Perspectives on Enhancing Consumer Outcomes with Topical Antifungals

1. Perspectives on Enhancing Consumer Outcomeswith Topical Antifungals

2. Helmut H. Albrecht, MD, MS, FFPMVice PresidentClinical & Medical DevelopmentNovartis 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 Pedis 4

5. The Consumer Experience:Time Course of Mycology, Signs & Symptoms 4 Weeks 1 Week: Symptom Resolution Consumer Decides to Discontinue Treatment 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: 396-400, 1992 Petranyi, G, Meingassner, JG, Mieth, H. Antimicrobial Agents Chemother 31: 1365 – 1368, 1987. 8

9. Pivotal Study for OTC Switch 1 Week BID Treatment Study (pivotal study # 2506-01 (n=67) in Lamisil AT Cream NDA) - Terbinafine 88% - Vehicle 64% 7% 21% 20% 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 # 2508-01 (n=97) 10

11. 4 Week Treatment vs. Clotrimazole - Terbinafine 84% - Clotrimazole 83% 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 # 2508-01 (n=97) 11

12. Relapse/Reinfection Rates at 12 Weeks -Terbinafine - Clotrimazole 1 Week Treatment 4 Week Treatment Novartis Lamisil AT 1% Cream Study # 2508-01 (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. 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. Evaluating Lack of Effectiveness Reports LOE Cases as % of Purchases 17

18. Terbinafine Effectiveness Over Time 1991 - 1992 1995 - 1999 Study # 2-1 (n=77) and # 2-2 (n=91) Study # 98-001 (n=135) and # 351 (n=86) -Terbinafine 88% 85% - Vehicle 65% 67% 11% 30% 8% 26% 23% 1% 3% 14% Mycological Cure Effective Treatment Mycological Cure Complete 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 • 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 Good Very Good Excellent Fair 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. Proposed Product Labeling 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 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