1. Valtrex® (valacyclovir HCl) Caplets NDA 20-550 / S-019 Harry W. Haverkos, M.D. Medical Reviewer Fraser Smith, Ph.D. Statistical Reviewer Division of Antiviral Drug Products, FDA Harry W. Haverkos, M.D. Medical Reviewer Fraser Smith, Ph.D. Statistical Reviewer Division of Antiviral Drug Products, FDA

2. 2 Presentation Outline Study Design Efficacy Summary Virology, Safety and Behavioral Results Conclusions Questions for Committee Study Design Efficacy Summary Virology, Safety and Behavioral Results Conclusions Questions for Committee

3. 3 Supplemental NDA Overview Submission Date: October 31, 2002 NDA Due Date: September 1, 2003 Dosage: Valacyclovir 500 mg qd Proposed Indication: To reduce the risk of transmission of genital herpes with the use of suppressive therapy and safer sex practices Submission Date: October 31, 2002 NDA Due Date: September 1, 2003 Dosage: Valacyclovir 500 mg qd Proposed Indication: To reduce the risk of transmission of genital herpes with the use of suppressive therapy and safer sex practices

4. 4 Background Current Indications Treatment of initial genital herpes - 1000 mg bid x 10 days Treatment of recurrent genital herpes - 500 mg bid x 3 days Chronic suppressive treatment of recurrent genital herpes - 1000 mg qd or - 500 mg qd (alternate dose) Treatment of initial genital herpes - 1000 mg bid x 10 days Treatment of recurrent genital herpes - 500 mg bid x 3 days Chronic suppressive treatment of recurrent genital herpes - 1000 mg qd or - 500 mg qd (alternate dose)

5. 5 Supplemental NDA Submission A single study - HS2AB3009 Design -multinational, randomized, double blind trial - evaluate valacyclovir for prevention of HSV-2 - discordant, monogamous, heterosexual couples Sample size: 1500 couples (4030 screened) Valacyclovir 500 mg qd versus placebo Treatment duration: 8 months All subjects encouraged to: - use condoms - abstain from sex during HSV outbreak Design -multinational, randomized, double blind trial - evaluate valacyclovir for prevention of HSV-2 - discordant, monogamous, heterosexual couples Sample size: 1500 couples (4030 screened) Valacyclovir 500 mg qd versus placebo Treatment duration: 8 months All subjects encouraged to: - use condoms - abstain from sex during HSV outbreak

6. 6 HS2AB3009 (continued) Inclusion criteria Monogamous, heterosexually active couples Source partner - HSV-2 antibody positive AND - < 10 symptomatic recurrences/year AND - a candidate for suppressive therapy Susceptible partner - HSV-2 antibody negative Monogamous, heterosexually active couples Source partner - HSV-2 antibody positive AND - < 10 symptomatic recurrences/year AND - a candidate for suppressive therapy Susceptible partner - HSV-2 antibody negative

7. 7 HS2AB3009 Primary endpoint Proportion of susceptible partners with: –clinical evidence of first episode of genital HSV-2 –confirmed by laboratory (for HSV-2) viral culture, PCR and/or serology Proportion of susceptible partners with: –clinical evidence of first episode of genital HSV-2 –confirmed by laboratory (for HSV-2) viral culture, PCR and/or serology

8. 8 HS2AB3009 Monitoring Safer sex counseling at each visit. Source partner: Monthly –review of diary cards for HSV symptoms and recurrence –expected to return for HSV recurrence Susceptible partner: Monthly –Review of diary of sex exposures and practices, and signs of HSV –Return for any suspect HSV infection Safer sex counseling at each visit. Source partner: Monthly –review of diary cards for HSV symptoms and recurrence –expected to return for HSV recurrence Susceptible partner: Monthly –Review of diary of sex exposures and practices, and signs of HSV –Return for any suspect HSV infection

9. 9 VirologyVirology HSV-2 lab confirmation defined as one or more positive findings by: –Viral culture –Viral DNA amplified by PCR –Serology by Western blot Seattle lab conducted all samples except 5 Canadian viral cultures in Vancouver lab HSV-2 lab confirmation defined as one or more positive findings by: –Viral culture –Viral DNA amplified by PCR –Serology by Western blot Seattle lab conducted all samples except 5 Canadian viral cultures in Vancouver lab

10. 10 Virology Logistical Concerns Samples from about 100 sites in >20 countries transported to Seattle or Vancouver Protocol violations included: failure to report at first sign of genital herpes, contamination, loss of sample Effects of transit on virology results Samples from about 100 sites in >20 countries transported to Seattle or Vancouver Protocol violations included: failure to report at first sign of genital herpes, contamination, loss of sample Effects of transit on virology results

11. 11 Pre-study GSK-FDA Discussions Primary endpoint Source patient inclusion: - history of clinical HSV recurrences - candidate for suppressive therapy, and - less than 10 recurrences in past year Two studies (different populations) versus one study Primary endpoint Source patient inclusion: - history of clinical HSV recurrences - candidate for suppressive therapy, and - less than 10 recurrences in past year Two studies (different populations) versus one study

12. 12 Endpoints: HSV-2 transmission Primary endpoint: Clinical signs/symptoms of HSV and laboratory confirmation Secondary endpoint: HSV-2 seroconversion Overall acquisition: Meeting either or both of above endpoints Primary endpoint: Clinical signs/symptoms of HSV and laboratory confirmation Secondary endpoint: HSV-2 seroconversion Overall acquisition: Meeting either or both of above endpoints

13. 13 Study History Initiated February 1998, completed April 2002 4030 couples screened, 1498 enrolled, 1484 randomized and received medication July 1998 amendment: HSV shedding substudy added May 2000 amendments: Sites added in Australia, Eastern Europe, and South America, Gender stratification waived Initiated February 1998, completed April 2002 4030 couples screened, 1498 enrolled, 1484 randomized and received medication July 1998 amendment: HSV shedding substudy added May 2000 amendments: Sites added in Australia, Eastern Europe, and South America, Gender stratification waived

14. Efficacy Summary Efficacy Summary Fraser Smith, Ph.D. Statistical Reviewer Division of Biometrics III Fraser Smith, Ph.D. Statistical Reviewer Division of Biometrics III

15. 15 Overview of Presentation Demographic and Baseline Characteristics Primary and selected secondary results Robustness of analyses to discontinuations Regional differences Demographic and Baseline Characteristics Primary and selected secondary results Robustness of analyses to discontinuations Regional differences

16. 16 Patients Screened and Enrolled 1498 / 4030 screened couples were randomized Primary reason for Screen Failure: Lack of HSV-2 discordance within couples 1498 / 4030 screened couples were randomized Primary reason for Screen Failure: Lack of HSV-2 discordance within couples

17. 17 Demographic Characteristics Susceptible Partners (ITT Population) 2/3 Male, 1/3 Female Median Age = 35 years 90% White 5% Hispanic 3% Black 1% Asian <1% Other Races 2/3 Male, 1/3 Female Median Age = 35 years 90% White 5% Hispanic 3% Black 1% Asian <1% Other Races

18. 18 Baseline Sexual History Susceptible Partners 1% had sexual relations with other partners in last 3 months Median duration of relationship with source partner was 2 years 22% had been treated for an STD 1% had sexual relations with other partners in last 3 months Median duration of relationship with source partner was 2 years 22% had been treated for an STD

19. 19 Baseline Sexual History Susceptible Partners 97% had sexual intercourse with source partner in last month Median number of contacts in last month = 7 97% had sexual intercourse with source partner in last month Median number of contacts in last month = 7

20. 20 Condom Use for Vaginal / Anal Intercourse at Baseline

21. 21 Summary of HSV-1 Status for Female Susceptible Partners at Randomization

22. 22 Summary of HSV-1 Status for Male Susceptible Partners at Randomization

23. Efficacy Evaluations

24. 24 Percentage of susceptible partners who acquired HSV-2 infection defined by the primary and selected secondary endpoints

25. 25 Percentage of Susceptible Partners who acquired HSV-2 infection defined by the primary and selected secondary endpoints Withdrawals were regarded as being transmission free

26. 26 Median 1 Condom Use for Vaginal / Anal Intercourse during the study 1 Median usage over months 1-8

27. 27 Percentage (+/- 95% CI) of Susceptible Partners with Clinical Endpoints, by Median Condom Use for Vaginal / Anal Intercourse Never Sometimes Nearly Always Never Sometimes Nearly Always Never Sometimes Nearly Always Never Sometimes Nearly Always 4 / 401 0 / 91 0 / 211 11 / 389 2 / 1023 / 212 4 / 401 0 / 91 0 / 211 11 / 389 2 / 1023 / 212 Valacyclovir Placebo Valacyclovir Placebo p-value for treatment effect = 0.011 p-value for condom use = 0.08

28. 28 Percentage of Susceptible Partners with Events, by Median Condom Use for Vaginal / Anal Intercourse Valacyclovir Placebo p-values represent the effect of condom use

29. Robustness of Efficacy Analyses to Discontinuations

30. 30 Percentage of Patients with a First Episode of Genital HSV-2 and Discontinuations Susceptible Partners

31. 31 Principal Reasons for Withdrawal of Susceptible Partners

32. 32 DiscontinuationsDiscontinuations None of the susceptible partners withdrew due to adverse events or lack of efficacy <1% of source partners withdrew due to adverse events (16 / 1484) <1% of source partners withdrew due to lack of efficacy (9 / 1484) None of the susceptible partners withdrew due to adverse events or lack of efficacy <1% of source partners withdrew due to adverse events (16 / 1484) <1% of source partners withdrew due to lack of efficacy (9 / 1484)

33. 33 Sensitivity Analyses: % of Clinical Episodes of Genital HSV-2 in Susceptible Partners vs. % of Withdrawals counted as treatment failures KM analysis p=0.008 162 / 743 179 / 741 19 / 743 31 / 741 11 / 743 23 / 741 4 / 743 16 / 741

34. Regional Differences

35. 35 Percentage of Patients with a First Episode of Genital HSV-2 in Susceptible Partners, by Country p-value for effect of geographic region=0.01

36. 36 Percentage of Patients with Confirmed Clinical Endpoints, by Geographic Region P-value for the effect of geographic region on the clinical evidence of genital HSV-2 = 0.01

37. 37 Overall Acquisition of Genital HSV-2 Infection in Susceptible Partners p-value for overall effect of geographic region=0.11 for placebo patients

38. 38 Overall Acquisition of Genital HSV-2 Infection by Geographic Region p-value for overall effect of geographic region=0.11 for placebo patients

39. 39 Condom use for Vaginal / Anal Intercourse by Country

40. 40 Summary / Conclusions The percentage of dropouts (>20%) was much higher than the percentage of susceptible partners classified as having clinical evidence of a first episode of genital HSV-2 Primary reasons for discontinuation include withdrawal of consent, loss to follow-up, and the ending of relationships The percentage of dropouts (>20%) was much higher than the percentage of susceptible partners classified as having clinical evidence of a first episode of genital HSV-2 Primary reasons for discontinuation include withdrawal of consent, loss to follow-up, and the ending of relationships

41. 41 Summary / Conclusions Statistical significance of primary endpoint depends on assumptions about how many discontinuations should be counted as treatment failures No transmissions were reported in Europe where approximately 20% of the patients were enrolled Statistical significance of primary endpoint depends on assumptions about how many discontinuations should be counted as treatment failures No transmissions were reported in Europe where approximately 20% of the patients were enrolled

42. 42 Summary / Conclusions Largest treatment effects observed in Australia and Canada US results similar to results for primary endpoint for all countries combined Differences between valacyclovir and placebo were not as significant for HSV-2 seroconversions and overall acquisitions, particularly in the U.S. Largest treatment effects observed in Australia and Canada US results similar to results for primary endpoint for all countries combined Differences between valacyclovir and placebo were not as significant for HSV-2 seroconversions and overall acquisitions, particularly in the U.S.

43. Viral Shedding Substudy / Safety and Behavioral Results / Conclusions Harry W. Haverkos, M.D.

44. 44 Viral Shedding Substudy 85 SOURCE patients followed intensively for 2 months at 4 U.S. sites Daily diary recording signs/symptoms of HSV recurrence Daily viral sample collection and self-exam Biweekly clinic visit for review of diary, clinical genital exam, and additional viral studies 85 SOURCE patients followed intensively for 2 months at 4 U.S. sites Daily diary recording signs/symptoms of HSV recurrence Daily viral sample collection and self-exam Biweekly clinic visit for review of diary, clinical genital exam, and additional viral studies

45. 45 Viral Shedding Substudy Results

46. 46 Background Safety WARNINGS: TTP/HUS and death occurred in patients with advanced HIV disease and allogeneic BMT and renal transplant recipients receiving valacyclovir 8 grams per day Frequently reported adverse events include nausea, headache, vomiting, dizziness, and abdominal pain WARNINGS: TTP/HUS and death occurred in patients with advanced HIV disease and allogeneic BMT and renal transplant recipients receiving valacyclovir 8 grams per day Frequently reported adverse events include nausea, headache, vomiting, dizziness, and abdominal pain

47. 47 Safety Summary No deaths No reports of TTP/HUS 14 valacyclovir and 12 placebo patients developed serious adverse events 12 valacyclovir and 5 placebo patients discontinued treatment due to AE 8 valacyclovir and 8 placebo patients became pregnant No deaths No reports of TTP/HUS 14 valacyclovir and 12 placebo patients developed serious adverse events 12 valacyclovir and 5 placebo patients discontinued treatment due to AE 8 valacyclovir and 8 placebo patients became pregnant

48. 48 Serious Adverse Events (None associated with study medications) Valacyclovir (14) Glomerulonephritis (Discontinued) Breast cancer Intestinal obstruction Spontaneous abortion, uterine fibroid Appendicitis, localized infection, lymphadenitis, meningitis Arthralgia, disk herniation, osteoarthritis Syncope, vasovagal attack Valacyclovir (14) Glomerulonephritis (Discontinued) Breast cancer Intestinal obstruction Spontaneous abortion, uterine fibroid Appendicitis, localized infection, lymphadenitis, meningitis Arthralgia, disk herniation, osteoarthritis Syncope, vasovagal attack Placebo (12) Coronary artery disease (Discontinued) Anal canal cancer Spontaneous abortion (3), Bartholin’s cyst, ovarian cyst Appendicitis, erysipelas, pancreatitis Disk herniation, lower limb fracture

49. 49

50. 50 Pregnancy outcomes (16) 4 valacyclovir-treated source patients: – –2 healthy infants, – –2 spontaneous abortions 7 placebo-treated source patients: – –3 healthy infants, – –3 spontaneous and 1 elective abortions 1 susceptible partner treated with valacyclovir – –elected abortion 4 other susceptible partners – –outcome data not presented

51. 51 STD Guidelines - 2002 Counseling Critical to management of genital herpes Goals: – –help patients cope with the infection – –prevent sexual and perinatal transmission Inform partner before initiating sexual relationship Transmission can occur during asymptomatic periods

52. 52 STD Guidelines - 2002 Counseling (continued) Abstain from sex when lesions or prodromal symptoms are present Condoms, when used consistently and correctly, can reduce the risk Sex partners might be infected even if no symptoms, testing encouraged

53. 53 STD Guidelines - Background Effect of condoms on reducing the transmission of HSV-2 from men to women Wald et al. JAMA 2001;285:3100-3106 Re-analysis of ineffective HSV-2 vaccine trial, 528 monogamous HSV-2 discordant couples followed for 18 months HSV-2 transmission occurred in 31 couples (6%) Condom use protective for women (adjusted hazard ratio - 0.085) but not for men Effect of condoms on reducing the transmission of HSV-2 from men to women Wald et al. JAMA 2001;285:3100-3106 Re-analysis of ineffective HSV-2 vaccine trial, 528 monogamous HSV-2 discordant couples followed for 18 months HSV-2 transmission occurred in 31 couples (6%) Condom use protective for women (adjusted hazard ratio - 0.085) but not for men

54. 54 Condom use reported by susceptible partners at baseline and during the study

55. 55 Limitations of Behavioral Data Condom use, oral sex poorly defined No analysis conducted concerning abstinence during outbreaks Limited descriptive data concerning relationships Multinational, multi-lingual Missing diaries Condom use, oral sex poorly defined No analysis conducted concerning abstinence during outbreaks Limited descriptive data concerning relationships Multinational, multi-lingual Missing diaries

56. 56 SummarySummary Valacyclovir appears to reduce clinical HSV-2 outbreaks among source partners and transmission to susceptible partners among monogamous, heterosexual couples The viral shedding substudy results support the use of valacyclovir to reduce HSV-2 transmission among such couples No new safety issues were identified Valacyclovir appears to reduce clinical HSV-2 outbreaks among source partners and transmission to susceptible partners among monogamous, heterosexual couples The viral shedding substudy results support the use of valacyclovir to reduce HSV-2 transmission among such couples No new safety issues were identified

57. 57 Summary (continued) Subjects continued not to use condoms during every sex act, especially oral sex acts, and not to abstain from sex during symptomatic recurrences despite monthly STD counseling Behavioral research to improve STD counseling effectiveness is urgently needed Subjects continued not to use condoms during every sex act, especially oral sex acts, and not to abstain from sex during symptomatic recurrences despite monthly STD counseling Behavioral research to improve STD counseling effectiveness is urgently needed

58. 58 Questions for the Advisory Committee 1. Does the information presented by the applicant support the use of valacyclovir to reduce the risk of transmission of genital herpes among monogamous heterosexual couples? If the answer to question #1 is yes, please address the following questions. If the answer to question #1 is no, then what additional studies should be conducted? 1. Does the information presented by the applicant support the use of valacyclovir to reduce the risk of transmission of genital herpes among monogamous heterosexual couples? If the answer to question #1 is yes, please address the following questions. If the answer to question #1 is no, then what additional studies should be conducted?

59. 59 Questions for the Advisory Committee 2. Does the information presented support the use of valacyclovir to reduce the risk of transmission of genital herpes among populations other than monogamous heterosexual couples?

60. 60 Questions for the Advisory Committee 3. In study HS2AB3009, over 4,000 couples were screened, but only 1,498 were enrolled. A large number of couples were excluded because “susceptible” partners were found to be HSV-2 positive without clinical symptoms. Please discuss the implications of screening susceptible partners for HSV prior to initiating therapy of the source partner with valacyclovir. 3. In study HS2AB3009, over 4,000 couples were screened, but only 1,498 were enrolled. A large number of couples were excluded because “susceptible” partners were found to be HSV-2 positive without clinical symptoms. Please discuss the implications of screening susceptible partners for HSV prior to initiating therapy of the source partner with valacyclovir.

61. 61 Questions for the Advisory Committee 4. In your opinion, will marketing of valacyclovir for reduction of genital herpes transmission have an impact on use of condoms and abstinence from sex during clinical HSV-2 outbreaks?

62. 62 Questions for the Advisory Committee 5. Although patients in the registrational trial were treated for eight months, valacyclovir for suppression of transmission of genital herpes will likely be used for significantly longer periods of time. What additional studies would you suggest to evaluate the potential for longer-term adverse events, including development of resistance to valacyclovir? 5. Although patients in the registrational trial were treated for eight months, valacyclovir for suppression of transmission of genital herpes will likely be used for significantly longer periods of time. What additional studies would you suggest to evaluate the potential for longer-term adverse events, including development of resistance to valacyclovir?

63. 63 Questions for the Advisory Committee 6. The primary endpoint in HS2AB3009 was the proportion of couples with clinical evidence of a first episode of genital HSV-2 in the susceptible partner. Would you recommend that primary endpoint in future studies with agents to prevent transmission of HSV-2? If not, what primary endpoint would you recommend? 6. The primary endpoint in HS2AB3009 was the proportion of couples with clinical evidence of a first episode of genital HSV-2 in the susceptible partner. Would you recommend that primary endpoint in future studies with agents to prevent transmission of HSV-2? If not, what primary endpoint would you recommend?

64. 64 Review Team Anita H. Bigger, Ph.D., Pharmacology Debra Birnkrant, M.D., Division Director Nilambar Biswal, Ph.D., Microbiology Anthony DeCicco, R.Ph., Chief, Project Management Jim Farrelly, Ph.D., Pharmacology Team Leader Stanka Kukich, M.D., Medical Team Leader Ko-Yu Lo, Ph.D., Chemistry Stephen P. Miller, Ph.D., Chemistry Team Leader Jeffrey S. Murray, M.D., M.P.H., Deputy Director Jules O'Rear, Ph.D., Microbiology Team Leader Nitin Patel, R.Ph., Regulatory Project Manager Kellie Reynolds, Pharm.D., Pharmacokinetics Team Leader Greg Soon, Ph.D., Statistical Team Leader Anita H. Bigger, Ph.D., Pharmacology Debra Birnkrant, M.D., Division Director Nilambar Biswal, Ph.D., Microbiology Anthony DeCicco, R.Ph., Chief, Project Management Jim Farrelly, Ph.D., Pharmacology Team Leader Stanka Kukich, M.D., Medical Team Leader Ko-Yu Lo, Ph.D., Chemistry Stephen P. Miller, Ph.D., Chemistry Team Leader Jeffrey S. Murray, M.D., M.P.H., Deputy Director Jules O'Rear, Ph.D., Microbiology Team Leader Nitin Patel, R.Ph., Regulatory Project Manager Kellie Reynolds, Pharm.D., Pharmacokinetics Team Leader Greg Soon, Ph.D., Statistical Team Leader