# Presentation: 373524

## 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**
**Questions for Committee **

## 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**

## 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)**

## 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**

## 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**

## 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**
**     **

## 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****               **

## 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**

## 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**** **

## 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**

## 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**

## 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**

##      Efficacy Summary 

**Fraser Smith, Ph.D.**
**Statistical Reviewer**
**Division of Biometrics III**

## Overview of Presentation

**Demographic and Baseline Characteristics**
**Primary and selected secondary results**
**Robustness of analyses to discontinuations**
**Regional differences**

## Patients Screened and Enrolled

**1498 / 4030 screened couples were randomized**
**Primary reason for Screen Failure:**
**   ****Lack of HSV-2 discordance within**
**   ****couples**

## 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**

## 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**

## Baseline Sexual History Susceptible Partners

**97% had sexual intercourse with source partner in last month**
**Median number of contacts in last month = 7**

## Condom Use for Vaginal / Anal Intercourse at Baseline 

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

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

## Efficacy Evaluations

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

## Percentage of Susceptible Partners who acquired HSV-2 infection defined by the primary and selected secondary endpoints 

- Withdrawals were regarded as being transmission free

## Median1 Condom Use for Vaginal / Anal Intercourseduring the study 

- 1 Median usage over months 1-8

## 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

## Percentage of Susceptible Partners with Events,  by Median Condom Use for Vaginal / Anal Intercourse

- Valacyclovir

- Placebo

- p-values represent the
- effect of condom use

## Robustness of Efficacy Analyses to Discontinuations

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

## Principal Reasons for Withdrawal of Susceptible Partners

**Principal Reasons for Withdrawal of Susceptible Partners**

## 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)**

## 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

## Regional Differences

## 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

## 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

## Overall Acquisition of Genital HSV-2 Infection in Susceptible Partners 

- p-value for overall effect of geographic region=0.11 for placebo patients

## Overall Acquisition of Genital HSV-2 Infection by Geographic Region

- p-value for overall effect of geographic region=0.11 for placebo patients

## Condom use for Vaginal / Anal Intercourse by Country

## 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**

## 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**

## 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.**

## Viral Shedding Substudy / Safety and Behavioral Results / Conclusions

**Harry W. Haverkos, M.D.**

## 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**

## Viral Shedding Substudy Results

## 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**** **

## 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**

## 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****	**

**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**

## Slide 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 **

## 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**

## 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**

## 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**

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

## 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**

## Summary

**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**

## 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 **

## 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?

## 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?

## 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.

## 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?

## 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?

## 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?

## 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