arava - aventis 7-aug-15 mm-1 fda arthritisadvisory committee march 5, 2003 fda arthritis advisory...

ARAVA - Aventis Apr 19, 2023 MM-1

FDA ArthritisFDA Arthritis Advisory CommitteeAdvisory Committee

March 5, 2003March 5, 2003

ARAVAARAVA®® (Leflunomide) (Leflunomide)

Aventis PharmaceuticalsAventis Pharmaceuticals

MM-2

Leflunomide – Presentation Agenda

Introduction Michael Rozycki, PhDUS Regulatory Affairs

Aventis Pharmaceuticals

Patient-Reported Outcomes Joseph Doyle, RPh, MBA

Physical Function: Efficacy Data Karen Simpson, MD

Conclusions Michael Rozycki, PhD

MM-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”?

MM-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

MM-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

MM-6

Maintenance of Effect Data

• 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

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

MM-7

Requested Labeling

1. to reduce signs and symptoms

2. to retard structural damage as evidenced by x-ray erosions and joint space narrowing

3.3. and to improve physical functionand to improve physical function

ARAVA is indicated in adults for the treatment of active RA:

MM-8

Aventis Expert ConsultantsHepatology

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

MM-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

MM-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

MM-11


Introduction Michael Rozycki, PhD

Patient-Reported Outcomes Joseph Doyle, RPh, MBAHealth Economics andOutcomes ResearchAventis Pharmaceuticals

Clinical Efficacy: Physical Function Karen Simpson, MD


MM-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

MM-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. A&R. 1996;39:616-622. 2 Gremillion et al. RA. 1988;103:2:103-123. 3 Wolfe et al. J Rheumatol. 1991;18:1290-1297.4 Wolfe F. Am J of Managed Care. 1999;5:S852-859.

MM-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

MM-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

MM-16

0

2000

4000

6000

8000

10000

12000

14000

0 - 0.5 0.5 - 1.0 1.0 - 1.5 2.0 - 2.5 2.5 - 3.0

HAQ Disability Index

An

nu

al D

irec

t C

ost

s (

$)

1.5 - 2.0

Physical Function and Annual Costs

Singh et al. Arthritis Rheum. 1996;39(suppl):S318.

MM-17

Disability in RA with Standard Care

Scott DL et al. Rheumatol. 2000;39:122-132.

0

10

20

30

40

50

60

70

Wolfe et al

Lassere et al

Sherrer et al

Scott et al

7 12 18

Disease Duration (years)

Per

cen

t M

axim

um

Dis

abil

ity

MM-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 Stabilized5

1Gardiner et al. Br J Rheumatol. 1993;32:724-728. 2Fries et al. Arth Rheum. 1996;39:616-622.3Monroe et al. Ann Rheum Dis. 1998;57:88-93. 4Uhlig et al. Rheumatol. 2000;39:732-741.5Young et al. Rheumatol. 2000;39:603-611.

MM-19

Infliximab: Mean HAQ DI Over Time ATTRACT: Year-2 Patients 0 to 24 Months

Impr

oved

Kavanaugh et al: A&R. 2000;43:S147.

0.5

0.7

0.9

1.1

1.3

1.5

1.7

Baseline Month 6 Month 12 Month 24

1.3 1.3 1.3 1.3

1.7

1.5 1.5 1.51.6

All Infliximab + MTX PBO + MTX

ITT (n=340) (n=86)

Completed 54 weeks (n=296) (n=50)

MM-20

Etanercept 25mg(n= 177)

Etanercept: Mean HAQ DI Over Time ERA: Year-2 Patients 0 to 24 Months

Genovese et al: A&R. 2002;46:1443-50.

0.3

0.5

0.7

0.9

1.1

1.3

1.5

1.7


Impr

oved

MM-21

US301(n=97)

MN301/3/5 (n=51)

MN302/4(n=248)

0.3

0.5

0.7

0.9

1.1

1.3

1.5

1.7


50%

46%

32%

Impr

oved

Leflunomide: Mean Improvement in HAQ DI Over Time

Year-2 Cohorts - 0 to 24 Months

MM-22

Problem Elicitation Technique(PET Top 5)

Self-administered questionnaire to assess:

• Individual patient’s 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

MM-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

MM-24

Baseline SF-36 Scores US Norms vs US301 Study Population

0PhysicalFunction

RolePhysical

BodilyPain

GeneralHealth

Perception

Vitality SocialFunction

RoleEmotion

MentalHealth

RA Study PopulationUS Norms (A/G Adjusted)

10

20

30

40

50

60

70

80

90

100

MM-25

SF-36 Two-Component Summary Scores

PhysicalComponent (PCS)

PhysicalFunction

RolePhysical

BodilyPain

GeneralHealth

MentalComponent (MCS)

VitalitySocial

FunctionRole

EmotionMentalHealth

MM-26

Walking x xClimbing Steps x xReaching xGetting in and out of a car xArising xReaching over head xGripping xEating x xSelf care ADLs

Hygiene xDressing, grooming x x

Instrumental Activities xDiscretionary Activities

Walking > 1 mile xClimbing several sets of stairs xModerate activities xVigorous activities x

Physical Activities Assessed:HAQ vs SF-36 Physical Function Domain

Activities Assessed HAQ SF-36

MM-27

Correlation Between HAQ and SF-36

Reference Study Scales Correlation

Ruta1 — PCS -0.77

Talamo2 — PF -0.72

Kavanaugh3 Infliximab/ATTRACT PCS -0.51PF -0.54

Kosinski4 Etanercept/ERA PCS -0.60PF -0.61

Lubeck5 Etanercept/RAPOLO PCS -0.79PF -0.82

Strand6 Leflunomide/US301 PCS -0.60PF -0.74

1Ruta et al. Br J Rheum. 1998;37:425-436.2Talamo et al. Br J Rheum. 1997;36:463-469.3Kavanaugh et al. A&R. 2000;43:S147.4Kosinski et al. Medical Care. 1999;37:MS23-39.5Lubeck et al. Value in Health. 2001;4:MS2,163.6Strand et al. A&R. 2001;44:S187.

MM-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

MM-29

1 Guzman et al. A&R. 1996;39:5208. 2 Kosinski et al. A&R. 2000;43:1478-87. 3 Redelmeier et al. Arch Intern Med. 1993;153:1337-42. 4 Wells et al. J Rheumatol. 1993;20:557-60. 5 Kosinski et al. A&R. 2000;43:S140. 6 Samsa et al. Pharmacoeconomics. 1999;15(2):141-155. 7 Thumboo et al. J Rheumatol. 1999;26(1):97-102.

Minimum Clinically Important Differences (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 50±10 2.5 to 5 points

Score Direction of

Range Improvement MCID

mean

MM-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

MM-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

MM-32




Clinical Efficacy: Physical Function Karen Simpson, MDUS Medical AffairsAventis Pharmaceuticals


MM-33

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

Pivotal Studies

• Study Designs

• Patient Populations and Disposition

• Results

• Efficacy Summary

MM-34

Phase III LeflunomideRandomized Controlled Trials

6 months 24 months12 months

US301

MN301 MN303 MN305

MN304MN302

LEFMTXPBO

LEFSSZPBO

LEFMTX

LEF=leflunomide; MTX=methotrexate; SSZ=sulfasalazine; PBO=placebo

MM-35

Phase III Study Cohorts

6 months 24 months

ITT CohortYear-2 Cohort

US301

MN301

12 months

MN303 MN305

MN304MN302

ACR20% ACR20%

X-ray

Physical FunctionHRQOL (US301)

Physical FunctionHRQOL (US301)

ACR20%

X-rayX-ray (MN301)

Physical Function

MM-36

Phase III Study Cohorts

6 months 24 months

ITT CohortYear-2 Cohort

US301

MN301

12 months

MN303 MN305

MN304MN302

MAINTENANCE

BENEFIT

MM-37

US301

N 508

Control PlaceboMTX: 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 USCanada


MM-38

US301 MN301/3/5

N 508 358

Control Placebo PlaceboMTX: 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 61224 mos

Initiated 1995 1994

Countries US EuropeCanada South Africa

Australia


MM-39

US301 MN301/3/5 MN302/4

N 508 358 999

Control Placebo PlaceboMTX: 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 61224 mos 1224 mos

Initiated 1995 1994 1994

Countries US Europe EuropeCanada South Africa South Africa

Australia


MM-40


Pivotal Studies

• Study Designs


• Results


MM-41

US301 Study Completion Rates

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

LEF PBO MTX

MM-42

US301 Study Completion Rates

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)

LEF PBO MTX

(85% of Y2C) (75% of Y2C) (79% of Y2C)

Withdrew prior to 12 mo 92 (48) 92 (72) 89 (47)Entered Alternate Tx 25 (13) 56 (44) 35 (18)Completed Alternate Tx 16 (8) 34 (27) 17 (9)

Total Completing Protocol 99 (52) 61 (48) 97 (51)

Y2C = Year-2 Cohort

MM-43

US301: Discontinuation Due to Lack of EfficacyITT Cohort

Pe

rce

nt

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24

Months

MTX PBO LEF

MM-44

LEF PBO SSZ

MN301/3/5 Study Completion Rates

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

MM-45

MN302/4 Study Completion Rates

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)

LEF MTX

(87% of Y2C)(88% of Y2C)

Y2C = Year-2 Cohort

MM-46

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

Baseline CharacteristicsITT Cohorts

MM-47

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

Baseline CharacteristicsYear-2 Cohort

MM-48


Pivotal Studies

• Study Designs


• Results


MM-49

US301: ACR20 Responders Over Time ITT Cohort: 0-12 Months (LOCF)

% R

esp

on

der

s

0

10

20

30

40

50

60

70

80

90LEF MTX PBO

ITT: (n=186) (n=188) (n=128)

3 6 9 12 18 24Months

1

26%

52%

44%

*

*LEF vs PBO; p0.0001LEF vs MTX; p=NS

MM-50

US301: ACR20 Responders Over Time ITT Cohort: 0-24 Months

% R

esp

on

der

s

0

10

20

30

40

50

60

70

80

90

53%48%

LEF MTX PBO ITT: (n=186) (n=188) (n=128)

3 6 9 12 18 24Months

1

LEF vs MTX; p=NS

MM-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

MM-52

HAQ DI Improvement Across Studies ITT Cohort at 6 or 12 Month Endpoint

12 MonthsUS301

-1

-0.5

0

-0.22

-0.45

-0.26

* †

-0.03

LEF MTX PBO

(166)

1.3

(101)

1.3

(169)

1.3

Mea

n C

han

ge

fro

m B

asel

ine

Impr

oved

*LEF vs PBO; p<0.001†LEF vs MTX; p<0.01

BL

MM-53


12 MonthsUS301

-1

-0.5

0

-0.22

-0.45

-0.26

* †

6 MonthsMN301

-0.03

-0.56

-0.37

-0.08

* †

LEF MTX PBO SSZ

(113)

1.7

(81)

1.6

(111)

1.5

(166)

1.3

(101)

1.3

(169)

1.3

Mea

n C

han

ge

fro

m B

asel

ine

Impr

oved

*LEF vs PBO; p<0.001†LEF vs SSZ; p<0.05


BL

MM-54


12 MonthsUS301

12 MonthsMN302

-1

-0.5

0

-0.22

-0.45

-0.26

-0.44

-0.54* †

6 MonthsMN301

‡MTX vs LEF; p<0.05

-0.03

-0.56

-0.37

-0.08

* † ‡

LEF MTX PBO SSZ

(464)

1.5

(463)

1.5

(113)

1.7

(81)

1.6

(111)

1.5

(166)

1.3

(101)

1.3

(169)

1.3

Mea

n C

han

ge

fro

m B

asel

ine

Impr

oved

*LEF vs PBO; p<0.001†LEF vs SSZ; p<0.05


BL

MM-55

* LEF vs PBO; p<0.05† LEF vs MTX; p<0.05

US301: Improvement in HAQ Subscales ITT Cohort at 12 Months

Mea

n C

han

ge

fro

m B

asel

ine

PBOLEF MTXHAQ DI BL = 1.3 BL = 1.3 BL = 1.3

n =166 n =169 n =101

Dressing

Arising

Eating

Walking

Hygiene

Reaching

Gripping

Activities

*

-1

-0.5

0

0.25

*†*†

*†

*† *†* *

Impr

oved

-0.22

MM-56

Mean HAQ DI Over Time US301: Year-2 Cohort

*LEF vs MTX; p<0.01

50%

% achieving MCID: LEF: 71% MTX: 59%

1.2

0.70.6 0.6

1.2

0.90.8 0.8

0

0.5

1

1.5

2

Baseline Month 6 Month 12 Month 18 Month 24

*

LEF (n=97) MTX (n=101)

31%

Impr

oved

MM-57

Mean HAQ DI Over TimeMN301/3/5: Year-2 Cohort

1.6

0.9 0.9 0.9

1.5

0.90.8

0.9

% achieving MCID: LEF: 80% SSZ: 71%

46%

37%

LEF (n=51) SSZ (n=46)

0

0.5

1

1.5

2


Impr

oved

MM-58

Mean HAQ DI Over Time MN302/4: Year-2 Cohort

% achieving MCID: LEF: 67% MTX: 73%

1.5

1.00.9

1.1

0.91.0

0.9 37%

32%

LEF (n=248) MTX (n=273)

0

0.5

1

1.5

2


Impr

oved

MM-59

HAQ DI Improvement Across Studies Year-2 Cohort at 24 Months

Mea

n C

han

ge

fro

m B

asel

ine

LEF MTX

US301

*LEF vs MTX; p=0.005-1

-0.5

0

-0.22

-0.6

-0.37

*

(97)

1.2

(101)

1.2

Impr

oved

BL

MM-60


Mea

n C

han

ge

fro

m B

asel

ine

LEF MTX

US301

SSZ

MN301/3/5


-0.5

0

-0.22

-0.73

-0.6

-0.37

*

(51)

1.6

(46)

1.5

(97)

1.2

(101)

1.2

Impr

oved

BL

-0.56

MM-61


Mea

n C

han

ge

fro

m B

asel

ine

LEF MTX

US301 MN302/4

SSZ

MN301/3/5


-0.5

0

-0.22

-0.73

-0.56-0.6

-0.37

-0.48

-0.56

*

(248)

1.5

(273)

1.5

(51)

1.6

(46)

1.5

(97)

1.2

(101)

1.2

Impr

oved

BL

MM-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

MM-63

Baseline SF-36 Scores US Norms vs US301 Population

0PhysicalFunction

RolePhysical

BodilyPain

GeneralHealth

Perception

Vitality SocialFunction

RoleEmotion

MentalHealth

RA Study PopulationUS Norms (A/G Adjusted)

10

20

30

40

50

60

70

80

90

100

MM-64

PBO (n=101)LEF (n=157) MTX (n=162)


US301: Improvement in SF-36 Domains ITT Cohort at 12 Months

Physical Role Bodily General Vitality Social Role MentalFunction Physical Pain Health Function Emotion Health

Perception

-4

0

4

8

12

16

20

24

*

*

*

* *

†

†

Mea

n C

han

ge

fro

m B

asel

ine

Impr

oved

MM-65

US Norms (A/G Adjusted)

Baseline Year-2 Cohort


Perception

0

10

20

30

40

50

60

70

80

90

Mea

n S

core

sImpr

oved

US301: SF-36 Domain Scores Year-2 Cohort at 24 Months:

Leflunomide and Methotrexate

MM-66

LEF 24 Months (n = 93)MTX 24 Months (n = 89)

US Norms (A/G Adjusted)

Baseline Year-2 Cohort


Perception

0

10

20

30

40

50

60

70

80

90

Mea

n S

core

sImpr

oved

US301: SF-36 Domain Scores Year-2 Cohort at 24 Months:

Leflunomide and Methotrexate

MM-67

US301: SF-36 Domain Scores Leflunomide Year-2 Cohort at Months 12 and 24


Perception

0

10

20

30

40

50

60

70

80

90

US Norms (A/G Adjusted)LEF Baseline Year-2 Cohort

Mea

n S

core

sImpr

oved

MM-68

US301: SF-36 Domain Scores Leflunomide Year-2 Cohort at Months 12 and 24


Perception

0

10

20

30

40

50

60

70

80

90

12 Months (n = 93)24 Months (n = 93)


Mea

n S

core

sImpr

oved

MM-69

0

10

20

30

40

50

60

PCS

30.9

42.7 41.7

US Norm

US301: Improvement in PCS Scores Leflunomide and Methotrexate: Year-2 Cohort

2 SDs below

US Norm

30.2

38.6 38.8

LEF (n=97) MTX (n=101)

BL 12 M 24 M BL 12 M 24 M

Mea

n S

core

s

Impr

oved

MM-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. A&R. 2001;44:S187.

MM-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

MM-72

Correlation of HAQ DI with SF-36 PCS US301: Leflunomide ITT

-2.5

-2

-1.5

-1

0.5

1

-20 -10 10 20 30 40

HAQ DI

SF-36 PCS

R = - 0.60

-0.5

MM-73

Year-2 Cohorts at 24 Months:Responses in HAQ DI

US301

MN301/3/5

MN302/4

100 1000Worsened Same/Improved

17%

31%

84%

69%

14% 86%

18% 82%

26% 74%

22% 78%

LEF (n=400) MTX (n=380) SSZ (n=46)

Any worsening from baseline to month 24

MM-74

Responses in Patient-Reported Outcomes: US301 Year-2 Cohort at 24 Months

100 1000Worsened Same/Improved

HAQ DI17% 84%

31% 69%

LEF (n =97) MTX (n=101)

Any worsening from baseline to month 24

SF-36 PCS21% 80%

23% 77%

MM-75


Pivotal Studies

• Study Designs


• Results


MM-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

MM-77




Clinical Efficacy: Physical Function Karen Simpson, MD

Conclusions Michael Rozycki, PhDUS Regulatory AffairsAventis Pharmaceuticals

MM-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

MM-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



March 5, 2003March 5, 2003



MM-81


Introduction Michael Rozycki, PhDUS Regulatory AffairsAventis Pharmaceuticals

Epidemiology Overview William Holden, PhD

Benefit-Risk Synopsis Vibeke Strand, MD


MM-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

MM-83



Epidemiology Overview William Holden, PhDAventis Pharmaceuticals

Benefit-Risk Synopsis Vibeke Strand, MD


MM-84

Pharmacovigilance and Epidemiology Overview

• Pooled analysis of clinical trials

• Reporting rate analysis/liver transplant data

• Aetna cohort study

• Nested case-control study

MM-85






MM-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

Grand total = 2857 pts, 4262 PY

Total LEF = 1693 pts, 2533 PY

PY = Patient years

MM-87

Serious Adverse EventsCumulative Rates Per 100 PY - 6 Months

LEF

MT

X

CV/TE

Hepatic AEs

Pulmonary

Infection

Malignancy

Cutaneous

0

1

2

3

4

5

6

0 1 2 3 4 5 6

Hypertension

MM-88


Hypertension

CV/TE

Hepatic AEs

PulmonaryMalignancy

Cutaneous

0 1 2 3 4 5 6

Infection

LEF

MT

X

0

1

2

3

4

5

6

MM-89


Hypertension

CV/TE

Hepatic AEs

Pulmonary

Infection

Malignancy

Cutaneous

0 1 2 3 4 5

LEF

MT

X

0

1

2

3

4

5

6

MM-90

Hepatic Adverse EventsCumulative Rates Per 100 PY - 6 Months

Hepatic AEs

AST/ALT > 3x ULN

AST/ALT > 5x ULN

AST/ALT > 10x ULN0

5

10

15

20

25

30

0 5 10 15 20 25 30

LEF

MT

X

MM-91


Hepatic AEs

AST/ALT > 3x ULN

AST/ALT > 5x ULN

AST/ALT > 10x ULN0

5

10

15

20

25

0 5 10 15 20 25

LEF

MT

X

MM-92


Hepatic AEs

AST/ALT > 3x ULN

AST/ALT > 5x ULN

AST/ALT > 10x ULN0

3

6

9

12

15

18

0 3 6 9 12 15 18

LEF

MT

X

MM-93


Hypertension

CV/TE

Hepatic AEs

Pulmonary

Infection

Malignancy

Cutaneous0

1

2

3

4

5

6

7

8

0 2 4 6 8

SS

Z

LEF

MM-94


Hypertension

CV/TE

HepaticAEs

Pulmonary

Infection

Malignancy

Cutaneous

0

1

2

3

4

5

6

0 1 2 3 4 5 6

SS

Z

LEF

MM-95


HypertensionCV/TE

HepaticAEs

Pulmonary

Infection

Malignancy

Cutaneous

0

1

2

3

4

5

0 1 2 3 4 5

SS

Z

LEF

MM-96


Hepatic AEsAST/ALT > 3x ULN

AST/ALT > 5x ULN

AST/ALT > 10x ULN

0

2

4

6

8

10

12

0 2 4 6 8 10 12

SS

Z

LEF

MM-97


Hepatic AEs

AST/ALT > 3x ULN

AST/ALT> 5x ULN

AST/ALT > 10x ULN

0

2

4

6

8

10

0 2 4 6 8 10

SS

Z

LEF

MM-98


Hepatic AEs

AST/ALT > 3x ULN

AST/ALT > 5x ULN

AST/ALT > 10x ULN0

3

6

0 3 6

SS

Z

LEF

MM-99

Pooled Analysis:Conclusions

• 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

MM-100






MM-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

MM-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

MM-103

Global & US Leflunomide UseEstimated Person-year (PY) Exposure, IMS Data

Cumulative through Sept 2002 = 405,000 PY

Cumulative through Dec 2002 = 450,000 PY

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

90,000

Q4 98-Q1 99

Q2 99-Q3 99

Q4 99-Q1 00

Q2 00-Q3 00

Q4 00-Q1 01

Q2 01-Q3 01

Q4 01-Q1 02

Q2 02-Q3 02

US

ROW

MM-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

LEF ETAN

Hep

atic

Fai

lure

Rep

ort

s/10

0,00

0 P

Y

MTX INFLIX

0

5

10

15

20

25

4Q98- 2Q99- 4Q99- 2Q00- 4Q00- 2Q01- 4Q01- 2Q02

MM-105

Reported Cases of Hepatic FailureFDA AERS Database

0

2

4

6

8

10

12

4Q98-1Q99

2Q99-3Q99

4Q99-1Q00

2Q00-3Q00

4Q00-1Q01

2Q01-3Q01

4Q01-1Q02

2Q02

LEF

MTX

ETAN

INFLIX

MM-106

UNOS DataLiver Transplant Etiology

1998 1999 2000 2001 2002

Nu

mb

er o

f T

ran

spla

nts

LEF *MTX

0

1

2

3

4

5

6

7

8

9

10

*2 transplant cases: 1 US, 1 Italy

MM-107






MM-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

MM-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

MM-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

MM-111

Study Design

• Covariates– Age– Gender

– Comorbidities

• Analysis– Description of the cohort

• Age, gender, person-time

– Poisson regression to estimate incidence rates

MM-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

MM-113

Aetna Cohort StudyResults

• 40,594 RA patients identified– Crude RA prevalence 0.63%

– 74% women

– Most in age range 51–64 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

MM-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

MM-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.

MM-116

MM-117

MM-118

Aetna Database – Cohort-wide Incidence Rates (Events per 1,000 Patient-years, Unadjusted)

139

1 0.3

85

3

38

8

0

20

40

60

80

100

120

140

160

Any Event

Hepatic

Hematologic

Cutaneous

Hypertension

Pancreatitis

Respiratory

Eve

nts

/1,0

00 P

Y

MM-119

Aetna Database – Incidence Rates Hepatic* (Events Per 1,000 Patient–years, Adjusted)

LEF MTX DMARD+ bDMARD

L + M L + D M + D

Eve

nts

/1,0

00 P

Y

22

87

246 7

19 64

0

2

4

6

8

10

12

14

16

*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.

MM-120

Aetna Database – Incidence Rates Severe Hepatic Events* (per 1,000 PY, 95% UCL)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

LEF MTX DMARD

Sev

ere

Hep

atic

Eve

nts

/1,0

00 P

Y

*Severe Hepatic Events = acute hepatic necrosis, non-infectious hepatitis, hepatocellular jaundice, cirrhosis.

N=11

N=40 N=120

MM-121

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

LEF MTX DMARDs

Aetna Database – Incidence Rates Acute Hepatic Necrosis* (per 1,000 PY, 95% UCL)

* ICD-9-CM code 570

n = 1 n = 2 n = 7AH

N E

ven

ts/1

,000

PY

MM-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

MM-123






MM-124

Study Design


• 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

MM-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

MM-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

MM-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

MM-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

MM-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

MM-130

Nested Case-control Study Results: Cohort-wide Event Rates

90

5

27

16

42

0.5 2 10

10

20

30

40

50

60

70

80

90

100

Any AE

Hepatic

Hematologic

Pancreatitis

Infection

Cutaneous

Pneumonitis

Lymphom

a

Eve

nts

/10,

000

PY

MM-131

Nested Case-control Study Results: Serious Hepatic* Event Rates

DMARD use Cases Controls Crude Adjusted**in prior year (n=25) (n=2,500) 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*Serious Hepatic Events = acute hepatic necrosis, non-infectious hepatitis, non-alcoholic cirrhosis, hepatic coma.

**Adjusted for age, gender, data source, non-use of DMARDs in year prior, use of NSAID, cox-2, glucocorticoids, and comorbidity

MM-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

MM-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

MM-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

MM-135

Pharmacovigilance & Epidemiology ActivitiesSummary of Results

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

MM-136



• Reporting rate analysis/liver transplant data– Hepatic failure rate of LEF comparable to other

biologic DMARDs

MM-137




biologic DMARDs

• Aetna cohort study– Hepatic and other event rates of LEF comparable to

other DMARDs

MM-138




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

MM-139




Benefit-Risk Discussion Vibeke Strand, MDBiopharmaceutical ConsultantClinical ProfessorDivision of Immunology and

RheumatologyStanford University


MM-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

MM-141

Limited RA Treatment Armamentarium

• 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

There is a frequent need to add or change therapy in patients with active RA:

MM-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

MM-143

Leflunomide and Methotrexateare Comparable Over 2 Years

% R

esp

on

der

s

LEF ACR20 MTX ACR20

US301 MN302/304

77

6560

0

50

100

12 M 24 M 12 M 24 M 12 M 24 M 12 M 24 M(n=98) (n=101) (n=286) (n=314)

77*

LEF vs MTX p=NS at 12 months *MTX vs LEF p<0.05 at 12 months

MM-144


% R

esp

on

der

s

LEF ACR20 MTX ACR20

US301 MN302/304

77

65 6460

6772

79†

0

50

100

12 M 24 M 12 M 24 M 12 M 24 M 12 M 24 M(n=98) (n=101) (n=286) (n=314)

77*

LEF vs MTX p=NS at 12 months†LEF vs MTX p<0.05 at 24 months

*MTX vs LEF p<0.05 at 12 monthsMTX vs LEF p=NS at 24 months

MM-145


% R

esp

on

der

s

LEF ACR20 MTX ACR20LEF ACR50 MTX ACR50

US301 MN302/304

77

65 6460

6772

79†

0

50

100

12 M 24 M 12 M 24 M 12 M 24 M 12 M 24 M(n=98) (n=101) (n=286) (n=314)

57 56

32

4339

4549 50

77*



MM-146


% R

esp

on

der

s

LEF ACR20 MTX ACR20LEF ACR50 MTX ACR50LEF ACR70 MTX ACR70

US301 MN302/304

77

65 6460

6772

79†

0

50

100

12 M 24 M 12 M 24 M 12 M 24 M 12 M 24 M(n=98) (n=101) (n=286) (n=314)

57 56

3226

32

43

2013

3945

49 50

1115 16

21

77*



MM-147

US301(n=97)

MN301/3/5 (n=51)

MN302/4(n=248)

0.3

0.5

0.7

0.9

1.1

1.3

1.5

1.7


1.0

Impr

oved

Leflunomide: Improvement in Physical Function is Maintained Over 2 Years

0.9

0.6

Mea

n H

AQ

DI

50%

46%

32%

MM-148

Etanercept: Mean Change in HAQ DI Over 12 Months (ERA)

Methotrexate Etanercept (25 mg)

Kosinski M et al. AJMC. 2002;8,:231-240.

Impr

oved M

ean

HA

Q D

I

1.7

1.5

1.3

1.1

0.9

0.7

0.5

Month 6 Month 12

0.8

0.9

0.3Baseline

MM-149

Infliximab: Mean HAQ DI Over Time ATTRACT: Year-2 Patients 0 to 24 months

Impr

oved

Kavanaugh et al: A&R. 2000;43:S147.

0.5

0.7

0.9

1.1

1.3

1.5

1.7


1.3 1.3 1.3 1.3

1.7

1.5 1.5 1.51.6

Mea

n H

AQ

DI

All Infliximab + MTX PBO + MTX

ITT (n=340) (n=86)Completed 54 weeks (n=296) (n=50)

MM-150

US301: Improvement in SF-36 Leflunomide Year-2 Cohort at Months 12 and 24


Perception

0

10

30

50

70

90

12 Months (n = 93)24 Months (n = 93)


Mea

n S

core

sImpr

oved

MM-151

Leflunomide: Mean Improvement in SF-36 PCS Year-2 Cohort (US301)

60

US Norm

2 SDs below

US Norm

LEF (93) MTX (97)

BL 12 M 24 M BL 12 M 24 M

Impr

oved

Mea

n S

core

s

0

10

20

30

40

50

30.9

42.7 41.7

30.2

38.6 38.8

MM-152

Etanercept: Mean Improvement in SF-36 PCS at 12 Months (ERA)

60

US Norm

2 SDs below

US Norm

Impr

oved

Mea

n S

core

s

0

10

20

30

40

50

BLBL 12M12M

Kosinski et al. AJMC. 2002;8:231-240.

ETN 25mg (193) MTX (199)

28.0

38.7

29.2

38.8

MM-153

Infliximab: Median Improvement inSF-36 PCS at Month 24 (ATTRACT)

Baseline: 23.9 –30.8

Kavanaugh et al. Arth Rheum. 2000;43:S147.

p-value vs. placebo

MTX + Placebo(n=88)

3 mg/kgq 8 wks

(n=86) 0.011

3 mg/kgq 4 wks

(n=86) <0.001

10 mg/kgq 8 wks(n=87)

<0.001

10 mg/kgq 4 wks

(n=81)<0.001

Med

ian

(IQ

R)

0

4

8

12

16

2.8

4.6

6.8 6.9 6.7

MM-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

MM-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

MM-156

% Patients with Abnormal CBCs and LFTs: AEs, SAEs, and Related SAEs at Year 1

25

% P

atie

nts

20

15

10

5

0

16.5

0.9 0.5

21.8

1.0 0.9

11.3

2.3 2.3

Leflunomide Methotrexate Sulfasalazine

AEs

SAEs

Treatment-Related SAEs

MM-157

% Patients with Abnormal CBCs and LFTs: AEs, SAEs, Year 1 vs 2

2

0

4

6

8

10

12

14

16

% P

atie

nts

Leflunomide Methotrexate Sulfasalazine

7.4

3.1

0.4 0.2

15.0

5.9

0.70.2

3.8

0.8

AEs – Year 1AEs – Year 2SAEs – Year 1SAEs – Year 2

MM-158

Pooled Clinical Trials

LEF PBO SSZ MTX(N=1693) (N=322) (N=133) (N=709)

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

Rate/100 patient years

MM-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

MM-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

MM-161

Risk Evaluation




– Aetna cohort study

– Nested case-control study

– National Data Bank for Rheumatic Diseases

MM-162

DMARD Use by Rheumatologists(U.S. Data)

Leflunomide 294,000 84.4%

Methotrexate 1,201,000 76.0%

Etanercept 240,000 98.2%

Infliximab 192,000 70.6%

Anakinra 25,000 85.2%

Verispan PDDA (January – December 2002)

% Prescribed # Scripts by Rheums

MM-163

Mean exposure time to leflunomide

• Aetna study– 1.6 years (19 months)

• Wolfe data1

– 1.3 years (15 months)

• Eisen data2

– 1.47 years (17.6 months)

1 Wolfe F, et al. ACR abstract, 2002, in press A&R

2 Siva C, et al. ACR abstract, 2002

MM-164

Reporting RatesMedDRA Terms Used

• Hepatic failure

– hepatic failure

• Interstitial lung disease

– interstitial pneumonitis

– interstitial lung disease

– pneumonitis NOS

• Serious Skin Reactions

– Erythema Multiforme

– TENS

– Stevens Johnson syndrome

• Vasculitis

– ANCA positive vasculitis

– vasculitic rash

– leukocytoclastic vasculitis

– skin vasculitis NOS

– vasculitis NOS

– vascular purpura

• Lymphoma

– Hodgkin’s disease

– lymphoma NEC

– Non-Hodgkin’s lymphoma

– lymphoma unspecified

MM-165

Reporting RatesHepatic Failure (FDA / IMS Data)

0

5

10

15

20

25

4q98- 2q99- 4q99- 2q00- 4q00- 2q01- 4q01- 2q02

Hep

atic

Fai

lure

Rep

ort

s/10

0,00

0 P

Y

LEF 8.2

MTX 0.5

ETAN 7.0 (3-11)

INFLIX 7.9 (4-11)

MM-166

Reporting RatesInterstitial Lung Disease (FDA / IMS Data)

0

20

40

60

80

100

120

140

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Res

pir

ato

ry R

epo

rts/

100,

000

PY

LEF

MTX

ETAN

INFLIX

MM-167

Reporting Rates: TEN, SJSCutaneous Reactions (FDA / IMS Data)

0

10

20

30

40

50

60

70

80

90

100

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Cu

tan

eou

s R

epo

rts/

100,

000

PY

LEF

MTX

ETAN

INFLIX

MM-168

Reporting RatesVasculitis (FDA / IMS Data)

0

5

10

15

20

25

30

35

40

45

50

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Vas

culi

tis

Rep

ort

s/10

0,00

0 P

Y

LEF

MTX

ETAN

INFLIX

MM-169

Reporting RatesLymphoma (FDA / IMS Data)

0

10

20

30

40

50

60

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Lym

ph

om

a R

epo

rts/

100,

000

PY

LEF

MTX

ETAN

INFLIX

MM-170

Reporting RatesMedDRA Terms Used

• Hypertension– accelerated HTN– hypertensive crisis– malignant HTN NOS– diastolic/systolic HTN– HTN NOS– labile HTN– aggravated HTN– essential HTN

• Pancytopenia– marrow depression and

hypoplastic anemias– thrombocytopenia– aggravated

thrombocytopenia

• Sepsis/TB– sepsis NOS– bacteremia– pulmonary sepsis– neutropenic sepsis– pulmonary Tb– tuberculosis NOS– reactivated Tb

• Demyelinating Disorders

MM-171

Reporting RatesHypertension (FDA / IMS Data)

0

50

100

150

200

250

300

350

400

450

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Hyp

erte

nsi

on

Rep

ort

s/10

0,00

0 P

Y LEF

MTX

ETAN

INFLIX

MM-172

Reporting RatesPancytopenia (FDA / IMS Data)

0

20

40

60

80

100

120

140

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Pan

cyto

pen

ia R

epo

rts/

100,

000

PY

LEF

MTX

ETAN

INFLIX

MM-173

Reporting RatesSepsis/Tuberculosis (FDA / IMS Data)

0

50

100

150

200

250

300

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Infe

ctio

n R

epo

rts/

100,

000

PY

LEF

MTX

ETAN

INFLIX

MM-174

Reporting RatesDemyelinating Disorders (FDA / IMS Data)

0

10

20

30

40

50

60

4q98 2q99 4q99 2q00 4q00 2q01 4q01

Dem

yeli

nat

ing

Rep

ort

s/10

0,00

0 P

Y

LEF

MTX

ETAN

INFLIX

MM-175

Post Marketing Surveillance: Conclusions

• Due to familiarity and long term use of the treatment, the intensity of reporting serious AEs with MTX is low

– Despite the known incidence of hepatic toxicity and interstitial lung disease with MTX

– SJS and TEN, in part may be related to use of NSAIDs

– Vasculitis and lymphoma in part may be related to active RA

• Reports of these AEs and pancytopenia, opportunistic infections and Tb, and demyelinating disorders show some differences between the newer DMARDs and may be represent signals of potential risk

MM-176

Spontaneous Reports of Acute Hepatic Failure (PMS)

• Cases are very rare

• Confounding factors are common

• Exact incidence unknown

• Reported rates comparable to other DMARDs

MM-177

Risk Evaluation




– Aetna cohort study:40,594 RA; 5000 LEF patients

– Nested case-control study:41,855 RA; 4300 LEF patients

– National Data Bank for Rheumatic Diseases:17,350 RA; 5437 LEF patients

MM-178

Aetna Cohort StudyConclusions

• 40,594 patients with RA

• Provided a direct measure of the strength of association between drug exposure and occurrence of an AE

• Rates of hepatic events observed in the leflunomide exposure group were comparable to rates in other mono or combination DMARD groups, including biologic DMARDs

MM-179

Nested Case-control StudyConclusions

• 41,855 patients with RA

• No increased risk for AEs was observed for leflunomide for:

– All serious AEs

– Serious hepatic AEs

– Serious hematologic AEs

– Serious pancreatic AEs

– Serious opportunistic infections/septicemia AEs

MM-180

National Data Bankfor Rheumatic Disease (Wolfe Database)

• 17,350 patients with RA– LEF: 5,437 patients; MTX: 10,767 patients

• Compared with MTX, there was no increase in LEF:– Reported hepatic adverse events

– Hepatic comorbidity

– Hepatic hospitalization

– Liver biopsy

• LEF treated patients are not at increased risk for liver events or mortality compared to MTX

MM-181

Estimates of Serious Liver AEs Background Rate

• General US population: ~0.1 / 10,000 PY (mixed cases)

• RA population:

– Aetna Study (hepatic necrosis):1.4 / 10,000 PY (95% CI 0.6 – 2.2 / 10,000 PY)

– Nested Case-Control Study (hospitalized serious hepatic injury):4.9 / 10,000 PY (95% CI 3.0 – 6.8 / 10,000 PY)

– ACR survey* (hepatic failure and cirrhosis):2.2 / 10,000 PY

– National Data Bank (hospitalized hepatic necrosis):0.2 / 10,000 PY (95% CI 0 – 1.2 / 10,000 PY)

*Walker AM, et al. Arthritis Rheum 1993;36:329-35.

MM-182

NDBRD – Lymphoma Evaluation

Treatment Group N pt/yrs OBS EXP SIRS (95% CI)

No MTX, INF, ETAN 3,564 7,122 5 3.8 1.3 (0.4 - 3.1)

MTX only 6,396 12,147 10 6.7 1.5 (0.7 - 2.7)

LEF (ALL) 3,300 5,039 2 2.38 0.84 (0.21 - 3.36)

INF 6,465 6,537 9 3.5 2.6 (1.2 - 4.9)

ETAN 3,381 5,099 8 2.1 3.8 (1.6 - 7.5)

18,557 patients 1998 – 2002 908 US Rheumatologists

MM-183

Risk Evaluation: Summary of Results

• RCTs and Pooled Analysis of clinical trials

– AE rates with LEF show no strong signal, comparable to MTX, SSZ


– Overall, comparable rates for LEF and biologic DMARDs, although rare events cannot be excluded

• Aetna cohort Nested case-control studies and NDBRD

– All rates with LEF comparable to other DMARDS

– Serious hepatic [and other] AE rates with LEF comparable to traditional and biologic DMARDS

MM-184

Number Needed to Treat (NNT)

• Defined as the number of patients who need to be treated to prevent one additional event (or attain one additional improvement)

• Calculated as the reciprocal of the incremental effect:

p1 = benefit of interest with old treatment (T1)

p2 = benefit of interest with new treatment (T2)

NNT = 1/Net Benefit = 1/p1-p2

MM-185

Number Needed to Treat to Achieve MCID HAQ DI, PET Top 5, SF-36 at 12 Months

LEF vs. PBO MTX vs. PBO LEF vs. MTX

HAQ DI 3 6 7[MCID: -0.22]

PET Top 5 4 14 7[MCID: -5.0]

SF-36 PCS 5 17 7[MCID: +5.0]

Strand et al. Arth Rheum. 2001;44:S123.

MM-186

MTX Combination Trials: ‘Step-Up Therapy’Hochberg Meta-analysis: NNT

ACR20% ACR50% ACR70%

Etanercept 2 3 7

Infliximab 3 4 8

Leflunomide 4 5 12

Anakinra 6 11 25

Hochberg M et al. EULAR 2002.

MM-187

Benefit / Risk Analysis of Leflunomide

• Provides significant and sustained improvements in clinical signs and symptoms and radiographic progression over 2 years of treatment

• Improves physical function over 2 years of treatment,

– Reflected in improvement in all domains of health-related quality of life

• Has a similar safety profile over 2 years of treatment

• Comparable benefit/risk profile to:

– ‘Gold standard’: MTX

– Newer biologic DMARDs

MM-188

In Summary

• Leflunomide has a positive benefit/risk profile

• Each of the 5 new DMARDs has a unique benefit/risk profile

• Their use must be tailored to the individual patient

• Rheumatologists need to be cognizant of these profiles; and have demonstrated we can carefully monitor these therapies

• All represent important treatments for this chronic disabling disease, in a population with limited therapeutic options

MM-189




Benefit-Risk Discussion Vibeke Strand, MD

Conclusions Michael Rozycki, PhDUS Regulatory AffairsAventis Pharmaceuticals

MM-190

Leflunomide Benefit-Risk

• Leflunomide is an effective and unique treatment for 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



March 5, 2003March 5, 2003




Backup Visuals Presented in Response to Q & A

MM-193

PRO Assessments: RCTs

RCT PRO Time

US301 HAQ BL, weeks 24, 52, 104 or early discontinuationPET BL, weeks 24, 52, 104 or early discontinuationSF-36 BL, weeks 24, 52, 104 or early discontinuation

MN301/3/5 HAQ BL, weeks 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 72, 104 or early discontinuation

MN302/4 HAQ BL, weeks 2, 4, 6, 8, 12, 24, 36, 52, 72, 104or early discontinuation

MM-194

Mean Changes in HAQ DI and MHAQ:Endpoint vs Baseline (ITT Analysis)

LEF PBO MTX

HAQ DIn 166 101 169Baseline 1.30 1.31 1.30Mean change -0.45*† 0.03 -0.26**Mean % vs PBO 37% - 22%

MHAQn 182 118 180Baseline 0.78 0.89 0.79Mean change -0.29*† 0.07 -0.15** Mean % vs

PBO 45% - 27%

* LEF vs PBO; p<0.0001† LEF vs MTX; p<0.01** MTX vs PBO; p<0.05

MM-195

Health-Related

Function &Well-beingFunction &Well-being

ClinicalOutcome

Physical

Function

Quality of Life

HAQ-DI

SF-36 PCS

Health Outcomes

MM-196

US301: Baseline Characteristics of PBO Month 24 Completers and Dropouts

N (% of ITT) 27 (21) 71 (55) 12 (9) 18 (14)

Mean Age(years) 55 56 54 49

% Female 67 69 83 83

Mean DiseaseDuration (years) 11.3 6.0 5.1 4.1

RF Positive (%) 44 66 67 6

Mean #DMARDs 0.9 1.0 0.8 0.7

Baseline HAQ DI 1.0 1.5 1.4 1.4

Completers LOE SafetyOther

DropoutsMonth 24

MM-197

US301: Mean Change HAQ DI in PBO Month 24 Completers and Dropouts

N (% of ITT) 27 (21) 71 (55) 12 (9) 18 (14)

Baseline HAQ DI 1.0 1.5 1.4 1.4

Mean HAQ DIBaseline to Dropout -0.30 0.13 -0.19 -0.39

Completers LOE SafetyOther

DropoutsMonth 24

MM-198

US301: HAQ DI Improvement and Maintenanceat 12 Months ITT and Year-2 Cohort at 24 Months

LEF MTX PBO

Mea

n C

han

ge

fro

m B

asel

ine

Imp

rove

d

% Improved/Same

% Achieving MCID

-0.22

12 Month ITT

-1

-0.5

0

-0.45

-0.26

-0.03

(166)

1.3

(101)

1.3

(169)

1.3BL

76% 63% 53%

-0.6

-0.37

-1

-0.5

0

(97)

1.2

(101)

1.2BL

Year-2 Cohort

84% 69%

71% 71% 59%59% 45%

MM-199

MN301/3/5: HAQ DI Improvement and Maintenanceat 12 Months ITT and Year-2 Cohort at 24 Months

-0.22

LEF SSZ PBO

12 Month ITT

-1

-0.5

0

-0.56

-0.37

-0.08

(113)

1.7

(81)

1.6

(111)

1.5BL

-0.73

-0.56

-1

-0.5

0

(51)

1.6

(46)

1.5BL

Year-2 Cohort

Mea

n C

han

ge

fro

m B

asel

ine

Imp

rove

d

% Improved/Same% Achieving MCID

80%70%

80%55%

70%37%

86%80%

82%71%

MM-200

MN302/4: HAQ DI Improvement and Maintenanceat 12 Months ITT and Year-2 Cohort at 24 Months

-0.22

LEF MTX

12 Month ITT

-1

-0.5

0

-0.44

-0.56

(464)

1.5

(463)

1.5BL

-0.48-0.56

-1

-0.5

0

(248)

1.5

(273)

1.5BL

Year-2 Cohort

Mea

n C

han

ge

fro

m B

asel

ine

Imp

rove

d

% Improved/Same% Achieving MCID

83% 89% 74% 78%

62% 67% 73%70%

MM-201

LEF MTX(N=97) (N=101)

US 301: Patients Achieving HAQ DI MCID Year-2 Cohort (Year 1 versus Year 2)

% Subjects Achieving HAQ DI MCID 76.3 58.4at Year 1 (LOCF)

% Subjects Achieving HAQ DI MCID 71.1 58.4at Year 2 (LOCF)

Change in Patients Achieving HAQ DI MCID Between Year 1 and Year 2:

Yes to Yes 67.0% 53.5%

No to Yes 4.1% 5.0%

Yes to No 9.3% 5.0%

No to No 19.6% 36.6%

MM-202

6-Month Withdrawals n (%) n (%) n (%)

Lack of Efficacy 10 (8) 29 (32) 14 (11)

Safety 19 (14) 6 (7) 25 (19)

Other 8 (6) 6 (7) 11 (8)

LEF PBO SSZTotal Enrolled (ITT Cohort) 133 92 133

n n n

Not Continuing into MN303 16 10 7Responder 7 1 3Non-responder 9 9 4

Continuing into MN303 80 41 to SSZ 76

MN301 Patient DispositionReasons for Withdrawal

arava - aventis 7-aug-15 mm-1 fda arthritisadvisory committee march 5, 2003 fda arthritis advisory...

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