Suppressive Therapy with Valtrex (valacyclovir HCl ...

Results

• Description of Study Couples
• Primary Endpoint
• Secondary Endpoints

A 51

Results

• Description of Study Couples
• Primary Endpoint
• Secondary Endpoints

– Recurrences in Source Partner
– Viral Shedding
– Overall Acquisitions

A 52

Proportion of Source Partners
Recurrence-Free at 8 Months

Percentage Recurrence-Free 60 P <0.001
50 47% RR: 3.45 (95% CI: 2.83, 4.20)
40 346 / 743
30 13%
20 100 / 741
10
Placebo
0

Valtrex

A 53

Viral Shedding by PCR

Placebo Valtrex P

(n=50) (n=39) Value

Subjects shedding on 82% 49% 0.002
1 or more days

% of days with shedding 10.8% 2.9% <0.001
(mean)

HSV DNA copies/mL 4.2 1.7 <0.001
on all days (mean log10)

A 54

Endpoint Evaluations

71 1,355
Symptomatic Asymptomatic

Endpoint Committee 51
20 Endpoint
Endpoint Rejection
Confirmation

15 5 3 18
Seropositive Culture and/or Seropositive Seropositive
± Culture/PCR PCR Positive No swabs taken

Summary: 20 Confirmed 10 Endpoints

41 Overall Acquisitions

A 55

Proportion of Susceptible Partners with
Overall Acquisition of HSV-2 Infection

Percentage with HSV-2 Infection 4 3.6% P = 0.054
RR: 0.52 (95% CI: 0.27, 0.97)
27 / 741

3

2 1.9%

14 / 743

1

0 Valtrex
Placebo

A 56

Percentage with HSV-2 InfectionTime to Overall Acquisition of HSV-2
Infection in Susceptible Partners

P = 0.039
5 HR: 0.52 (95% CI: 0.27, 0.99)

4

3 Placebo (n=741)

2

1 Valtrex (n=743)

0
0 20 40 60 80 100 120 140 160 180 200 220 240

Time (days)

A 57

Scope of Presentation

• Rationale
• Design Considerations
• Study Methods
• Results
• Safety
• Conclusions

A 58

Summary of Adverse Events
Source Partner: Double-Blind Phase

Placebo Valtrex
(n=741) (n=743)

Any adverse event 75% 79%
Drug-related adverse event 9% 11%
Serious adverse event 2%
AE leading to treatment d/c 2%
Deaths <1% 2%
0% 0%

A 59

Most Common Adverse Events
Source Partner: Double-Blind Phase

0 20 40 60 80 100

Headache

Nasopharyngitis Placebo
URT I Valtrex

Pharyngolaryngeal pain

Diarrhea
Influenza

Nausea

Back pain

Sinusitis

Abdominal pain Percent

A 60

Clinically Significant Laboratory
Abnormalities

Source Partner: Double-Blind Phase

Placebo Valtrex
(n=741) (n=743)

Alk. phosphatase (>1.5 x ULN) 0 (0%) 0 (0%)
ALT (>2 x ULN) 16 (2%) 11 (1%)
Creatinine (>1.5 x ULN)
Hemoglobin (<0.8 x LLN) 0 (0%) 0 (0%)
Platelets (<100,000/mm3) 3 (<1%) 5 (<1%)
WBCs (<0.75 x LLN) 0 (0%) 1 (<1%)
13 (2%) 8 (1%)

A 61

Summary of Adverse Events
Source Partner:

Open-Label Follow-up Phase

• 831 Source Partners
• 68% experienced an adverse event
• Most common:

– Headache 16%
– Nasopharyngitis 13%

• 3% serious adverse events
• <1% adverse events leading to withdrawals
• No deaths

A 62

Scope of Presentation

• Rationale
• Design Considerations
• Study Methods
• Results
• Safety
• Conclusions

A 63

Conclusions
• Study HS2AB3009 met its objectives
• 75% reduction in transmission of

clinical infection and 48% overall

• Benefit additional to safer sex

counseling and use of condoms

• Well-characterized safety profile

A 64

Sponsor’s Presentation

• Introduction

– David M. Cocchetto, PhD

• Study Design, Methods, and Results

– Stuart M. Harding, MD

• Concluding Remarks

– Clarence L. Young, MD

A 65



Valtrex For Prevention Of Genital
Herpes Transmission:

Implications For Patients And
Healthcare Providers

Clarence L. Young, M.D.

Vice President, Anti-Infectives
Clinical Development & Medical Affairs

GlaxoSmithKline

A 67

Implications for Patients and
Healthcare Providers

• Landmark Study
• New Option for Patient Management
• Communication Plan
• Benefits of Prescribing Information
• Overall Conclusions

A 68

Implications for Patients and
Healthcare Providers

• Landmark Study
• New Option for Patient Management
• Communication Plan
• Benefits of Prescribing Information
• Overall Conclusions

A 69

Implications for Patients and
Healthcare Providers

• Landmark Study
• New Option for Patient Management
• Communication Plan
• Benefits of Prescribing Information
• Overall Conclusions

A 70

Implications for Patients and
Healthcare Providers

• Landmark Study
• New Option for Patient Management
• Communication Plan
• Benefits of Prescribing Information
• Overall Conclusions

A 71

Implications for Patients and
Healthcare Providers

• Landmark Study
• New Option for Patient Management
• Communication Plan
• Benefits of Prescribing Information
• Overall Conclusions

A 72

Acknowledgements

• Couples who participated in the study
• Clinical investigators and research personnel
• Some clinical investigators who are here

today:

– Larry Corey, MD, Univ of Washington
– Zane Brown, MD, Univ of Washington
– Rhoda Ashley Morrow, PhD, Univ of Washington
– Larry Stanberry, MD, PhD, Univ of Texas, Galveston
– Anna Wald, MD, MPH, Univ of Washington
– Terri Warren, ANP, Westover Heights Clinic, Portland, OR

A 73



Subject # 7753
Source Treatment: Valtrex

• Country: USA
• Randomization Date: October 22, 1999
• Date of onset clinical endpoint: June 9, 2000
• Signs and symptoms: Subject reported dysuria

approximately four days before noticing a large
erythematous papule on her external labia on June
13, 2000. On exam four additional erythematous
lesions were identified.
• Confirmatory Labs: Culture taken on June 15, 2000
was positive.

F 54

Subject # 7961
Source Treatment: Valtrex

• Country: USA
• Randomization Date: May 6, 1998
• Date of onset clinical endpoint: August 31, 1998

• Signs and symptoms: Subject returned to the clinic on
September 2, 1998 with a suspected genital herpes outbreak.
Subject stated that prodromal symptoms started on August 31,
1998, with lesions appearing on September 2, 1998. Symptoms
reported at the September 2, 1998 office visit included tender,
palpable lymph nodes in the bilateral groin, fatigue/malaise, and
genital rash.

• Confirmatory Labs: Culture and PCR taken on September 2,
1998 were negative, but serology became atypical on October
13, 1998, then positive on December 2, 1998.

F 55

Subject # 8625
Source Treatment: Valtrex

• Country: USA
• Randomization Date: June 22, 1998
• Date of onset clinical endpoint: December 2, 1998
• Signs and symptoms: Subject returned to the clinic

on December 2, 1998 with complaints of sore throat,
genital tenderness, and genital lesion that started on
December 2.
• Confirmatory Labs: Both culture and PCR from
December 2, 1998 visit were positive.

F 57

Subject # 10987
Source Treatment: Valtrex

• Country: USA
• Randomization Date: April 21, 1998
• Date of onset clinical endpoint: April 29, 1998
• Signs and symptoms: Subject presented to the clinic

on May 1, 1998 complaining of dysuria lasting 2 days.
On exam, the labia was erythematous with no
discrete lesions and extensive cervicitis.

• Confirmatory Labs: Culture and PCR from the May 1,
1998 visit were positive. In addition, serology from
the May 20, 1998 visit (month 1 of episode) was
positive.

F 61

Summary of Missing Data for
Primary Endpoint (ITT)

Susceptible partners who Placebo Valtrex
discontinued before (n = 741) (n = 743)
completing the 8 month
double-blind study 163 (22%) 158 (21%)

Time followed for primary 90 (55%) 85 (54%)
endpoint prior to 55 (34%) 52 (33%)
discontinuation: 18 (11%) 21 (13%)
< 3 months
3 to < 6 months
≥ 6 months

D2

Sensitivity Analyses for the
Prospectively Defined Primary Endpoint

Key sensitivity analyses were provided to FDA:

• Time-to-Event Analysis: uses all data for a

susceptible partner up to the time of discontinuation

• As Treated Analysis: analysis excludes susceptible

partners who discontinued

• Imputation Approach: endpoints imputed at the

placebo rate for both treatment groups
All 3 methods show superiority of Valtrex over placebo

D3

Figure 3

Susceptible Partner Discontinuations:
Length of Time Followed for Primary Endpoint

Number of discontinuations 200 Placebo
180 Valtrex
160
140 20 40 60 80 100 120 140 160 180 200 220 240
120
100

80
60
40
20

0
0

Length of time subject followed for primary endpoint (days)

D7

Summary of Key Sensitivity Analyses
for Primary Endpoint

Analysis Point Estimate 95% confidence p-value
Primary Odds Ratio = 0.24 limit

(0.06, 0.76) 0.011

Time-to-event Hazard Ratio = 0.25 (0.08, 0.75) 0.008

As treated Odds Ratio = 0.25 (0.06, 0.77) 0.012

Placebo rate imputation: Odds Ratio = 0.39 (0.15, 0.94) 0.033
4 events added Odds Ratio = 0.42 (0.17, 0.96) 0.040
5 events added

D9

Potential Discontinuation Bias Based On
Various Factors

Potential Predictive Predictive Differential
Predictive for for Primary Discontinuation
Factor
Discontinuation Outcome by Treatment

Gender No ---- ----
HSV-1 for source No ---- ----
Age for source No ---- ----
Age for susceptible No ---- ----
Recurrence history (source) No ---- ----
HSV-1 for susceptible Yes No ----
Country (US, Non-US) Yes Yes No
Duration of relationship Yes Yes No
Duration of HSV-2 (source) Yes Yes Yes*

*Implies a potential bias against Valtrex because shorter duration of HSV-2
infection is correlated with clinical acquisition, and is also associated with a higher
discontinuation rate for placebo.

D 27

Endpoint Evaluations

71 1,355
Symptomatic Asymptomatic

Endpoint Committee 51
20 Endpoint
Endpoint Rejection
Confirmation

15 5 3 18
Seropositive Culture and/or Seropositive Seropositive
± Culture/PCR PCR Positive No swabs taken

Summary: 20 Confirmed 10 Endpoints A 44
36 Seroconversions
41 Overall Acquisitions

Summary by Compliance of Symptomatic Genital
HSV-2 Infection in Susceptible Partners

Placebo Valtrex
(n=16) (n=4)

<80% 00

80-<85% 11
85-<90% 00
90-<95% 20
>=95% 13 3

Subjects with missing information for number of tablets returned were considered compliant
E 23
Subjects with any other missing information were considered non-compliant

Summary by Compliance of Overall Acquisition of
Genital HSV-2 Infection in Susceptible Partners

Placebo Valtrex
(n=27) (n=14)

<80% 01

80-<85% 11
85-<90% 12
90-<95% 24
>=95% 23 6

Subjects with missing information for number of tablets returned will be considered compliant
E 37
Subjects with any other missing information will be considered non-compliant

Summary of Treatment Compliance
in Double Blind Phase

Placebo Valtrex Total
(n=741) (n=743) (n=1484)

n 741 743 1484
0%* 41 (6%)
<40% 0 (0%) 40 (5%) 81 (5%)
40%-<60% 5 (<1%)
60%-<80% 22 (3%) 1 (<1%) 1 (<1%)
>=80%
673 (91%) 1 (<1%) 6 (<1%)

10 (1%) 32 (2%)

691 (93%) 1364 (92%)

Subject with missing information for number of caplets returned were
considered fully compliant

*Subjects with any other missing information were considered non-
compliant

S5

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bbaasseelliinnee ((NN==774433)) ((NN==774411))
335522//771133 ((4499%%))
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NNeevveerr 447777//553377 ((8899%%))
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“Nearly Always” = 90-100% - Median usage over months 1-8.

54