9682305 1 GARDASIL®
[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant]
DESCRIPTION

GARDASIL* is a non-infectious recombinant, quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer.
GARDASIL is a sterile preparation for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein.
Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, and water for injection. The product does not contain a preservative or antibiotics.
After thorough agitation, GARDASIL is a white, cloudy liquid.

CLINICAL PHARMACOLOGY
Disease Burden

Human Papillomavirus (HPV) causes squamous cell cervical cancer (and its histologic precursor lesions Cervical Intraepithelial Neoplasia [CIN] 1 or low grade dysplasia and CIN 2/3 or moderate to high grade dysplasia) and cervical adenocarcinoma (and its precursor lesion adenocarcinoma in situ [AIS]). HPV also causes approximately 35-50% of vulvar and vaginal cancers. Vulvar Intraepithelial Neoplasia (VIN) Grade 2/3 and Vaginal Intraepithelial Neoplasia (VaIN) Grade 2/3 are immediate precursors to these cancers.
Cervical cancer prevention focuses on routine screening and early intervention. This strategy has reduced cervical cancer rates by approximately 75% in compliant individuals by monitoring and removing premalignant dysplastic lesions.
HPV also causes genital warts (condyloma acuminata) which are growths of the cervicovaginal, vulvar, and the external genitalia that rarely progress to cancer. HPV 6, 11, 16, and 18 are common HPV types.
HPV 16 and 18 cause approximately:


• 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 cases; and

• 50% of CIN 2 cases.


HPV 6, 11, 16, and 18 cause approximately:


• 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases; and

• 90% of genital wart cases.

* Registered trademark of MERCK & CO., Inc. Whitehouse Station, NJ 08889, USA COPYRIGHT © 2006 MERCK & CO., Inc. All rights reserved GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] 9682305 2
Mechanism of Action

HPV only infects humans, but animal studies with analogous (animal, not human) papillomaviruses suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.

CLINICAL STUDIES

CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer; thus, they serve as surrogate markers for prevention of cervical cancer.
Efficacy was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (Protocol 005, N = 2391) and the second evaluated all components of GARDASIL (Protocol 007, N = 551). The Phase III studies, termed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease), evaluated GARDASIL in 5442 (FUTURE I or Protocol 013) and 12,157 (FUTURE II or Protocol 015) subjects. Together, these four studies evaluated 20,541 women 16 to 26 years of age at enrollment. The median duration of follow-up was 4.0, 3.0, 2.4, and 2.0 years for Protocol 005, Protocol 007, FUTURE I, and FUTURE II, respectively. Subjects received vaccine or placebo on the day of enrollment, and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies combined according to a prospective clinical plan.

Prophylactic Efficacy

GARDASIL is designed to prevent HPV 6-, 11-, 16-, and/or 18-related cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts. GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of subjects regardless of baseline HPV status (i.e., Polymerase Chain Reaction [PCR] status or serostatus). Subjects who were infected with a particular vaccine HPV type (and who may already have had disease due to that infection) were not eligible for prophylactic efficacy evaluations for that type.
The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population, consisting of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit.
Overall, 73% of subjects were naïve (i.e., PCR negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment.
A total of 27% of subjects had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these subjects, 74% had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were naïve (PCR negative and seronegative) to the remaining 3 types.
In subjects who were naïve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, and VaIN caused by any of the 4 vaccine HPV types were counted as endpoints.
Among subjects who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the subject was naïve (PCR negative and seronegative) were counted.
For example, in subjects who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types.
GARDASIL was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types in those who were PCR negative and seronegative at baseline (Table 1). GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] 9682305 3


†(80.9, 100.0)
‡
†(92.9, 100.0)
†(89.5, 100.0)
†P-values were computed for pre-specified primary hypothesis tests. All p-values were <0.001, supporting the following conclusions: efficacy against HPV 16/18-related CIN 2/3 is >0% (FUTURE II); efficacy against HPV 16/18-related CIN 2/3 is >25% (Combined Protocols); and efficacy against HPV 6/11/16/18-related CIN is >20% (FUTURE I).
‡Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria.
n = Number of subjects with at least 1 follow-up visit after Month 7.
Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up.
Note 2: The first analysis in the table (i.e., HPV 16- or 18-related CIN 2/3, AIS or worse) was the primary endpoint of the vaccine development plan.
Note 3: FUTURE I refers to Protocol 013; FUTURE II refers to Protocol 015.
sourc pdf

Table 1
Analysis of Efficacy of GARDASIL in the PPE* Population**

Population
GARDASIL
Placebo
% Efficacy (95% CI)
n
Number of cases
n
Number of cases

HPV 16- or 18-related CIN 2/3 or AIS

Protocol 005***

755
0
750
12
100.0 (65.1, 100.0)
Protocol 007
231
0
230
1
100.0 (-3734.9, 100.0)
FUTURE I
2200
0
2222
19
100.0 (78.5, 100.0)
FUTURE II
5301
0
5258
21
100.0
Combined Protocols 8487
0
8460
53
100.0

HPV 6-, 11-, 16-, 18-related CIN (CIN 1, CIN 2/3) or AIS

Protocol 007

235
0
233
3
100.0 (-137.8, 100.0)
FUTURE I
2240
0
2258
37
100.0
FUTURE II
5383
4
5370
43
90.7 (74.4, 97.6)
Combined Protocols
7858
4
7861
83
95.2 (87.2, 98.7)

HPV 6-, 11-, 16-, or 18-related Genital Warts

Protocol 007

235
0
233
3
100.0 (-139.5, 100.0)
FUTURE I
2261
0
2279
29
100.0 (86.4, 100.0)
FUTURE II
5401
1
5387
59
98.3 (90.2, 100.0)
Combined Protocols
7897
1
7899
91
98.9 (93.7, 100.0)

*The PPE population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7).
**See Table 2 for analysis of vaccine impact in the general population.
***Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL.