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Pharmacology: Pharmacodynamics: Mechanism of action: GARDASIL 9 is an adjuvanted non-infectious recombinant 9-valent vaccine. It is prepared from the highly purified virus-like particles (VLPs) of the major capsid L1 protein from the same four HPV types (6, 11, 16, 18) in qHPV vaccine GARDASIL and from 5 additional HPV types (31, 33, 45, 52, 58). It uses the same amorphous aluminum hydroxyphosphate sulphate adjuvant as qHPV vaccine. The VLPs cannot infect cells, reproduce or cause disease. The efficacy of L1 VLP vaccines is thought to be mediated by the development of a humoral immune response.
Based on epidemiology studies, GARDASIL 9 is anticipated to protect against the HPV types that cause approximately: 90% of cervical cancers, more than 95% of adenocarcinoma in situ (AIS), 75-85% of high-grade cervical intraepithelial neoplasia (CIN 2/3), 85-90% of HPV related vulvar cancers, 90-95% of HPV related high-grade vulvar intraepithelial neoplasia (VIN 2/3), 80-85% of HPV related vaginal cancers, 75-85% of HPV related high-grade vaginal intraepithelial neoplasia (VaIN 2/3), 90-95% of HPV related anal cancer, 85-90% of HPV related high-grade anal intraepithelial neoplasia (AIN2/3), and 90% of genital warts.
The indication of GARDASIL 9 is based on: demonstration of efficacy of qHPV vaccine to prevent persistent infection and disease related to HPV types 6, 11, 16 and 18 in females aged 16 to 45 years and males aged 16 to 26 years and robust immunogenicity in males aged 27 to 45 years.
Demonstration of non-inferior immunogenicity between GARDASIL 9 and the qHPV vaccine for HPV Types 6, 11, 16 and 18 in girls and women 9 to 26 years of age; consequently, efficacy for Gardasil 9 against persistent infection and disease related to HPV Types 6, 11, 16, or 18 can be inferred to be comparable to that of the qHPV vaccine.
Demonstration of efficacy against persistent infection and disease related to HPV Types 31, 33, 45, 52 and 58 in girls and women 16 to 26 years of age, and demonstration of non-inferior immunogenicity against the GARDASIL 9 HPV Types in boys and girls 9 to 15 years of age, men 16 to 26 years of age, and women aged 27 to 45 years compared to girls and women 16 to 26 years of age.
Clinical studies for qHPV vaccine: Efficacy In 16 - 26 year-old women and men: Efficacy was assessed in 6 placebo-controlled, double-blind, randomized Phase II and III clinical studies evaluating 28,413 individuals (20,541 girls and women 16 through 26 years of age, 4,055 boys and men 16 through 26 years of age, 3,817 women 24 through 45 years of age). The efficacy and long-term effectiveness of qHPV vaccine against HPV 6-, 11-, 16-, and 18-related disease endpoints have been demonstrated in clinical studies in the PPE (Per Protocol Efficacy) population. The PPE population consisted of individuals who received all 3 vaccinations with qHPV vaccine in the base study within 1 year of enrollment without major deviations from the study protocol, were seronegative to the relevant HPV type(s) (types 6, 11, 16 and 18) prior to dose 1, and among subjects 16 years and older at enrollment in the base study, PCR negative to the relevant HPV type(s) prior to dose 1 through one month postdose 3 (Month 7). The qHPV vaccine was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN 2/3; and VaIN 2/3 related to vaccine HPV types 6, 11, 16, or 18 in girls and women in the PPE population (Table 1). The qHPV vaccine was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in boys and men in the PPE population. Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too reducing the incidence of anal intraepithelial neoplasia (AIN) grades 2 and 3 related to vaccine HPV types 6, 11, 16, and 18 in boys and men in the PPE population (Table 1). (See Table 1.)
Click on icon to see table/diagram/imageEfficacy In 24 - 45 year-old women: The efficacy of qHPV vaccine in 24- through 45-year-old women was assessed in 1 placebo-controlled, double-blind, randomized Phase III clinical study (Protocol 019, FUTURE III) including a total of 3,817 women.
In the PPE population, the efficacy of qHPV vaccine against the combined incidence of HPV 6-, 11-, 16-, or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancers was 88.7% (95% CI: 78.1, 94.8). The efficacy of qHPV vaccine against the combined incidence of HPV 16- or 18-related persistent infection, genital warts, vulvar and vaginal lesions, CIN of any grade, AIS, and cervical cancers was 84.7% (95% CI: 67.5, 93.7). (See Table 2.)
Click on icon to see table/diagram/imageLong-term efficacy studies: A subset of subjects who received 3 doses is currently being followed up for 10 to 14 years after qHPV vaccination for safety, immunogenicity and protection against clinical diseases related to HPV types 6/11/16/18.
Persistence of antibody response (postdose 3) has been observed for 10 years in adolescents who were 9-15 years of age at time of vaccination; 14 years in women, 16 through 23 years of age at time of vaccination; 9.5 years in men, 16 through 26 years of age at time of vaccination, and 9.5 years in women, 24 through 45 years of age at time of vaccination.
In the long-term extension registry study for 16-23 year old women vaccinated with qHPV vaccine in the base study (n=2,121), no cases of HPV diseases (HPV types 6/11/16/18 related high grade CIN) were observed up to approximately 14 years. In this study, a durable protection was statistically demonstrated to approximately 12 years.
In long-term extensions of clinical studies, protection has been observed postdose 3 in the PPE population. The PPE population consisted of individuals: who received all 3 vaccinations within 1 year of enrolment, did not have major deviations from the study protocol, were seronegative to the relevant HPV type(s) (types 6, 11, 16, and 18) prior to dose 1, and among subjects 16 years and older at enrolment in the base study, were PCR negative to the relevant HPV type(s) prior to dose 1 through one month post-dose 3 (Month 7).
In long term extensions of clinical studies, no cases of high-grade intraepithelial neoplasia and no cases of genital warts were observed in subjects who received qHPV vaccine in the base study: through 10.7 years in girls (n=369) and 10.6 years in boys (n=326), 9-15 years of age at time of vaccination (median follow-up of 10.0 years and 9.9 years, respectively); through 11.5 years in men (n=917), 16-26 years of age at time of vaccination (median follow-up of 9.5 years); and through 10.1 years in women (n=684), 24-45 years of age at time of vaccination (median follow-up of 8.7 years).
Persistence of antibody response to GARDASIL was also assessed in a clinical trial using a 2-dose regimen. One month after the last dose, antibody responses to the 4 HPV types were non-inferior among girls 9 through 13 years of age who received 2 doses of GARDASIL 6 months apart compared with girls and women 16 through 26 years of age who received 3 doses of the vaccine within 6 months. In post hoc analyses at 3 and 10 years of follow-up, non-inferiority criteria were also met for all 4 HPV types.
Efficacy in HIV infected subjects: A study documenting safety and immunogenicity of qHPV vaccine has been performed in 126 HIV infected subjects aged from 7-12 years with baseline CD4% ≥15 and at least 3 months of highly active antiretroviral therapy (HAART) for subjects with a CD4% <25 (of which 96 received qHPV vaccine). Seroconversion to all four antigens occurred in more than 96% of the subjects. The Geometric Mean Titers (GMTs) were somewhat lower than reported in non-HIV infected subjects of the same age in other studies. The clinical relevance of the lower response is unknown. The safety profile was similar to non-HIV infected subjects in other studies. The CD4% or plasma HIV RNA was not affected by vaccination.
Clinical studies for GARDASIL 9: Efficacy and/or immunogenicity of the 3 dose regimen of GARDASIL 9 were assessed in nine clinical studies. Clinical studies evaluating the efficacy of GARDASIL 9 against placebo were not acceptable because HPV vaccination is recommended and implemented in many countries for protection against HPV infection and disease.
Therefore, the pivotal clinical study (Protocol 001) evaluated the efficacy of GARDASIL 9 using qHPV vaccine as a comparator.
Efficacy against HPV Types 6, 11, 16, and 18 was primarily assessed using a bridging strategy that demonstrated comparable immunogenicity (as measured by Geometric Mean Titers [GMT]) of GARDASIL 9 compared with qHPV vaccine (Protocol 001 and GDS01C/Protocol 009, and 020).
In the pivotal study Protocol 001, the efficacy of GARDASIL 9 against HPV Types 31, 33, 45, 52, and 58 was evaluated compared to qHPV vaccine in women 16 through 26 years of age (N=14,204: 7,099 receiving GARDASIL 9; 7,105 receiving qHPV vaccine).
Protocol 002 evaluated immunogenicity of GARDASIL 9 in girls and boys 9 through 15 years of age and women 16 through 26 years of age (N=3,066: 1,932 girls; 666 boys; and 468 women receiving GARDASIL 9).
Protocol 003 evaluated immunogenicity of GARDASIL 9 in men 16 through 26 years of age and women 16 through 26 years of age (N= 2,515: 1,103 Heterosexual Men [HM]; 313 Men Who Have Sex with Men [MSM]; and 1,099 women receiving GARDASIL 9).
Protocol 004 evaluated immunogenicity of GARDASIL 9 in women 16 to 45 years (N=1,210: 640 women aged 27 to 45 years and 570 girls and women aged 16 to 26 years).
Protocols 005 and 007 evaluated GARDASIL 9 concomitantly administered with vaccines recommended routinely in girls and boys 11 through 15 years of age (N=2,295).
Protocol 006 evaluated administration of GARDASIL 9 to girls and women 12 through 26 years of age previously vaccinated with qHPV vaccine (N=921; 615 receiving Gardasil 9 and 306 receiving placebo).
GDS01C/Protocol 009 evaluated immunogenicity of GARDASIL 9 in girls 9 through 15 years of age (N=600; 300 receiving GARDASIL 9 and 300 receiving qHPV vaccine).
GDS07C/Protocol 020 evaluated immunogenicity of GARDASIL 9 in men aged 16 to 26 years (N=500; 249 receiving GARDASIL 9 and 251 receiving qHPV vaccine).
Protocol 010 evaluated the immunogenicity of 2 doses of GARDASIL 9 in girls and boys 9 through 14 years of age and 3 doses of GARDASIL 9 in girls 9 through 14 years of age and women 16 through 26 years of age; (N=1,516; 751 girls; 451 boys and 314 women).
Studies supporting the efficacy of GARDASIL 9 against HPV Types 6, 11, 16, 18: Comparison of GARDASIL 9 with qHPV vaccine with respect to HPV types 6, 11, 16, and 18 were conducted in a population of 16- through 26-year-old women from Protocol 001, 9- through 15-year-old girls from GDS01C/Protocol 009 and 16- through 26-year-old boys from GDS07C/Protocol 020.
A statistical analysis of non-inferiority was performed at Month 7 comparing cLIA anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs between individuals administered GARDASIL 9 and individuals administered GARDASIL. Immune responses, measured by GMT, for GARDASIL 9 were non-inferior to immune responses for GARDASIL (Table 3). In clinical studies 98.2% to 100% who received GARDASIL 9 became seropositive for antibodies against all 9 vaccine types by Month 7 across all groups tested. (See Table 3.)
Click on icon to see table/diagram/imageStudies supporting the efficacy of GARDASIL 9 against HPV Types 31, 33, 45, 52, and 58: The efficacy of GARDASIL 9 in 16- through 26-year-old women was assessed in an active comparator controlled, double-blind, randomized clinical study (Protocol 001) that included a total of 14,204 women (Gardasil 9 = 7,099; qHPV vaccine = 7,105). Subjects were followed up to 67 months postdose 3 with a median duration of 43 months post-dose 3.
GARDASIL 9 was efficacious in preventing HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease (Table 4). GARDASIL 9 also reduced the incidence of HPV 31-, 33-, 45-, 52-, and 58- related Pap test abnormalities, cervical and external genital procedures (i.e., biopsies), and cervical definitive therapy procedures (Table 4). (See Table 4.)
Click on icon to see table/diagram/imageAdditional efficacy evaluation of GARDASIL 9 against HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58: Since the efficacy of GARDASIL 9 could not be evaluated against placebo, the following exploratory analyses were conducted.
Efficacy evaluation of GARDASIL 9 against cervical high grade diseases caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the PPE: The efficacy of GARDASIL 9 against CIN 2 and worse related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to qHPV vaccine was 94.4% (95% CI 78.8 ; 99.0) with 2/5,952 versus 36/5,947 cases. The efficacy of GARDASIL 9 against CIN 3 related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to qHPV vaccine was 100% (95% CI 46.3 ; 100.0) with 0/5,952 versus 8/5,947 cases.
Impact of GARDASIL 9 against cervical biopsy and definite therapy related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the PPE: The efficacy of GARDASIL 9 against cervical biopsy related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to qHPV vaccine was 95.9% (95% CI 92.7 ; 97.9) with 11/6016 versus 262/6018 cases. The efficacy of GARDASIL 9 against cervical definitive therapy (including loop electrosurgical excision procedure [LEEP] or conisation) related to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 compared to qHPV vaccine was 90.7% (95% CI 76.3 ; 97.0) with 4/6016 versus 43/6018 cases.
Long-term effectiveness studies: A subset of subjects is being followed up for 10 to 14 years after Gardasil 9 vaccination for safety, immunogenicity, and effectiveness against clinical diseases related to the HPV types in the vaccine.
In the long-term extensions of clinical studies Protocols 001 and 002, effectiveness was observed in the PPE population. The PPE population consisted of individuals: who received all 3 vaccinations within 1 year of enrolment, without major deviations from the study protocol, who were seronegative to the relevant vaccine HPV type(s) prior to dose 1 and among women aged 16 to 26 years, PCR negative to the relevant vaccine HPV type(s) prior to dose 1 through one month postdose 3 (Month 7).
In Protocol 001 registry study, no cases of vaccine HPV types related high-grade CIN were observed through 9.5 years postdose 3 (median follow-up of 6.3 years) in women (n = 1,448) who were aged 16 to 26 years at time of vaccination with Gardasil 9.
In Protocol 002 extension study, no cases of high-grade intraepithelial neoplasia or genital warts were observed through 8.2 years postdose 3 (median follow-up of 7.6 years) in girls (n = 864) and through 8.1 years postdose 3 (median follow-up of 7.6 years) in boys (n = 261) who were aged 9 to 15 years at time of vaccination with Gardasil 9.
Immunogenicity: The minimum anti-HPV titer that confers protective efficacy has not been determined.
Type-specific immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate.
Immune response to GARDASIL 9 at month 7 across all clinical studies: Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT).
GARDASIL 9 induced robust anti-HPV 6, anti-HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti-HPV 52, and anti-HPV 58 responses measured at Month 7, in Protocols 001, 002, 004, 005, 007 and GDS01C/009 (Table 5). In clinical studies 99.2% to 100% who received GARDASIL 9 became seropositive for antibodies against all 9 vaccine types by Month 7 across all groups tested. GMTs were higher in girls and boys than in 16- through 26-year-old women, and higher in boys than in girls and women. As expected for women 27 through 45 years of age (Protocol 004), the observed GMTs were lower than those seen in girls and women 16 through 26 years of age. (See Table 5.)
Click on icon to see table/diagram/imageAnti-HPV responses at Month 7 among 9- through 15-year-old girls/boys were comparable to anti-HPV responses in 16- through 26-year-old women in the combined database of immunogenicity studies for Gardasil 9.
On the basis of this immunogenicity bridging, the efficacy of GARDASIL 9 in 9- through 15-year-old girls and boys is inferred.
In Protocol 003, anti-HPV antibody GMTs at Month 7 among 16- through 26-year-old boys and men (HM) were comparable to anti-HPV antibody GMTs among 16- through 26-year-old girls and women. High immunogenicity in 16- through 26-year-old MSM was also observed, although lower than in HM, similarly to qHPV vaccine. In Protocol 020/GDS07C, anti-HPV antibody GMTs at Month 7 among boys and men (HM) aged 16 to 26 years were comparable to anti-HPV antibody GMTs among boys and men (HM) aged 16 to 26 years administered with the qHPV vaccine for HPV 6, 11, 16 and 18. These results support the efficacy of Gardasil 9 in the male population.
In Protocol 004, anti-HPV antibody GMTs at Month 7 among women aged 27 to 45 years were non-inferior to anti-HPV antibody GMTs among girls and women aged 16 to 26 years for HPV 16, 18, 31, 33, 45, 52, and 58, with GMT ratios between 0.66 and 0.73. In a post-hoc analysis for HPV 6 and 11, the GMT ratios were 0.81 and 0.76, respectively. These results support the efficacy of Gardasil 9 in women aged 27 to 45 years. (See Table 6.)
Click on icon to see table/diagram/imageWomen 27 Years of Age and Older: Effectiveness of GARDASIL 9 against persistent infection and disease related to vaccine HPV types in 27- through 45-year-old women was inferred based on non-inferiority of GMTs following vaccination with GARDASIL 9 in 27- through 45-year-old women compared to 16- through 26-year-old girls and women and demonstration of efficacy of GARDASIL in girls and women 16 through 45 years of age. In Protocol 004, GARDASIL 9 elicited seroconversion rates for all nine vaccine HPV types greater than 99% in girls and women 16 through 45 years of age. Anti-HPV antibody GMTs at Month 7 among women 27 through 45 years of age were non-inferior to anti-HPV antibody GMTs among girls and women 16 through 26 years of age for HPV 16, 18, 31, 33, 45, 52, and 58. These results support the efficacy of GARDASIL 9 in women 27 through 45 years of age.
Immune Responses to GARDASIL 9 Using a 2-dose Schedule in Individuals 9- through 14 Years of Age: Protocol 010 measured HPV antibody responses to the 9 HPV types after GARDASIL 9 vaccination in the following cohorts: girls and boys 9- through 14 years of age receiving 2 doses at a 6 month or 12- month interval (+/- 1 month); girls 9- through 14 years of age receiving 3 doses (at 0, 2, 6 months); and women 16- through 26 years of age receiving 3 doses (at 0, 2, 6 months).
GMTs were non-inferior in girls and boys who received 2 doses of GARDASIL 9 (at either 0, 6 months or 0, 12 months) to GMTs in 16 through 26 year old girls and women who received 3 doses of GARDASIL 9 (at 0, 2, 6 months) for each of the 9 vaccine HPV types. On the basis of this immunogenicity bridging, the efficacy of a 2-dose regimen of GARDASIL 9 in 9 through 14 year old girls and boys is inferred. One month following the last dose of the assigned regimen, between 97.9% and 100% of subjects across all groups became seropositive for antibodies against the 9 vaccine HPV types (Table 7).
In the same study, in girls and boys 9 through 14 years of age, GMTs at one month after the last vaccine dose were numerically lower for some vaccine types after a 2-dose schedule than in girls 9 through 14 years of age after a 3-dose schedule (HPV types 18, 31, 45, and 52 after 0, 6 months and HPV type 45 after 0, 12 months; Table 7). The clinical relevance of these findings is unknown.
In girls and boys receiving 2 doses at 6-or 12-monthinterval (+/-1-month), persistence of antibody response was demonstrated through Month 36; depending on HPV type, 81% to 99% of girls and boys receiving 2 doses at 6-month interval and 88% to 100% of girls and boys receiving 2 doses at 12-month interval were seropositive. At Month 36, the GMTs in girls and boys aged 9 to 14 years receiving 2 doses at a 6-month interval (+/-1-month) remained non-inferior to GMTs in women aged 16 to 26 years receiving 3 doses of Gardasil 9.
Duration of protection of a 2-dose schedule of GARDASIL 9 has not been established. (See Table 7.)
Click on icon to see table/diagram/imagePersistence of immune response to GARDASIL 9: The persistence of antibody response following a complete schedule of vaccination with GARDASIL 9 is being studied in a subset of individuals who will be followed up for at least 10 years after vaccination for safety, immunogenicity and effectiveness.
In 9-15 year-old boys and girls (Protocol 002), persistence of antibody response has been demonstrated for at least 7 years; depending on HPV type, 91 to 99% of subjects were seropositive.
In 16-26 year-old women (Protocol 001), persistence of antibody response has been demonstrated for at least 5 years; depending on HPV type, 78 to 100% of subjects were seropositive. Efficacy was maintained in all subjects regardless of seropositivity status for any vaccine HPV type through the end of the study (up to 67 months postdose 3; median follow-up duration of 43 months postdose 3).
GMTs for HPV-6, -11, -16 and -18 were numerically comparable in subjects who received qHPV vaccine or GARDASIL 9 for at least 3.5 years.
Evidence of Anamnestic (Immune Memory) Response: Evidence of an anamnestic response was seen in vaccinated women who were seropositive to relevant HPV type(s) prior to vaccination. In addition, women (n = 150) who received 3 doses of GARDASIL 9 in Protocol 001 and a challenge dose 5 years later, exhibited a rapid and strong anamnestic response that exceeded the anti-HPV GMTs observed 1 month postdose 3.
Administration of GARDASIL 9 to individuals previously vaccinated with qHPV vaccine: Protocol 006 evaluated the immunogenicity of GARDASIL 9 in 921 girls and women (12 through 26 years of age) who had previously been vaccinated with qHPV vaccine. For subjects receiving GARDASIL 9 after receiving 3 doses of qHPV vaccine, there was an interval of at least 12 months between completion of vaccination with qHPV vaccine and the start of vaccination with GARDASIL 9 with a 3-dose regimen (the time interval ranged from approximately 12 to 36 months).
Seropositivity to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the per protocol population ranged from 98.3 to 100% by Month 7 in individuals who received GARDASIL 9. The GMTs to HPV Types 6, 11, 16, 18 were higher than in the population who had not previously received qHPV vaccine in other studies whereas the GMTs to HPV Types 31, 33, 45, 52 and 58 were lower. The clinical significance of this observation is not known.
Pregnancy: Specific studies of GARDASIL 9 in pregnant women were not conducted. The qHPV vaccine was used as an active control during the clinical development program for GARDASIL 9.
During the clinical development of GARDASIL 9; 2,586 women (1,347 in the Gardasil 9 group vs. 1,239 in the qHPV vaccine group) reported at least one pregnancy. The types of anomalies or proportion of pregnancies with an adverse outcome in individuals who received GARDASIL 9 or qHPV vaccine were comparable and consistent with the general population.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: A repeat dose toxicity study in rats, which included an evaluation of single-dose toxicity and local tolerance, revealed no special hazards to humans.
GARDASIL 9 administered to female rats had no effects on mating performance, fertility, or embryonic/foetal development.
GARDASIL 9 administered to female rats had no effects on development, behaviour, reproductive performance or fertility of the offspring. Antibodies against all 9 HPV types were transferred to the offspring during gestation and lactation.
