Perspectives on Enhancing

Consumer Outcomeswith Topical Antifungals

Helmut H. Albrecht, MD, MS, FFPM

Vice PresidentClinical & Medical Development

Novartis Consumer Health

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Overview

Enhanced labeling to improve compliance and achieve optimal treatment benefit

Terbinafine offers unique efficacy and safety profile

Appropriate endpoints should guide product development, consumer expectation and labeling

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Presentation of Interdigital Tinea Pedis

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1 Week: Symptom ResolutionConsumer Decides to Discontinue Treatment

The Consumer Experience:Time Course of Mycology, Signs &

Symptoms

Mycology

Symptoms

Signs

4 Weeks 8-12 WeeksConsumer Symptom Recognition/Treatment Initiation

Schematic based upon market research: Athlete’s Foot Category Assessment Study. Protocol Research. December 2002 (n=300)

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Topical Terbinafine – Product Overview

Synthetic allylamine with fungicidal activity

Efficacy with only 1 week treatment; no need for additional therapy

Rx in US in 1992 and OTC in 1999

Demonstrated safety profile (>200 million exposures)

Only active ingredient in Lamisil AT line

Efficacy

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Terbinafine Activity

in vitro:

• MICs:

- 0.003 – 0.006 μg/mL

- 100 – 1000x more potent than other antifungals

in vivo:

• 7 days of treatment: 1000x MIC

• 7 days post-treatment: 100x MIC

Hill, S, Thomas, R, Smith, SG and Finlay, AY. Br. J. Derm 127: 396-400, 1992

Petranyi, G, Meingassner, JG, Mieth, H. Antimicrobial Agents Chemother 31: 1365 – 1368, 1987.

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0%

100%

Pivotal Study for OTC Switch

- Terbinafine- Vehicle

1 Week BID Treatment Study(pivotal study # 2506-01 (n=67) in Lamisil AT Cream NDA)

Mycological Cure Effective Treatment

Complete Cure

88%

20%

64%

7%

21% 0%

p<0.001

p<0.001p<0.001

10

0%

100%

1 Week Treatment vs. Clotrimazole

- Terbinafine- Clotrimazole

Mycological Cure Complete Cure

92%

55%61%

38%

19%13%

Novartis Lamisil AT 1% Cream Study # 2508-01 (n=97)

p<0.001p=0.065

p=0.532

Effective Treatment

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0%

100%

4 Week Treatment vs. Clotrimazole

- Terbinafine- Clotrimazole

Mycological Cure Complete Cure

Novartis Lamisil AT 1% Cream Study # 2508-01 (n=97)

83% 84%

71%

47%

13%

24%

p>0.999p=0.029

p=0.271Effective Treatment

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Relapse/Reinfection Rates at 12 Weeks

9% 11%

47%

30%

0%

100%

1 Week Treatment 4 Week Treatment

- Terbinafine- Clotrimazole

Novartis Lamisil AT 1% Cream Study # 2508-01 (n=193)

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%

%

0 1 2 3 4 5 6 7 8 9 10 11 12

0

100

Terbinafine - 1 Week BID

Terbinafine - 4 Week BID

Clotrimazole - 1 Week BID

Cotrimazole - 4 Week BID

Time Course for Negative Mycology

Mycological Response

1 Week BID – Terbinafine vs. Clotrimazole: p=0.003 (6 weeks); p<0.001 (12 weeks)Bergstresser PR et al. J Am Acad Dermatol. 28:648-51, 1993.

Study Week

% N

eg

ati

ve M

ycolo

gy

Terbinafine 1 Week

Terbinafine 4 Weeks

Clotrimazole 1 Week

Clotrimazole 4 Weeks

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0 1 2 3 4 5 6 7 8 9 10 11 12

0%

100%

Terbinafine - 1 Week

Terbinafine - 4 Week

Clotrimazole - 1 Week

Clotrimazole - 4 Week

Time Course for Signs & Symptoms

Clinical Response

1 Week BID – Terbinafine vs. Clotrimazole: p=0.055 (6 weeks); p=0.006 (12 weeks)Bergstresser PR et al. J Am Acad Dermatol. 28:648-51, 1993.

Study Week

% R

ed

ucti

on

in

Sig

ns a

nd

S

yp

mto

ms

Terbinafine 1 Week

Terbinafine 4 Weeks

Clotrimazole 1 Week

Clotrimazole 4 Weeks

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New Product Development Requirements

Efficacy to be established based solely on separation from placebo New Chemical Entities (NCEs):

Dose ranging studies needed

Line Extensions: Dermal PK/MIC data to establish dose Frequency and duration studies may be

necessary

Safety

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Evaluating Lack of Effectiveness Reports

LOE Cases as % of Purchases

0.002%0.002%

0.003%0.003%

0.005%

0.000%

0.006%

Year 1999 2000 2001 2002 2003

LOE Cases 221 178 169 135 139

Units Sold 4,106,655 5,529,761 5,515,180 5,561,519 6,085,244

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0%

100%Study # 98-001 (n=135) and # 351

(n=86)

0%

100%

Terbinafine Effectiveness Over Time

-Terbinafine

- Vehicle

1991 - 1992 1995 - 1999

Effective Treatment

Mycological Cure

(each represents avg. of 2 double-blind, placebo controlled studies, 1 week BID)

Effective Treatment

Mycological Cure

85%

14%

67%

8%26% 3%

Complete Cure

Complete Cure

88%

23%

65%

11% 30%1%

Study # 2-1 (n=77) and # 2-2 (n=91)

p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001

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Cellulitis

Rare Occurrence

−13 cases since 1965

−5 cases with Lamisil since 1993

Relationship to drug unclear

Associated with underlying condition

−Risk reduced by treatment

−Labeling recommendation to include warnings for at risk populations (e.g. diabetics)

Labeling

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0%

100%

Relationship Between Clinical Outcomes and Patient Assessment

- Effective Treatment- Complete Cure

6.5%

16.1%

7.7%

22.6%

30.8%

54.8%

61.6%

Novartis Data on File (sub-analysis from a controlled clinical trial)

Poor Fair Good Very Good Excellent

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Goals of Recommended Label

• Set appropriate expectations• Enhance compliance• Optimize treatment outcomes• Provide stronger safety guidance

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Current Product Labeling

Remove “Cures Most Athlete’s Foot”

Replace with “Athlete’s Foot Treatment”

To enhance compliance

Add “Must be used twice daily for full 7 days to eliminate fungal infection”

Move “Relieves itching and burning” to Drug Facts

Proposed Product Labeling

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Proposed Product Labeling: Drug Facts

Optimize treatment outcomes Set appropriate expectations

“Many get relief from their symptoms (itching and burning) after 1 week of treatment. Signs such as redness will last longer until the outer layer of skin naturally replaces itself.”

• Provide stronger safety guidance “Stop use and ask a doctor if condition

worsens or new symptoms develop; this is especially important if you have diabetes.”

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Conclusions

Terbinafine is a safe and effective 1-week treatment for tinea pedis No evidence of increases in LOE or resistance

development

Effective Treatment appropriate endpoint for efficacy data in labeling

New product developments require different standards for NCEs and NDA line extensions Approval standard based on separation from placebo

Proposed label would set appropriate expectations, enhance compliance, optimize treatment outcomes and provide stronger safety guidance