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Valtrex® (valacyclovir HCl) Caplets NDA 20-550 / S-019

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. Presentation Outline . Study Design Efficacy Summary Virology, Safety and Behavioral Results Conclusions

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Valtrex® (valacyclovir HCl) Caplets NDA 20-550 / S-019

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

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

  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

  4. BackgroundCurrent 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)

  5. Supplemental NDA SubmissionA 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

  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

  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

  8. HS2AB3009Monitoring • 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. Virology • 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. 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

  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

  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

  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

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

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

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

  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

  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

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

  20. Condom Use for Vaginal / Anal Intercourse at Baseline

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

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

  23. Efficacy Evaluations

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

  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. Median1 Condom Use for Vaginal / Anal Intercourseduring the study 1 Median usage over months 1-8

  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 4 / 401 0 / 91 0 / 211 11 / 389 2 / 102 3 / 212 Valacyclovir Placebo p-value for treatment effect = 0.011 p-value for condom use = 0.08

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

  31. Principal Reasons for Withdrawal of Susceptible Partners

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

  34. Regional Differences

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

  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. Condom use for Vaginal / Anal Intercourse by Country

  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

  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

  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.

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

  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

  45. Viral Shedding Substudy Results

  46. BackgroundSafety • 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. 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

  48. 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 Serious Adverse Events(None associated with study medications)

  49. 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

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