Overview of Overview of Sheryl Murphy, MS, RD Medical Affairs GlaxoSmithKline.

Overview ofOverview of

Sheryl Murphy, MS, RDSheryl Murphy, MS, RDMedical Affairs Medical Affairs

GlaxoSmithKline GlaxoSmithKline

Agenda

Overview – Rx History and Clinical Experience 60 mg Efficacy and Safety Data Actual Use Study Results alli Label and Program alli vs. Xenical.

Extensive Clinical & Post-Marketing History

More than 100 clinical studiesMore than 100 clinical studies

30,000 clinical trial patients30,000 clinical trial patients

Data in up to 4 years of treatmentData in up to 4 years of treatment

25 million patient treatments 25 million patient treatments

Available in more than 145 countries.Available in more than 145 countries.

absorptionabsorption

Passes through GI Tract

Fat absorption blocked25%

A Unique Mechanism of ActionA Unique Mechanism of ActiontriglyceridelipaseOrlistat

Monoglycerides

Small intestine wall

Fatty acids

Benefits Based on the Drug’s Mechanism Based on the Drug’s Mechanism of Action of Action

Non-systemic acting

Non-CNS acting

Non-addictive

No negative impact on cardiovascular system

Minimally absorbed

No residual effect.

Dose-Response CurveDose-Response Curve%

fec

al f

at e

xcre

tio

n

Orlistat dose (mg) tid

30 120 240 40060

60

50

40

30

20

10

0

Zhi J et al. Clin Pharmacol Ther 1994; 56: 82–85

60 mg Ideal Dose for OTC60 mg Ideal Dose for OTCDose Ranging StudyDose Ranging Study

6 month randomized, double-blind, placebo-controlled, multi-center, confirmatory dose ranging study

Weight Loss Results:

60 mg is minimum effective dose 120

123

122

NP-value

Active vs. Placebo

Placebo-Subtracted Weight Loss (kg)

Dose

- 2.55

- 1.86

- 0.95

p<0.002120 mg

P=0.00260 mg

p=0.10630 mg

Van Gaal LF, Broom JI, Enzi G, Toplak H. Efficacy and tolerability of orlistat in the treatment of obesity – a 6 month dose-ranging study. Eur J Clin Pharmacol 1998 (54): 125-132.

60 mg Controlled Clinical Studies60 mg Controlled Clinical Studies

Plc, 60, 120 mg25-431,729Total

Plc, 60 mg25-284 months378U.S.Anderson

Plc, 60, 120 mg30-432 years635U.S.Hauptman

Plc, 60, 120 mg28-432 years716EuropeRossner

DoseBMIDurationN

ITTLocationStudy

Rossner S, Sjostrom L, Noack R, et al. Obesity Research 2000; 1: 49-61

Hauptman J, Lucas C, Boldrin M, et al. Arch Fam Med 2000; 9: 160-167

Anderson J, Schwartz S, Hauptman J, et al. Ann Pharmacother 2006; 40: 1717-23

Significant and Consistent Weight Loss Significant and Consistent Weight Loss Across All StudiesAcross All Studies

Placebo

60 mg tid

120 mg tid

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24

Pooled Rossner and Hauptman Studies

% c

han

ge

fro

m b

asel

ine

Study Week

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24

Anderson Study

% c

han

ge

fro

m b

asel

ine

Study Week

ITT population, observed data; mean +/-- SE

60 mg tid

Placebo

Percent of Patients Who Lost Percent of Patients Who Lost ≥ 5% Body ≥ 5% Body WeightWeight at 6 months at 6 months

49.3*5.1 0.24451120 mg tid

46.7*4.6 0.2445260 mg tid

26.42.10.25448Placebo

% of Subjects with ≥ 5% Weight ≥ 5% Weight

LossLoss Kg. lost

SENTreatment

* Significant difference with respect to placebo (P<0.05). ITT, LOCF.

Improvements In Risk Factors at 4 months in Overweight Subjects

* Significance from baseline at 4 months for 60 mg vs. placebo, p<0.05ITT population, observed data

Total-C LDL-C Systolic BP Diastolic BP

*

*

**

-6

-5

-4

-3

-2

-1

0

1%

ch

ang

e fr

om

ran

do

miz

atio

n

Placebo

60 mg tid

A Well Established Safety ProfileA Well Established Safety Profile

Extensive clinical trial data and post-marketing experience

Overall good tolerability

Low withdrawal rates

Few drug interactions

Minimal impact on fat soluble vitamins.

05

101520253035404550

Oily spotting Flatus withDischarge

Fecal incontinence Fecal urgency

60 mg 120 mg

Onset of GI AEs during first 4 weeks of Onset of GI AEs during first 4 weeks of treatment: 60 vs. 120 mgtreatment: 60 vs. 120 mgPooled Studies

Events with significantly different time to first occurrence (P<0.05) using generalized Wilcoxon test to compare survival curves.Data from orlistat 60 mg pooled studies

4 Weeks

% p

atie

nts

wit

h a

n e

ven

t

Low Withdrawal Rates at 6 MonthsLow Withdrawal Rates at 6 Months

0

5

10

15

20

25

Placebo 60 mg tid 120 mg tid

% o

f su

bje

cts

Non-AE Non-GI AE GI AE

19.7% 10.4% 10.8%

1.4%

1.8% 2.0%

0.8%

3.2%

5.4%

60 mg vs. 120 mg60 mg vs. 120 mg

Advantages of 60 mg vs 120 mg:

– Fewer GI events with 60 mg dose

– Significantly lower chance of GI events in first four weeks of treatment

– One third fewer GI events within first week

– Lower withdrawal rate due to GI event

60 mg dose provides overall better tolerability to enhance compliance

Low Potential for MisuseLow Potential for Misuse

No abuse liability

– Not centrally acting

– No subjective effect

Low misuse potential

– 4 published cases of misuse reported worldwide1

– No published reports of misuse by anorexics/teens

– No dose dependent effect

1 as of January, 06

Rate of Rate of 2 Consecutive Below-Normal2 Consecutive Below-NormalVitamin Levels in 6 Months of Treatment Vitamin Levels in 6 Months of Treatment

* Significant difference between 60-mg and 120-mg doses; Fisher’s Exact Test at p<0.05

This analysis includes all U.S. Studies (NM14336, NM14161, and NM14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation.

40/977 (4.1)3/207 (1.4)2/576 (0.3)Beta-carotene

29/944 (3.1)

50/954 (5.2)

15/962 (1.6)

120 mg (%)

7/196 (3.6)

2/209 (1.0)*

1/203 (0.5)

2/565 (0.4)Vitamin E

13/558 (2.3)Vitamin D

3/580 (0.5)Vitamin A

60 mg (%)Placebo (%)

Daily Multivitamin Daily Multivitamin RecommendationRecommendation

When using this product• you need to take a multivitamin once daily, at bedtime. Orlistat can reduce the absorption of some vitamins.

Directions• you need to take a multivitamin once daily, at bedtime, when using orlistat capsules

Low Potential Low Potential for Drug Interactionsfor Drug Interactions

WarningsOrgan transplant alert• do not use if you have had an organ transplant. Orlistat interferes with the medicines used to prevent transplant rejection.Do not use• if you are taking cyclosporine• if you have been diagnosed with problems absorbing food• if you are not overweight

Ask a doctor or pharmacist before use if you are• taking warfarin (blood thinning medicine). You should have your blood testedregularly during weight loss.• taking medicine for diabetes or thyroid disease. Your medication dose may need to be

adjusted during weight loss.• taking other weight loss products

Low Potential Low Potential for Drug Interactionsfor Drug Interactions

Efficacy and Safety RecapEfficacy and Safety Recap

plus diet always significantly better than placebo and diet alone– Data demonstrate 50 percent more weight loss than dieting alone,

e.g., for every 5 pounds lost from diet alone, orlistat will help provide 2-3 pounds more.

Safety and tolerability suitable for OTC– No abuse liability

– Low misuse potential

– Very manageable tolerability by adhering to the recommended diet

Will Consumers use alli correctlyonce they take it home

and use it without supervision?

Actual Use Trial Design:Usage Phase Procedures

Dispensing

– drug + behavioral materials

– No instruction/counseling Data collection by phone

– Days 14, 30, 60, 90 Usage patterns

– AEs

– Weight loss

– Satisfaction

BMI Distribution of Self-Selectors inBMI Distribution of Self-Selectors inActual Use TrialActual Use Trial

0

5

10

15

20

25

30

35

18.5 18.5-22 22-25 25-30 30-35 35

Baseline BMI (kg/m2)

% o

f su

bje

cts

(N=

543)

Under Normal Over Obese

Consumers Took Product 2-3 Times a DayConsumers Took Product 2-3 Times a Day

0

10

20

30

40

50

60

70

0 1 2 3 4+Occasions per day

% o

f su

bje

cts

Day 14 (N=217) Day 90 (N=148)

95% with 95% with mealsmeals

Users Managed GI EffectsUsers Managed GI Effects

No alli-specificGI effects

50%Discontinue

9%

Continue

33%Interrupt

8%

Actual Use Trial Recap Actual Use Trial Recap

Recognize overweight

Understand the orlistat label

Used orlistat correctly, according to label

Used orlistat safely

Lost weight and were satisfied

Modified their diet and increased exercise.

Label and ProgramLabel and Program

OTC vs. Rx Orlistat

IndicationIndication Promote Weight Promote Weight LossLoss

Obesity management including weight loss, weight maintenance, and prevention of weight regain

AgeAge >= 18 years>= 18 years >= 12 years>= 12 years

DoseDose 60 mg TID with each meal containing fat

120 mg TID with each meal containing fat

OTC Drug Facts Label OTC Drug Facts Label

For weight loss in overweight adults, 18 years and older

1 capsule with each meal containing fat; not to exceed 3 capsules daily

Duration Guidelines: – Continue until you reach your

weight loss goal. Most weight loss usually occurs within the first six months.

– If you stop using orlistat, continue with a diet and exercise program

– If you stop taking orlistat you may regain weight. You may need to continue taking orlistat along with a reduced calorie, low-fat diet and exercise program.

OTC Drug Facts LabelOTC Drug Facts Label

Take a multivitaminTake a multivitamin Follow a well-balanced diet, low in Follow a well-balanced diet, low in

fat and calories fat and calories Start diet and exercise before you Start diet and exercise before you

begin taking orlistat begin taking orlistat You may experience bowel You may experience bowel

changeschanges– Reducing the fat in your diet Reducing the fat in your diet

should decrease these changesshould decrease these changes Weight loss will varyWeight loss will vary

– 5 pounds you lose from diet 5 pounds you lose from diet alone, orlistat can help you alone, orlistat can help you lose 2-3 pounds morelose 2-3 pounds more

– Average weight loss was 5-10 Average weight loss was 5-10 pounds over 6 monthspounds over 6 months

Is it right for me?

Orlistat is not for everyone, so read the Orlistat is not for everyone, so read the label carefully before you beginlabel carefully before you begin

Orlistat is only for people who are Orlistat is only for people who are overweightoverweight

To determine if orlistat is right for you:To determine if orlistat is right for you:– find your height find your height – You may consider starting a weight You may consider starting a weight

loss program with orlistat if your loss program with orlistat if your weight is the same or more than the weight is the same or more than the weight shown for your heightweight shown for your height

More Than A Pill…It’s a Program

Starter Pack: Extensive Educational Materials

Welcome Guide Keys to Success Companion Guide QuickFact Cards Healthy Eating Guide Calorie and Fat Counter Daily Journal

Online Year-Long Support Program alli 60mg Capsules Convenient Carrying Case

Refill Pack: Companion Guide Online Year-Long

Support Program alli 60mg Capsules

myalliplan.com Dedicated Behavioral Support Site

Objectives– Reinforce understanding of alli

– Ensure successful adoption of healthy eating habits

Online support for 1 Year

Interactive

Web and print

myalliplan tailored to the individual:– Gender

– Activity level

– Knowledge of a low-fat diet

– Eating patterns

– Weight loss goal

Behavioral Support Program FormatBehavioral Support Program Format

Phase 1 (up to one year)

– Weekly for 8 weeks

– Biweekly for 14 weeks

– Monthly for 30 weeks

Phase 2 (after stopping alli)

– Diet and exercise tips

Weight Loss Maintenance

Key Elements of Consumer Success Key Elements of Consumer Success

Target consumers ready to commit to long-term lifestyle change, work hard–Willing to adopt a low-fat, reduced-calorie diet

–Willing to participate in behavior support program

–Not looking for a magic pill

A focus on education –Set realistic weight loss expectations

–Communicate how alli works

–Educate consumers on healthy, sensible eating and exercise

ConclusionsConclusions

Only FDA-approved, OTC weight-loss product

Studied extensively and safely taken by millions

Provides 50% more weight loss than diet alone

Doesn’t act upon CV or CNS systems

Tolerability managed by adhering to diet

Comprehensive program with a sensible diet.