1. Perspectives on Enhancing Consumer Outcomes with Topical Antifungals

2. Helmut H. Albrecht, MD, MS, FFPM Vice President Clinical & Medical Development Novartis Consumer Health

3. 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 3

4. Presentation of Interdigital Tinea Pedis4

5. The Consumer Experience: Time Course of Mycology, Signs & Symptoms
1 Week:
Symptom Resolution
Consumer Decides to Discontinue Treatment
4 Weeks
8-12 Weeks
Consumer Symptom Recognition/Treatment Initiation
Schematic based upon market research: Athlete’s Foot Category Assessment Study. Protocol Research. December 2002 (n=300) 5

6. 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 6

7. Efficacy

8. 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: , 1992
Petranyi, G, Meingassner, JG, Mieth, H. Antimicrobial Agents Chemother 31: – 1368, 1987. 8

9. Pivotal Study for OTC Switch
1 Week BID Treatment Study
(pivotal study # (n=67) in Lamisil AT Cream NDA)
- Terbinafine
88%
- Vehicle
64% 7%
20%
21% 0%
Mycological Cure
Complete Cure
Effective
Treatment
p<0.001
p<0.001
p<0.001 9

10. 1 Week Treatment vs. Clotrimazole
- Terbinafine
92%
- Clotrimazole
61%
55%
38%
19%
13%
Mycological Cure
Complete Cure
Effective
Treatment
p<0.001
p=0.532
p=0.065
Novartis Lamisil AT 1% Cream Study # (n=97) 10

11. 4 Week Treatment vs. Clotrimazole
- Terbinafine
83%
84%
- Clotrimazole
71%
47%
24%
13%
Mycological Cure
Complete Cure
Effective
Treatment
p>0.999
p=0.271
p=0.029
Novartis Lamisil AT 1% Cream Study # (n=97) 11

12. Relapse/Reinfection Rates at 12 Weeks
- Terbinafine
- Clotrimazole
1 Week Treatment
4 Week Treatment
Novartis Lamisil AT 1% Cream Study # (n=193) 12

13. Time Course for Negative Mycology
Mycological Response
% Negative Mycology
Terbinafine 1 Week
Terbinafine 4 Weeks
Clotrimazole 1 Week
Clotrimazole 4 Weeks
Study Week
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. 13

14. % Reduction in Signs and Sypmtoms
Time Course for Signs & Symptoms
Clinical Response
% Reduction in Signs and Sypmtoms
Terbinafine 1 Week
Terbinafine 4 Weeks
Clotrimazole 1 Week
Clotrimazole 4 Weeks
Study Week
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. 14

15. 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 15

16. Safety

17. LOE Cases as % of Purchases
Evaluating Lack of Effectiveness Reports
LOE Cases as % of Purchases
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 17

18. Study # 2-1 (n=77) and # 2-2 (n=91)
Terbinafine Effectiveness Over Time
Study # 2-1 (n=77) and # 2-2 (n=91)
Study # (n=135) and # 351 (n=86)
-Terbinafine
88%
85%
- Vehicle
65%
67%
11%
30% 8%
23% 1%
26% 3%
14%
Mycological Cure
Effective Treatment
Complete Cure
Mycological Cure
Effective Treatment
Complete Cure
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
(each represents avg. of 2 double-blind, placebo controlled studies, 1 week BID) 18

19. Cellulitis Rare Occurrence Relationship to drug unclear
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) 19

20. Labeling

21. Relationship Between Clinical Outcomes and Patient Assessment
- Effective Treatment
- Complete Cure
61.6%
54.8%
30.8%
22.6%
16.1%
7.7%
6.5%
Poor
Fair
Good
Very Good
Excellent
Novartis Data on File (sub-analysis from a controlled clinical trial) 21

22. Goals of Recommended Label
Set appropriate expectations
Enhance compliance
Optimize treatment outcomes
Provide stronger safety guidance 22

23. Current Product Labeling
Proposed 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 23

24. 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.” 24

25. 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 25