# Presentation: 839017

## FDA Arthritis Advisory CommitteeMarch 5, 2003

***ARAVA******®***** (Leflunomide)**
**Aventis Pharmaceuticals**

## 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

## 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”?

## 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

## 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

## 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

## Requested Labeling

*to reduce signs and symptoms*
*to retard structural damage as evidenced by x-ray erosions and joint space narrowing *
_***and to improve physical function***_

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

## 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

## 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

## 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

## 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

## 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

## 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.**

## 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

## 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

## Physical Function and Annual Costs

**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**

**Annual Direct Costs  ($)**

**1.5 - 2.0**

**Physical Function and Annual Costs**

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

## 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)**

**Percent Maximum Disability**

## Progression of HAQ DIwith 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

**1****Gardiner et al. *****Br J Rheumatol.***** 1993;32:724-728.  **
**2****Fries et al. *****Arth Rheum.***** 1996;39:616-622.**
**3****Monroe et al. *****Ann Rheum Dis*****. 1998;57:88-93. **
**4****Uhlig et al. *****Rheumatol.***** 2000;39:732-741.**
**5****Young et al. *****Rheumatol.***** 2000;39:603-611.**

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

- Improved

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

**All Infliximab + MTX**

**PBO + MTX**

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

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

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

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

- Improved

## Leflunomide: Mean Improvement in HAQ DI Over TimeYear-2 Cohorts - 0 to 24 Months

**US301****(n=97)**

**MN301/3/5**** (n=51)**

**MN302/4****(n=248)**

- Improved

**Leflunomide: Mean Improvement in ****HAQ DI Over Time****Year-2 Cohorts - 0 to 24 Months**

## 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

## 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

## Baseline SF-36 Scores  US Norms vs US301 Study Population

**0**

**Physical****Function**

**Role****Physical**

**Bodily****Pain**

**General****Health****Perception**

**Vitality**

**Social**
**Function**

**Role****Emotion**

**Mental****Health**

**RA Study Population**

**US Norms (A/G Adjusted)**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

## SF-36 Two-Component Summary Scores

**SF-36 Two-Component Summary Scores**

**Physical****Component (PCS)**

**Physical****Function**

**Role****Physical**

**Bodily****Pain**

**General****Health**

**Mental****Component (MCS)**

**Vitality**

**Social****Function**

**Role****Emotion**

**Mental****Health**

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

**Walking****	****x****	****x****Climbing Steps****	****x****	****x****Reaching****	****x****Getting in and out of a car****	****x****Arising****	****x****Reaching over head****	****x****Gripping****	****x****Eating****	****x****	****x****Self care ADLs****	****Hygiene****	****x****	****Dressing, grooming****	****x****	****x****Instrumental Activities****	****x****Discretionary Activities****	****Walking > 1 mile****	****	****x****	****Climbing several sets of stairs****	****x****	****Moderate activities****	****	****x****	****Vigorous activities****	****	****x**

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

**Activities Assessed****	****HAQ****	****SF-36**

## Correlation Between HAQ and SF-36

**Reference****	****Study****	****Scales****	****Correlation**
**Ruta****1****	****—****	****PCS****	****-0.77**
**Talamo****2****	****—****	****PF****	****-0.72**
**Kavanaugh****3****	**** Infliximab/ATTRACT ****	****PCS****	****-0.51****	****	****PF****	****-0.54**
**Kosinski****4****	****Etanercept/ERA****	****PCS****	****-0.60****	****	****PF****	****-0.61**
**Lubeck****5****	****Etanercept/RAPOLO****	****PCS****	****-0.79****	****	****PF****	****-0.82**
**Strand****6****	****Leflunomide/US301****	****PCS****	****-0.60****	****	****	****PF****	****-0.74**

**1****Ruta et al. *****Br J Rheum*****. 1998;37:425-436.****2****Talamo et al. *****Br J Rheum*****. 1997;36:463-469.****3****Kavanaugh et al. *****A&R*****. 2000;43:S147.****4****Kosinski et al. *****Medical Care*****. 1999;37:MS23-39.****5****Lubeck et al. *****Value in Health.***** 2001;4:MS2,163.****6****Strand et al. *****A&R*****. 2001;44:S187.**

## 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

## Minimum Clinically Important Differences (MCID)

**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

## 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

## 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

## 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

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

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

**Pivotal Studies**
**Study Designs**
- Patient Populations and Disposition
- Results
- Efficacy Summary

## Phase III LeflunomideRandomized Controlled Trials

**6 months**

**24 months**

**12 months**

**US301**

**MN301**

**MN303**

**MN305**

**MN304**

**MN302**

**LEF**
**MTX**
**PBO**

**LEF**
**SSZ**
**PBO**

**LEF**
**MTX**

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

## Phase III Study Cohorts

**6 months**

**24 months**

**ITT Cohort**

**Year-2 Cohort**

**US301**

**MN301**

**12 months**

**MN303**

**MN305**

**MN304**

**MN302**

**ACR********20%**

**ACR********20%**

**X-ray**

**Physical Function****HRQOL (US301)**

**Physical Function****HRQOL (US301)**

**ACR********20%**

**X-ray**

**X-ray (MN301)**

**Physical Function**

## Phase III Study Cohorts

**6 months**

**24 months**

**ITT Cohort**

**Year-2 Cohort**

**US301**

**MN301**

**12 months**

**MN303**

**MN305**

**MN304**

**MN302**

**MAINTENANCE**

**BENEFIT**

## Phase III LeflunomideRandomized 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****	****	****	****	**

**Phase III Leflunomide****Randomized Controlled Trials**

## Phase III LeflunomideRandomized Controlled Trials

**	**** ****US301****	****MN301/3/5****	**
**N****	****508****	****358****	**
**Control****	****Placebo****	****Placebo****	****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****	****	****Canada****	****South Africa****	****	****	****Australia****	**

**Phase III Leflunomide****Randomized Controlled Trials**

## Phase III LeflunomideRandomized Controlled Trials

**	**** ****US301****	****MN301/3/5****	****MN302/4**
**N****	****508****	****358****	****999**
**Control****	****Placebo****	****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****	**

**Phase III Leflunomide****Randomized Controlled Trials**

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

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

**Pivotal Studies**
- Study Designs
**Patient Populations and Disposition**
- Results
- Efficacy Summary

## US301 Study Completion Rates

**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**

## US301 Study Completion Rates

**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**

## US301: Discontinuation Due to Lack of EfficacyITT Cohort

**Percent**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Months**

**MTX**

**PBO **

**LEF **

## MN301/3/5 Study Completion Rates

**	****	****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**

## MN302/4 Study Completion Rates

**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**

## Baseline CharacteristicsITT Cohorts

**Mean Age (years)****	****54****	****59****	****58**
**Mean Disease****Duration (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 Prior****DMARD (%)****	****42****	****47****	****33**
**HAQ DI****	****1.3****	****1.6****	****1.5**

**Baseline Characteristics****ITT Cohorts**

## Baseline CharacteristicsYear-2 Cohort

**Mean Age (years)****	****54****	****58****	****57**
**Mean Disease****Duration (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 Prior****DMARD (%)****	****44****	****47****	****34**
**HAQ DI****	****1.2****	****1.6****	****1.5**

**Baseline Characteristics****Year-2 Cohort**

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

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

**Pivotal Studies**
- Study Designs
- Patient Populations and Disposition
**Results**
- Efficacy Summary

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

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

**% Responders**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**LEF **

**MTX**

**PBO **

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

**3**

**6**

**9**

**12**

**18**

**24**

**Months**

**1**

**26%**

**52%**

**44%**

- *

***LEF vs PBO; p********0.0001****LEF vs MTX; p=NS**

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

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

**% Responders**

**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**

**24**

**Months**

**1**

**LEF vs MTX; p=NS**

## 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**

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

**12 Months****US301**

**-1**

**-0.5**

**0**

**-0.22**

**-0.45**

**-0.26**

******* †**

**-0.03**

**LEF**

**MTX**

**PBO**

**(166)**
**1.3**

**(101)**
**1.3**

**(169)**
**1.3**

**Mean Change from Baseline**

- Improved

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

**BL**

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

**12 Months****US301**

**-1**

**-0.5**

**0**

**-0.22**

**-0.45**

**-0.26**

******* †**

**6 Months****MN301 **

**-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**

**Mean Change from Baseline**

- Improved

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

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

**BL**

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

**12 Months****US301**

**12 Months****MN302**

**-1**

**-0.5**

**0**

**-0.22**

**-0.45**

**-0.26**

**-0.44**

**-0.54**

******* †**

**6 Months****MN301 **

**‡****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**

**Mean Change from Baseline**

- Improved

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

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

**BL**

## US301: Improvement in HAQ Subscales ITT Cohort at 12 Months

**†****	****LEF vs MTX; p<0.05**

**US301: Improvement in HAQ Subscales ****ITT Cohort at 12 Months**

**Mean Change from Baseline**

**PBO**

**LEF**

**MTX**

**HAQ 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**

*******†**

*******†**

*******†**

*******†**

*******†**

*****

*****

- Improved

**-0.22**

## Mean HAQ DI Over Time US301:  Year-2 Cohort

**Mean HAQ DI Over Time ****US301:  Year-2 Cohort**

***LEF vs MTX; p<0.01**

**50%**

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

**1.2**

**0.7**

**0.6**

**0.6**

**1.2**

**0.9**

**0.8**

**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%**

- Improved

## Mean HAQ DI Over TimeMN301/3/5: Year-2 Cohort

**1.6**

**0.9**

**0.9**

**0.9**

**1.5**

**0.9**

**0.8**

**0.9**

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

**46%**

**37%**

**LEF (n=51)**

**SSZ (n=46)**

**0**

**0.5**

**1**

**1.5**

**2**

**Baseline**

**Month 6**

**Month 12**

**Month 18**

**Month 24**

- Improved

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

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

**1.5**

**1.0**

**0.9**

**1.1**

**0.9**

**1.0**

**0.9**

**37%**

**32%**

**LEF (n=248)**

**MTX (n=273)**

**0**

**0.5**

**1**

**1.5**

**2**

**Baseline**

**Month 6**

**Month 12**

**Month 18**

**Month 24**

- Improved

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

**Mean Change from Baseline**

**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**

- Improved

**BL**

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

**Mean Change from Baseline**

**LEF**

**MTX**

**US301**

**SSZ**

**MN301/3/5 **

***LEF vs MTX; p=0.005**

**-1**

**-0.5**

**0**

**-0.22**

**-0.73**

**-0.6**

**-0.37**

*****

**(51)**
**1.6**

**(46)**
**1.5**

**(97)**
**1.2**

**(101)**
**1.2**

- Improved

**BL**

**-0.56**

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

**Mean Change from Baseline**

**LEF**

**MTX**

**US301**

**MN302/4**

**SSZ**

**MN301/3/5 **

***LEF vs MTX; p=0.005**

**-1**

**-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**

- Improved

**BL**

## 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

## Baseline SF-36 Scores  US Norms vs US301 Population

**0**

**Physical****Function**

**Role****Physical**

**Bodily****Pain**

**General****Health****Perception**

**Vitality**

**Social**
**Function**

**Role****Emotion**

**Mental****Health**

**RA Study Population**

**US Norms (A/G Adjusted)**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

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

**PBO (n=101)**

**LEF (n=157)**

**MTX (n=162)**

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

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

**Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****Perception**

**-4**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

*****

*****

*****

*****

*****

- †

- †

**Mean Change from Baseline**

- Improved

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

**US Norms (A/G Adjusted)**

**Baseline Year-2 Cohort**

**	****Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**Mean Scores**

- Improved

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

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

**LEF 24 Months (n = 93)**

**MTX 24 Months (n = 89)**

**US Norms (A/G Adjusted)**

**Baseline Year-2 Cohort**

**	****Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**Mean Scores**

- Improved

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

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

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

**Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**US Norms (A/G Adjusted)**

**LEF Baseline Year-2 Cohort**

**Mean Scores**

- Improved

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

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

**Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**12 Months (n = 93)**

**24 Months (n = 93)**

**US Norms (A/G Adjusted)**

**LEF Baseline Year-2 Cohort**

**Mean Scores**

- Improved

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

**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**

**Mean Scores**

- Improved

## 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.**

## 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

## 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**

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

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

**US301**

**MN301/3/5**

**MN302/4**

**100**

**100**

**0**

**Worsened**

**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**

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

**100**

**100**

**0**

**Worsened**

**Same/Improved**

**LEF (n =97)**

**MTX (n=101)**

_**Any**_** worsening from baseline to month 24**

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

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

**Pivotal Studies**
- Study Designs
- Patient Populations and Disposition
- Results
**Efficacy Summary**

## Conclusions

**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

## 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**

## 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

## 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

## FDA Arthritis Advisory CommitteeMarch 5, 2003

***ARAVA******®***** (Leflunomide)**
**Aventis Pharmaceuticals**

## 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

## 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

## Leflunomide – Presentation Agenda

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

## Pharmacovigilance and Epidemiology Overview

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

## Pharmacovigilance and Epidemiology Overview

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

## 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**

## Serious Adverse EventsCumulative Rates Per 100 PY - 6 Months

**LEF**

**MTX**

**CV/TE**

**Hepatic AEs**

**Pulmonary**

**Infection**

**Malignancy**

**Cutaneous**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**Hypertension**

## Serious Adverse EventsCumulative Rates Per 100 PY - 12 Months

**Hypertension**

**CV/TE**

**Hepatic AEs**

**Pulmonary**

**Malignancy**

**Cutaneous**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**Infection**

**LEF**

**MTX**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

## Serious Adverse EventsCumulative Rates Per 100 PY - 24 Months

**Hypertension**

**CV/TE**

**Hepatic AEs**

**Pulmonary**

**Infection**

**Malignancy**

**Cutaneous**

**0**

**1**

**2**

**3**

**4**

**5**

**LEF**

**MTX**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

## Hepatic Adverse EventsCumulative Rates Per 100 PY - 6 Months

**Hepatic AEs****	**

**AST/ALT > 3x ULN**

**AST/ALT ****> 5x ULN**

**AST/ALT > 10x ULN**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**LEF**

**MTX**

## Hepatic Adverse EventsCumulative Rates Per 100 PY - 12 Months

**Hepatic AEs****	**

**AST/ALT ****> 3x ULN**

**AST/ALT ****> 5x ULN**

**AST/ALT > 10x ULN**

**0**

**5**

**10**

**15**

**20**

**25**

**0**

**5**

**10**

**15**

**20**

**25**

**LEF**

**MTX**

## Hepatic Adverse EventsCumulative Rates Per 100 PY - 24 Months

**Hepatic AEs****	**

**AST/ALT > 3x ULN**

**AST/ALT ****> 5x ULN**

**AST/ALT > 10x ULN**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**LEF**

**MTX**

## Serious Adverse EventsCumulative Rates Per 100 PY - 6 Months

**Hypertension**

**CV/TE**

**Hepatic AEs**

**Pulmonary**

**Infection**

**Malignancy**

**Cutaneous**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**0**

**2**

**4**

**6**

**8**

**SSZ**

**LEF**

## Serious Adverse EventsCumulative Rates Per 100 PY - 12 Months

**Hypertension**

**CV/TE**

**Hepatic****AEs**

**Pulmonary**

**Infection**

**Malignancy**

**Cutaneous**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**SSZ**

**LEF**

## Serious Adverse EventsCumulative Rates Per 100 PY - 24 Months

**Hypertension**

**CV/TE**

**Hepatic****AEs**

**Pulmonary**

**Infection**

**Malignancy**

**Cutaneous**

**0**

**1**

**2**

**3**

**4**

**5**

**0**

**1**

**2**

**3**

**4**

**5**

**SSZ**

**LEF**

## Hepatic Adverse EventsCumulative Rates Per 100 PY - 6 Months

**Hepatic AEs****	**

**AST/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**

**SSZ**

**LEF**

## Hepatic Adverse EventsCumulative Rates Per 100 PY - 12 Months

**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**

**SSZ**

**LEF**

## Hepatic Adverse EventsCumulative Rates Per 100 PY - 24 Months

**Hepatic AEs****	**

**AST/ALT ****> 3x ULN**

**AST/ALT ****> 5x ULN**

**AST/ALT ****> 10x ULN**

**0**

**3**

**6**

**0**

**3**

**6**

**SSZ**

**LEF**

## 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

## Pharmacovigilance and Epidemiology Overview

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

## Spontaneous ReportsLimitations 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

## 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**

## Global & US Leflunomide UseEstimated 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**

## Reporting RatesHepatic 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**

## Reported Cases of Hepatic FailureFDA 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**

## UNOS DataLiver Transplant Etiology 

**1998**

**1999**

**2000**

**2001**

**2002**

**Number of Transplants**

**LEF ***

**MTX**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**10**

***2 transplant cases: 1 US, 1 Italy**

## Pharmacovigilance and Epidemiology Overview

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

## 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**

## 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

## 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

## Study Design

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

## 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

## Aetna Cohort StudyResults

**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

## Aetna Cohort StudyResults

**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

## Aetna cohort studyCase 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: P*h*RMA/FDA/AASLD. *Drug-Induced Hepatotoxicity White Paper: Postmarketing Considerations*. November 2000.

## Slide 116

## Slide 117

## 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**

**Events/1,000 PY**

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

**LEF**

**MTX**

**DMARD****+ bDMARD**

**L + M**

**L + D**

**M + D**

**Events/1,000 PY**

**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.**

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

**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**

**Severe Hepatic Events/1,000 PY**

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

**N=11**

**N=40**

**N=120**

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

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

*** ICD-9-CM code 570**

**n = 1**

**n = 2**

**n = 7**

**AHN Events/1,000 PY**

## Aetna Cohort StudyConclusions

- 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

## Pharmacovigilance and Epidemiology Overview

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

## 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

## 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

## 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

## 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

## Nested Case-control StudyLimitations

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

## Nested Case-control StudyResults

**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

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

**90**

**5**

**27**

**16**

**42**

**0.5**

**2**

**1**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Any AE**

**Hepatic**

**Hematologic**

**Pancreatitis**

**Infection**

**Cutaneous**

**Pneumonitis**

**Lymphoma**

**Events/10,000 PY**

## 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**

## Leflunomide Hepatic Event Case #1Nested 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

## Leflunomide Hepatic Event Case #2Nested 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

## Nested Case-control StudyConclusions

**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

## Pharmacovigilance & Epidemiology ActivitiesSummary of Results

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

## Pharmacovigilance & Epidemiology ActivitiesSummary 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

## Pharmacovigilance & Epidemiology ActivitiesSummary 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

## Pharmacovigilance & Epidemiology ActivitiesSummary 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

## 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

## 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

## 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:

## 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

## Leflunomide and Methotrexateare Comparable Over 2 Years

**% Responders**

**LEF ACR20**

**MTX ACR20**

**US301**

**MN302/304**

**77**

**65**

**60**

**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**

## Leflunomide and Methotrexateare Comparable Over 2 Years

**% Responders**

**LEF ACR20**

**MTX ACR20**

**US301**

**MN302/304**

**77**

**65**

**64**

**60**

**67**

**72**

**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 months**
**MTX vs LEF p=NS at 24 months**

## Leflunomide and Methotrexateare Comparable Over 2 Years

**% Responders**

**LEF ACR20**

**MTX ACR20**

**LEF ACR50**

**MTX ACR50**

**US301**

**MN302/304**

**77**

**65**

**64**

**60**

**67**

**72**

**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**

**43**

**39**

**45**

**49**

**50**

**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 months**
**MTX vs LEF p=NS at 24 months**

## Leflunomide and Methotrexateare Comparable Over 2 Years

**% Responders**

**LEF ACR20**

**MTX ACR20**

**LEF ACR50**

**MTX ACR50**

**LEF ACR70**

**MTX ACR70**

**US301**

**MN302/304**

**77**

**65**

**64**

**60**

**67**

**72**

**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**

**26**

**32**

**43**

**20**

**13**

**39**

**45**

**49**

**50**

**11**

**15**

**16**

**21**

**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 months**
**MTX vs LEF p=NS at 24 months**

## Leflunomide: Improvement in Physical Function is Maintained Over 2 Years

**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**

**Baseline**

**Month 6**

**Month 12**

**Month 24**

**1.0**

- Improved

**Leflunomide: Improvement in Physical Function is Maintained Over 2 Years**

**0.9**

**0.6**

**Mean HAQ DI**

**50%**

**46%**

**32%**

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

**Methotrexate**

**Etanercept (25 mg)**

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

- Improved

**Mean HAQ DI**

**1.7**

**1.5**

**1.3**

**1.1**

**0.9**

**0.7**

**0.5**

**Month 6**

**Month 12**

**0.8**

**0.9**

**0.3**

**Baseline**

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

- Improved

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

**Mean HAQ DI**

**All Infliximab + MTX**

**PBO + MTX**

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

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

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

**Physical****	****Role****	****Bodily****	****General****	****Vitality****	****Social****	****Role****	****Mental****	****Function****	****Physical****	****Pain****	****Health****	****	****Function****	****Emotion****	****Health****	****	****	****	****Perception**

**0**

**10**

**30**

**50**

**70**

**90**

**12 Months (n = 93)**

**24 Months (n = 93)**

**US Norms (A/G Adjusted)**

**LEF Baseline Year-2 Cohort**

**Mean Scores**

- Improved

## 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**

- Improved

**Mean Scores**

**0**

**10**

**20**

**30**

**40**

**50**

**30.9**

**42.7**

**41.7**

**30.2**

**38.6**

**38.8**

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

**60**

**US Norm**

**2 SDs ****below ****US Norm**

- Improved

**Mean Scores**

**0**

**10**

**20**

**30**

**40**

**50**

**BL**

**BL**

**12M**

**12M**

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

**ETN 25mg (193)**

**MTX (199)**

**28.0**

**38.7**

**29.2**

**38.8**

## Infliximab: Median Improvement inSF-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/kg****q 8 wks**
**(n=86) ****0.011**

**3 mg/kg****q 4 wks**
**(n=86) ****<0.001**

**10 mg/kg****q 8 wks****(n=87)**
**<0.001**

**10 mg/kg****q 4 wks**
**(n=81)****<0.001**

**Median (IQR)**

**0**

**4**

**8**

**12**

**16**

**2.8**

**4.6**

**6.8**

**6.9**

**6.7**

## 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

## 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

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

**25**

**% Patients**

**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**

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

**2**

**0**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**% Patients**

**Leflunomide**

**Methotrexate**

**Sulfasalazine**

**7.4**

**3.1**

**0.4**

**0.2**

**15.0**

**5.9**

**0.7**

**0.2**

**3.8**

**0.8**

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

## 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**

## 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

## 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

## Risk Evaluation

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

## 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

## 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**** **

## Reporting RatesMedDRA 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

## Reporting RatesHepatic Failure (FDA / IMS Data)

**0**

**5**

**10**

**15**

**20**

**25**

**4q98-**

**2q99-**

**4q99-**

**2q00-**

**4q00-**

**2q01-**

**4q01-**

**2q02**

**Hepatic Failure Reports/100,000 PY**

**LEF****	****8.2**

**MTX****	****0.5**

**ETAN****	****7.0 (3-11)**

**INFLIX****	****7.9 (4-11)**

## Reporting RatesInterstitial Lung Disease (FDA / IMS Data)

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**140**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Respiratory Reports/100,000 PY**

**LEF**

**MTX**

**ETAN**

**INFLIX**

## Reporting Rates: TEN, SJSCutaneous Reactions (FDA / IMS Data)

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Cutaneous Reports/100,000 PY**

**MTX**

**ETAN**

**INFLIX**

## Reporting RatesVasculitis (FDA / IMS Data)

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**45**

**50**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Vasculitis Reports/100,000 PY**

**LEF**

**MTX**

**ETAN**

**INFLIX**

## Reporting RatesLymphoma (FDA / IMS Data)

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Lymphoma Reports/100,000 PY**

**MTX**

**ETAN**

**INFLIX**

## Reporting RatesMedDRA 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

## Reporting RatesHypertension (FDA / IMS Data)

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**400**

**450**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Hypertension Reports/100,000 PY**

**MTX**

**ETAN**

**INFLIX**

## Reporting RatesPancytopenia (FDA / IMS Data)

**0**

**20**

**40**

**60**

**80**

**100**

**120**

**140**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Pancytopenia Reports/100,000 PY**

**LEF**

**MTX**

**ETAN**

**INFLIX**

## Reporting RatesSepsis/Tuberculosis (FDA / IMS Data)

**0**

**50**

**100**

**150**

**200**

**250**

**300**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Infection Reports/100,000 PY**

**MTX**

**ETAN**

**INFLIX**

## Reporting RatesDemyelinating Disorders (FDA / IMS Data)

**Reporting Rates****Demyelinating Disorders (FDA / IMS Data)**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**4q98**

**2q99**

**4q99**

**2q00**

**4q00**

**2q01**

**4q01**

**Demyelinating Reports/100,000 PY**

**MTX**

**ETAN**

**INFLIX**

## 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

## Spontaneous Reports of Acute Hepatic Failure (PMS)

- Cases are very rare
- Confounding factors are common
- Exact incidence unknown
- Reported rates comparable to other DMARDs

## Risk Evaluation

- Randomized Controlled Trials
- Post Marketing Surveillance
- Epidemiologic Studies
- 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

## Aetna Cohort StudyConclusions

- 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

## Nested Case-control StudyConclusions

- 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

## National Data Bankfor 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

## 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.**

## 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**

## Risk Evaluation: Summary of Results

- RCTs and Pooled Analysis of clinical trials
- AE rates with LEF show no strong signal, comparable to MTX, SSZ
- Post Marketing Surveillance
- 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

## 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

## 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.**

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

**	****ACR********20%****	****ACR********50%****	****ACR********70%**
**Etanercept****	****2****	****3****	****7**
**Infliximab****	****3****	****4****	****8**
**Leflunomide****	****4****	****5****	****12**
**Anakinra****	****6****	****11****	**** 25**

**Hochberg M et al. EULAR 2002.**

## 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

## 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

## Leflunomide – Presentation Agenda

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

## 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

## FDA Arthritis Advisory CommitteeMarch 5, 2003

***ARAVA******®***** (Leflunomide)**
**Aventis Pharmaceuticals**

## Backup Visuals Presented in Response to Q & A

## PRO Assessments: RCTs

**RCT****	****PRO****	****Time**
**US301****	****HAQ****	****BL, weeks 24, 52, 104 or early discontinuation****	****PET****	****BL, weeks 24, 52, 104 or early discontinuation****	****SF-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, 104****	****	****or early discontinuation**

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

- 		**LEF****	****PBO****	****MTX**
**HAQ DI****	****	****	****n****	****166****	****101****	****169****	****Baseline****	****1.30****	****1.31****	****1.30****	****Mean change****	****-0.45*****†****	****0.03****	****-0.26******	****Mean % vs PBO****	****37%****	****-****	****22%**
**MHAQ****	****	****n****	****182****	****118****	****180****	****Baseline****	****0.78****	****0.89****	****0.79****	****Mean 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**

## Health Outcomes

**Health-Related**

**Function &**
**Well-being**

**Function &**
**Well-being**

**Clinical****Outcome**

**Physical**

**Function **

**Quality of Life**

**HAQ-DI**

**SF-36 PCS**

**Health Outcomes**

## 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 Disease****Duration (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****	****Safety****	****Other**

**Dropouts**

**Month 24**

## 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 DI****Baseline to Dropout****	****-0.30****	****0.13****	****-0.19****	****-0.39**

**	****Completers****	****LOE****	****Safety****	****Other**

**Dropouts**

**Month 24**

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

**Mean Change from Baseline**

**Improved**

**% 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)**
**1.3**

**BL**

**76%**

**63%**

**53%**

**-0.6**

**-0.37**

**-1**

**-0.5**

**0**

**(97)**
**1.2**

**(101)**
**1.2**

**BL**

**Year-2 Cohort**

**84%**

**69%**

**71%**

**71%**

**59%**

**59%**

**45%**

## MN301/3/5: HAQ DI Improvement and Maintenanceat 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)**
**1.5**

**BL**

**-0.73**

**-0.56**

**-1**

**-0.5**

**0**

**(51)**
**1.6**

**(46)**
**1.5**

**BL**

**Year-2 Cohort**

**Mean Change from Baseline**

**Improved**

**% Improved/Same**

**% Achieving MCID**

**80%**

**70%**

**80%**

**55%**

**70%**

**37%**

**86%**

**80%**

**82%**

**71%**

## MN302/4: HAQ DI Improvement and Maintenanceat 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)**
**1.5**

**BL**

**-0.48**

**-0.56**

**-1**

**-0.5**

**0**

**(248)**
**1.5**

**(273)**
**1.5**

**BL**

**Year-2 Cohort**

**Mean Change from Baseline**

**Improved**

**% Improved/Same**

**% Achieving MCID**

**83%**

**89%**

**74%**

**78%**

**62%**

**67%**

**73%**

**70%**

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

**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%

## MN301 Patient DispositionReasons for Withdrawal

- 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****	****SSZ****Total Enrolled ****(ITT Cohort)****	****133****	****92****	****133**

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

**Continuing into MN303****	****80****	****     **41 to SSZ**	****76**

**MN301 Patient Disposition****Reasons for Withdrawal**