PsO: Review of AvailableAssessment Instruments and

Lessons from Trial Results - Part II

Steve Feldman, M.D., Ph.D

Professor of Dermatology, Pathology & Public Health Sciences

Wake Forest University School of Medicine

Part I

• Various ways to score psoriasis• Quantitative measures of lesions

– PASI

– OLA

– PGA (static anddynamic via a photo assisted approach)

– The Ellis Lattice

– NPF Psoriasis Score

– Target lesion

Part II

• Other ways to assess the disease– QOL: Impact on patients’ lives– Biopsies– Photographs– Geneomic approach (DNA, mRNA, proteomics)

• Lessons from Trial Results

Quality of Life (QOL)

• Doesn’t directly measure the impact of drug on the disease

• Does measure the impact on the patient’s life

• Clearly the overall goal is to improve patient’s lives

• But the direct measure of the disease is essential for drug trials

QOL vs Disease Severity

• Some patients have lots of lesions but aren’t bothered by them

• Some have very few lesions and are very bothered by them

• QOL correlates to a degree with skin lesions, but certainly not 100%

Correlation of Change in DLQI and Change in PASI and PGA

PASI PGA

Correlation of absolute changes

0.49 0.46

Correlation of percent changes

0.61 0.58

Spearman rank correlations Data on file, Centocor, Inc.

QOL is Complementary

• Want treatments that improve the disease enough to make a difference

• QOL tells you if the change in the disease made a difference

• Treatments that improve QOL without improving the disease shouldn’t be approved for the disease– Anxiolytics or narcotics might make patients feel better

without changing the character of the lesions

– They could be approved for the symptom

QOL Measures

• Non-specific– SF-36– Euro QOL– Utility

• Skin specific– DLQI– Skindex

• Psoriasis specific– PDI

Short Form-36

• General health, health change, physical functioning, limitations due to physical health/emotional health, social functioning, pain, energy, emotional well-being

• Walking, climbing stairs, working

• Physical and mental dimensions

Psoriasis: Impact on Physical Health–Comparison With Other

Diseases55

4745 45 44 43 43 42 42 41

35

30

35

40

45

50

55

60

Health

y ad

ults

Derm

atiti

s

Cance

r

Depre

ssio

n

Hyper

tensi

on

Arthrit

is

Myo

card

ial i

nfarc

tion

Chronic

lung d

isea

se

Type

2 dia

betes

Psoria

sis

Congestiv

e hea

rt fa

ilure

Rapp SR et al. J Am Acad Dermatol. 1999;41:401.

Ph

ysic

al C

om

po

nen

t S

um

mar

y S

core

of

SF

-36

Psoriasis: Impact on Mental Health–Comparison With Other

Diseases53 52 52 52

50 49 4946 46 45

35

30

35

40

45

50

55

Health

y ad

ults

Hyper

tensi

on

Type

2 dia

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Myo

card

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tion

Congestiv

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Cance

r

Arthrit

is

Derm

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s

Psoria

sis

Chronic

lung d

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Depre

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Men

tal

Co

mp

on

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Su

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Sco

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F-3

6

Rapp SR et al. J Am Acad Dermatol. 1999;41:401.

Skindex-16

• 16 items rated on a scale from 1-7 – Total score of 16-102– Higher score indicating worse QOL

• Symptoms– Itching, burning, pain, irritation, appearance, persistence

• Emotions– Worry, frustration, annoyance, depression,

embarrassment

• Social– Being with others, interactions, activities, affection, work

QOL Without The Condition

• Patients first rate overall QOL with the facial blemish

• Then rate what QOL would be without the facial pigmentary disorder – 8 subscales—work, family relationships, social life,

sexual relationships, recreation and leisure, physical health, money matters, and emotional well-being

– The difference between QOL with and without the facial pigmentary disorder (score range, 0-40)

Dermatology Life Quality Index

• Consists of 10 questions covering 6 domains– Symptoms and feelings– Daily activities– Leisure– Work and school– Personal relationships– Bother with psoriasis

treatment

• Response options– Very much: scored 3

– A lot: scored 2

– A little: scored 1

– Not at all: scored 0

• Range 0-30• Lower scores = Better

QOL

Finlay AY et al. Clin Exp Dermatol. 1994;19:210.

0 = Minimum effect on QOL; 30 = Maximum effect on QOL.

*P<0.001 vs placebo.

*

11.7 11.5 12.0

9.9

6.1 6.3

0

2

4

6

8

10

12

14

Placebo(n=170)

Efalizumab 1.0 mg/kg/wk

(n=162)

Efalizumab 2.0 mg/kg/wk

(n=166)

Mea

n D

LQ

I Sco

re

Baseline

Week 12

*

Feldman SR, et al. AAD Annual Meeting 2002; Poster.

6.1 6.3

15

Efalizumab Phase III Results: DLQI Scores at Weeks 0 & 12

Improvement From Baseline in DLQI at Week 10

10.3*

0

8*

10*8.8*

2.6

0

2

4

6

8

10

12

Placebo Infliximab 3mg/kg Infliximab 5mg/kg

Mean changeMedian change

Data on file, Centocor, Inc.

Imp

rove

men

t F

rom

Bas

elin

e In

DL

QI

*p<0.001 vs placebo

Percent Improvement FromBaseline in DLQI

Only patients with baseline score >0 included in the analysis Data on file, Centocor, Inc.

79*70*

16

91*84*

00

20

40

60

80

100

Placebo Infliximab 3mg/kg Infliximab 5mg/kg

Mean changeMedian change

% I

mp

rove

men

t F

rom

Bas

elin

e

*p<0.001 vs placebo

Responders with 50% reduction in PASI 2 weeks after last dose

Nonresponders

Alefacept IM Phase 3 StudyAlefacept IM Phase 3 Study

01020304050607080

2 weeks after last dose2 weeks after last dose 12 weeks after last dose12 weeks after last dose

Per

cen

tag

e

*P<0.001

Percentage Improvement from Baseline in DLQI Scores by Responder Status

56%*

49%*

19% 19%

PASI 50 Responders Achieved Substantial QOL Improvements Relative to Nonresponders

QOL Benefits Were Maintained 12 Weeks After Last Dose

Embarrassment 64% 27%Impact on daily activities 21% 7%Leisure or social activities 34% 18%Sexual difficulties 21% 15% Problems with partner, 20% 9%relatives, friends

Proportion responding “Very Much” or “A Lot”*

*Scale: 1=Very Much; 2= A Lot; 3= A Little; 4=Not At All; 5= Not Relevant

DLQI in Alefacept 15 mg IM

2 Weeks 2 Weeks After Last After Last

DoseDoseBaseline Baseline

Improvement in DLQI SubscalesM

ean

% C

ha

ng

e

-20

-10

00

1010

2020

3030

4040

5050

6060

7070

Symptoms and

Feelings

Daily Activities

Work and

School

Personal Relationships

Leisure Treatment

*p<0.01 vs. placebo†p<0.001 vs. placebo

§

§

§

§ §

§

§

§

†*

‡p=0.0001 vs. placebo§p<0.0001 vs. placebo

‡‡

††* §

§

§

PlaceboPlaceboEtanercept 25 mg QWkEtanercept 25 mg QWkEtanercept 25 mg BiWkEtanercept 25 mg BiWkEtanercept 50 mg BiWkEtanercept 50 mg BiWk

Leonardi C et al. International Investigative Dermatology 2003. Poster 409.

Timing of Improvement

• Mean PASI scores may show statistical significance early in the trial

• QOL measures can confirm that these changes are clinically meaningful– Whether there is improvement in QOL

Mean % Improvement in DLQI

00

1010

2020

3030

4040

5050

6060

7070

8080

00 44 88 1212 1616 2020 2424

Mea

n %

Im

pro

vem

ent

Mea

n %

Im

pro

vem

ent

Fro

m B

asel

ine

Fro

m B

asel

ine

Weeks22

54%53%

59%

74%

Placebo group received etanercept 25 mg BiWk after Week 12

Placebo/Etanercept 25 mg BiWPlacebo/Etanercept 25 mg BiWEtanercept 25 mg QWkEtanercept 25 mg QWkEtanercept 25 mg BiWkEtanercept 25 mg BiWkEtanercept 50 mg BiWkEtanercept 50 mg BiWk

p≤0.003 vs. placebo at all time points through Week 12Leonardi C et al. International Investigative Dermatology 2003. Poster 409.

QOL Success

• Any statistical improvement

• Predetermined degree of improvement

% With a Zero DLQI or a 5 Point Reduction in DLQI Score

Placebo/Etanercept 25 mg BiWPlacebo/Etanercept 25 mg BiWEtanercept 25 mg QWkEtanercept 25 mg QWkEtanercept 25 mg BiWkEtanercept 25 mg BiWkEtanercept 50 mg BiWkEtanercept 50 mg BiWk

00

1010

2020

3030

4040

5050

6060

7070

8080

00 44 88 1212 1616 2020 24242

62%62%

68%68%

67%67%

80%80%

Placebo group received etanercept 25mg BiWk after Week 12

Mea

n %

Im

pro

vem

ent

Mea

n %

Im

pro

vem

ent

Fro

m B

asel

ine

Fro

m B

asel

ine

Weeks

QOL of Zero

• No impact of the disease

• Very, very stringent measure of success

SPIRIT: Patients With DLQI of 0 at Week 10

Data on file, Centocor, Inc.

2

33*

40*

0

5

10

15

20

25

30

35

40

45

Placebo Infliximab 3mg/kg Infliximab 5mg/kg

% P

atie

nts

*p<0.001 compared to placebo

Biopsies

• Lab tests are attractive because they are objective– Work great for blood levels, such as glucose,

because there is uniformity within the blood– Biopsies can’t assess the severity of psoriasis

because one can’t achieve representative sampling

• Biopsies are at best nice for assessments of mechanism

Photographs

• In theory, could be used to confirm real time assessments of severity– Not clear that thickness or even scaliness of

lesions can be accurately assessed

• Real use is for the marketing department after the study is approved

Genomics

• Again the problem is finding a representative sample

• Perhaps will be useful for– Mechanistic understanding of the disease– Identifying specific subpopulations

• For prognostic information

• For guiding treatment

Summary

• Step 1 is to accurately determine the effect of drug on disease

• QOL measures supplement lesion measures

• Effective quantitative objective measures to assess overall severity (such as based on biopsy of lesions) aren’t available