA prevalence 0.63
• 74 women
• Most in age range 5164 years
• 81 on monotherapy or 2 drug combinations
• Total follow-up of 83,143 person-years (PY)
• DMARD alone or in combination 71,884 PY
• Leflunomide 11,180 PY

114
Aetna Cohort StudyResults

• Exposure groups were comparable
• Age, gender, mean exposure times
• Comorbidities
• Comparable between leflunomide and methotrexate
  and DMARD exposure groups
• Validation
• 20 sample of all hepatic events
• 100 agreement for hepatic necrosis (all cases
  reviewed and validated)
• 83 overall agreement

115
Aetna cohort studyCase validation process

• Aetna requested office/hospital notes and lab
  tests
• Office or hospital site received financial
  incentive to respond
• All responses de-identified and collected
  centrally by Aetna
• A trained clinical assessor reviewed all material
  and completed forms regarding the patient's pre-
  and post-diagnosis status as outlined in abstract
  forms, ref PhRMA/FDA/AASLD. Drug-Induced
  Hepatotoxicity White Paper Postmarketing
  Considerations. November 2000.

116
(No Transcript)
117
(No Transcript)
118
Aetna Database Cohort-wide Incidence Rates
(Events per 1,000 Patient-years, Unadjusted)
160
139
140
120
100
85
Events/1,000 PY
80
60
38
40
20
8
3
1
0.3
0
Hepatic
Any Event
Cutaneous
Respiratory
Pancreatitis
Hematologic
Hypertension
119
Aetna Database Incidence Rates Hepatic
(Events Per 1,000 Patientyears, Adjusted)
16
14
12
10
Events/1,000 PY
8
87
6
4
7
246
22
64
2
19
0
LEF
MTX
DMARD bDMARD
L M
L D
M D
Hepatic acute hepatic necrosis, hepatic coma,
non-infectious hepatitis, hepatocellular
jaundice, cirrhosis, elevated enzymes,
unspecified chronic liver disease, unspecified
liver disease, other unspecified liver disease.
120
Aetna Database Incidence Rates Severe Hepatic
Events (per 1,000 PY, 95 UCL)
5
4.5
4
3.5
N120
N40
3
Severe Hepatic Events/1,000 PY
2.5
N11
2
1.5
1
0.5
0
LEF
MTX
DMARD
Severe Hepatic Events acute hepatic necrosis,
non-infectious hepatitis, hepatocellular
jaundice, cirrhosis.
121
Aetna Database Incidence Rates Acute Hepatic
Necrosis (per 1,000 PY, 95 UCL)
AHN Events/1,000 PY
n 1
n 7
n 2
ICD-9-CM code 570
122
Aetna Cohort StudyConclusions

• Largest RA cohort study ever performed
• Study performed in closed system
• all members known, demographics known
• all dispensed DMARDs captured
• inpatient and outpatient diagnosis claims
  captured
• validated hepatic outcomes
• Direct measure of the strength of association
  between drug exposure and diagnosis
• Channeling bias
• sicker patients ? leflunomide (new drug)
• Rates of hepatic and other events were comparable
  between leflunomide and other DMARD groups

123
Pharmacovigilance and Epidemiology Overview

• Pooled analysis of clinical trials
• Reporting rate analysis/liver transplant data
• Aetna cohort study
• Nested case-control study

124
Study Design

• Nested case-control study
• Data source
• Protocare Sciences claims database, 10 million
  covered lives
• PharMetrics claims database, 16 million covered
  lives
• Time of follow-up September 1998 December 2001
• RA and diagnostic endpoints determined through
• ICD-9-CM codes

125
Study Design

• Cohort
• Patients had RA diagnosis
• Date of Rx for DMARD after September 1, 1998
• Patients 18 years or older at entry
• Patients needed 3 months eligibility prior to
  entry
• Patients with endpoints of interest in the 3
  months prior to entry were excluded
• Endpoints (cases)
• Hospitalized cases
• hepatic, hematologic, cutaneous, pancreatitis,
  pneumonitis
• Hospitalized plus outpatient cases
• lymphoma and opportunistic infection

126
Study Design

• Controls
• 10 to 100 controls matched to each case on date
  of cohort entry
• At risk on the day of the case event
• Exposure measurement
• DMARDs identified from dispensed prescription
  data
• Leflunomide (monotherapy, combination)
• Other DMARDs (hydroxychloroquine, sulfasalazine,
  gold, minocycline, chlorambucil, penicillamine,
  cyclosporine, cyclophosphamide)
• Biologic DMARDs (etanercept, infliximab)
• Methotrexate monotherapy
• NSAIDs, cox-2s, glucocorticoids used as covariates

127
Study Design

• Covariates
• Age
• Gender
• Source of data (Protocare Sciences, PharMetrics)
• Comorbid conditions
• Non-DMARD drugs
• Analysis
• Conditional logistic regression to estimate
  relative risks (RR) during the year prior to
  index date (methotrexate reference)
• Current use of leflunomide prescription within
  90 days of index date
• Past use of leflunomide any other use during
  the year prior to index date

128
Nested Case-control StudyLimitations

• Small number of events
• Serious cutaneous events (n 3)
• Interstitial pneumonitis (n 12)
• Lymphoma (n 5)
• No ability to validate diagnoses

129
Nested Case-control StudyResults

• PharMetrics Protocare Sciences
• 41,885 patients received DMARD after September 1,
  1998
• Mean age 49 (PM) and 59 (PS) years
• 76 female
• ?15 of the cohort patients had leflunomide use
  any time during follow-up
• 51,315 person-years of follow-up

130
Nested Case-control Study Results Cohort-wide
Event Rates
100
90
90
80
70
60
Events/10,000 PY
50
42
40
27
30
16
20
10
5
2
1
0.5
0
Any AE
Hepatic
Infection
Cutaneous
Lymphoma
Pancreatitis
Hematologic
Pneumonitis
131
Nested Case-control Study Results Serious
Hepatic Event Rates
DMARD use Cases Controls Crude Adjusted in
prior year (n25) (n2,500) RR RR 95 CI MTX
only 7 989 1.0 1.0 Ref LEF 2 270 1.1 0.9 0.2 -
4.9 LEF comb 153 1.9 1.6 0.3 - 8.7 LEF
past 76 3.8 2.6 0.4 - 15.5 LEF
mono 0 117 0.0 0.0 LEF current 0 194 0.0 0.0
bDMARDs 4 128 5.2 5.4 1.2 - 24.7 oDMARDs 12 911 1.
9 2.3 0.8 - 6.6
Adjusted for age, gender, data source, non-use
of DMARDs in year prior, use of NSAID, cox-2,
glucocorticoids, and comorbidity
Serious Hepatic Events acute hepatic necrosis,
non-infectious hepatitis, non-alcoholic
cirrhosis, hepatic coma.
132
Leflunomide Hepatic Event Case 1Nested
Case-control Study

• 77 year-old female with RA received MTX for at
  least two years and HCQ for at least 10 months
  prior to addition of LEF therapy
• Received only a one-month LEF prescription nine
  months prior to hospitalization
• Received azathioprine two months prior to
  hospitalization
• Hospital diagnosis of acute and subacute necrosis
  of liver, unspecified hepatitis, hepatic coma,
  and respiratory abnormality

133
Leflunomide Hepatic Event Case 2Nested
Case-control Study

• 55 year-old male with RA received MTX therapy for
  at least 6 months prior to addition of LEF
  therapy
• Received LEF prescriptions for 7 months which
  ended 10 months prior to hospitalization
• Continued MTX therapy until 2 months prior to
  hospitalization
• Azathioprine therapy was added 4 months prior to
  hospitalization and continued up to
  hospitalization
• Hospital diagnosis of abnormal liver tests and
  non-alcoholic cirrhosis

134
Nested Case-control StudyConclusions

• Leflunomide no increase in risk was observed for
  
• All serious events
• Serious hepatic events
• Serious hematologic events
• Serious pancreatic events
• Serious opportunistic infections/septicemia events

135
Pharmacovigilance Epidemiology
ActivitiesSummary of Results

• Pooled analysis of clinical trials
• AE rates of LEF comparable to MTX, SSZ

136
Pharmacovigilance Epidemiology
ActivitiesSummary of Results

• Pooled analysis of clinical trials
• AE rates of LEF comparable to MTX, SSZ
• Reporting rate analysis/liver transplant data
• Hepatic failure rate of LEF comparable to other
  biologic DMARDs

137
Pharmacovigilance Epidemiology
ActivitiesSummary of Results

• Pooled analysis of clinical trials
• AE rates of LEF comparable to MTX, SSZ
• Reporting rate analysis/liver transplant data
• Hepatic failure rate of LEF comparable to other
  biologic DMARDs
• Aetna cohort study
• Hepatic and other event rates of LEF comparable
  to other DMARDs

138
Pharmacovigilance Epidemiology
ActivitiesSummary of Results

• Pooled analysis of clinical trials
• AE rates of LEF comparable to MTX, SSZ
• Reporting rate analysis/liver transplant data
• Hepatic failure rate of LEF comparable to other
  biologic DMARDs
• Aetna cohort study
• Hepatic and other event rates of LEF comparable
  to other DMARDs
• Nested case-control study
• Serious hepatic and other rates of LEF comparable
  to other DMARDs

139
Leflunomide Presentation Agenda

• Conclusions Michael Rozycki, PhD
• Epidemiology Overview William Holden, PhD
• Benefit-Risk Discussion Vibeke Strand,
  MD Biopharmaceutical Consultant Clinical
  Professor Division of Immunology and
  Rheumatology Stanford University
• Conclusions Michael Rozycki, PhD

140
Challenges Current Treatment of RA

• Rheumatoid Arthritis is a Unique and Severe
  Disease
• Heterogeneous population
• Variable disease course substantial morbidity
  and impact on survival
• Long term deterioration in physical function /
  HRQOL
• Relevance of 2 year data in context of 20 years
  disease
• Current Practice has Changed Our Aim is to Halt
  Disease Progression and Improve Physical Function
• Introduction of 5 new DMARD therapies since 1998
• Multiple combination regimens data based on
  accrual of patients naïve to active comparator,
  or failing Rx

141
Limited RA Treatment Armamentarium
There is a frequent need to add or change therapy
in patients with active RA

• No DMARD works in every patient
• Not every patient responds to every DMARD
• Patients have 30-40 years disease duration
• Few if any spontaneous remissions
• Few if any cures
• Tachyphylaxis develops frequently

142
Efficacy Benefits of Leflunomide

• Demonstrated efficacy in RCTs
• By ACR Criteria
• Inhibit x-ray progression
• Improvement in outcomes important to patients
• Performance of physical activities importantto
  them
• Which results in improvements in ALL domains of
  health-related quality of life
• Comparable to MTX and the biologic DMARDs

143
Leflunomide and Methotrexateare Comparable Over
2 Years
LEF ACR20
100
MTX ACR20
77
77
65
60
Responders
50
0
12 M
24 M
12 M
24 M
12 M
24 M
12 M
24 M
(n98)
(n101)
(n286)
(n314)
US301
MN302/304
LEF vs MTX pNS at 12 months
MTX vs LEF plt0.05 at 12 months
144
Leflunomide and Methotrexateare Comparable Over
2 Years
LEF ACR20
100
MTX ACR20
79
77
77
72
67
65
64
60
Responders
50
0
12 M
24 M
12 M
24 M
12 M
24 M
12 M
24 M
(n98)
(n101)
(n286)
(n314)
US301
MN302/304
LEF vs MTX pNS at 12 months LEF vs MTX plt0.05
at 24 months
MTX vs LEF plt0.05 at 12 months MTX vs LEF pNS
at 24 months
145
Leflunomide and Methotrexateare Comparable Over
2 Years
LEF ACR20
100
MTX ACR20
LEF ACR50
MTX ACR50
79
77
77
72
67
65
64
60
57
56
50
49
Responders
50
45
43
39
32
0
12 M
24 M
12 M
24 M
12 M
24 M
12 M
24 M
(n98)
(n101)
(n286)
(n314)
US301
MN302/304
LEF vs MTX pNS at 12 months LEF vs MTX plt0.05
at 24 months
MTX vs LEF plt0.05 at 12 months MTX vs LEF pNS
at 24 months
146
Leflunomide and Methotrexateare Comparable Over
2 Years
LEF ACR20
100
MTX ACR20
LEF ACR50
MTX ACR50
LEF ACR70
MTX ACR70
79
77
77
72
67
65
64
60
57
56
50
49
Responders
50
45
43
39
32
32
26
21
20
16
15
13
11
0
12 M
24 M
12 M
24 M
12 M
24 M
12 M
24 M
(n98)
(n101)
(n286)
(n314)
US301
MN302/304
LEF vs MTX pNS at 12 months LEF vs MTX plt0.05
at 24 months
MTX vs LEF plt0.05 at 12 months MTX vs LEF pNS
at 24 months
147
Leflunomide Improvement in Physical Function is
Maintained Over 2 Years
MN301/3/5 (n51)
MN302/4(n248)
US301(n97)
1.7
1.5
1.3
1.1
1.0
Mean HAQ DI
32
0.9
46
0.9
0.7
Improved
0.6
50
0.5
0.3
Baseline
Month 6
Month 12
Month 24
148
Etanercept Mean Change in HAQ DI Over 12 Months
(ERA)
1.7
Methotrexate
Etanercept (25 mg)
1.5
1.3
1.1
Mean HAQ DI
0.9
0.9
0.8
0.7
Improved
0.5
0.3
Month 12
Month 6
Baseline
Kosinski M et al. AJMC. 20028,231-240.
149
Infliximab Mean HAQ DI Over Time ATTRACT
Year-2 Patients 0 to 24 months
Mean HAQ DI
All Infliximab MTX
PBO MTX
Improved
ITT (n340) (n86) Completed 54
weeks (n296) (n50)
Kavanaugh et al AR. 200043S147.
150
US301 Improvement in SF-36 Leflunomide Year-2
Cohort at Months 12 and 24
US Norms (A/G Adjusted)
12 Months (n 93)
LEF Baseline Year-2 Cohort
24 Months (n 93)
90
Improved
70
Mean Scores
50
30
10
0
Physical Role Bodily General Vitality Social Role
Mental Function Physical Pain Health Function Em
otion Health Perception
151
Leflunomide Mean Improvement in SF-36 PCS
Year-2 Cohort (US301)
60
US Norm
50
Improved
42.7
41.7
38.8
38.6
40
2 SDs below US Norm
30.9
30.2
Mean Scores
30
20
10
0
BL
12 M
24 M
BL
12 M
24 M
LEF (93)
MTX (97)
152
Etanercept Mean Improvement in SF-36 PCS at 12
Months (ERA)
60
US Norm
50
Improved
38.7
38.8
40
2 SDs below US Norm
Mean Scores
28.0
29.2
30
20
10
0
BL
BL
12M
12M
ETN 25mg (193)
MTX (199)
Kosinski et al. AJMC. 20028231-240.
153
Infliximab Median Improvement inSF-36 PCS at
Month 24 (ATTRACT)
16
Baseline 23.9 30.8
12
Median (IQR)
6.9
8
6.8
6.7
4.6
4
2.8
0
MTX Placebo(n88)
3 mg/kgq 8 wks (n86) 0.011
3 mg/kgq 4 wks (n86) lt0.001
10 mg/kgq 8 wks(n87) lt0.001
10 mg/kgq 4 wks (n81)lt0.001
p-value vs. placebo
Kavanaugh et al. Arth Rheum. 200043S147.
154
Summary of Efficacy Results from RCTs

• Leflunomide is comparable to Methotrexate by ACR
  responses for RA signs and symptoms, and
  inhibitionof structural damage by X-ray
  measurements.
• Improvements in physical function with
  Leflunomide measured by HAQ DI are observed at 6
  months and maintained over 2 years
• Clinically meaningful Improvements in 67-80
  patients in Year-2 cohorts exceeded MCID
• Reflect those physical activities important to
  patients
• Are closely reflected by improvements in HRQOL
• Comparable to improvements observed with
  biologic DMARDs

155
Risk Evaluation

• Randomized Controlled Trials
• Pooled analysis of Phase II and III RCTs
• Post Marketing Surveillance
• Epidemiologic Studies
• Aetna cohort study
• Nested case-control study
• National Data Bank for Rheumatic Diseases

156
Patients with Abnormal CBCs and LFTs AEs,
SAEs, and Related SAEs at Year 1
AEs SAEsTreatment-Related SAEs
25
21.8
20
16.5
15
Patients
11.3
10
5
2.3
2.3
1.0
0.9
0.9
0.5
0
Leflunomide
Methotrexate
Sulfasalazine
157
Patients with Abnormal CBCs and LFTs AEs,
SAEs, Year 1 vs 2
16
AEs Year 1 AEs Year 2 SAEs Year 1 SAEs
Year 2
15.0
14
12
10
Patients
7.4
8
5.9
6
3.8
3.1
4
2
0.7
0.8
0.4
0.2
0.2
0
Leflunomide
Methotrexate
Sulfasalazine
158
Pooled Clinical Trials
Rate/100 patient years
LEF PBO SSZ MTX (N1693) (N322) (N133)
(N709)Adverse event 2533 pt yrs 201 pt
yrs 188 pt yrs 1340 pt yrs Fatal
infection 0.0 0.0 0.0 0.5 Sepsis,
nonfatal 0.1 0.5 1.1 0.2 Malignancies 0.7 1.5 2.1
1.5 Lymphoproliferative disorders 0.1 0.0 1.1 0.2
Interstitial pneumonitis 0.0 0.0 0.0 0.4 Renal
failure 0.0 0.0 0.0 0.1 Agranulocytosis 0.0 0.0 1.
1 0.0 Vasculitis 0.7 0.0 0.5 0.4
159
Leflunomide Clinical Trial Safety Summary

• Year-2 safety profile remained similar to Year 1
• Common adverse events included diarrhea, URIs,
  nausea, headache, and common infections
• Elevations in LFTs normalized spontaneously
  orwith dose reductions or treatment
  discontinuation
• Serious hepatic AEs are comparable to MTX
  andSSZ, one case of severe hepatocellular injury

160
Pooled Analysis of RCTs Conclusions

• Withdrawals due to AEs with leflunomide were
  comparable to MTX
• Fewer serious AEs did not include interstitial
  pneumonitis and reversible renal failure
• Fewer hepatic events
• Withdrawals due to AEs with leflunomide were
  fewer than with SSZ
• SAEs were comparable, but did not include
  agranulocytosis
• Comparable hepatic events

161
Risk Evaluation

• Randomized Controlled Trials
• Post Marketing Surveillance
• Epidemiologic Studies
• Aetna cohort study
• Nested case-control study
• National Data Bank for Rheumatic Diseases

162
DMARD Use by Rheumatologists(U.S. Data)
Prescribed Scripts by Rheums
Leflunomide 2