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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 aluminium 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. The genotypes for the vaccine comprised of HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58 will be referred to as vaccine HPV types.
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: 1) 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.
2) demonstration of non-inferior immunogenicity between Gardasil 9 and the qHPV vaccine for HPV Types 6, 11, 16 and 18 in girls aged 9 to 15 years, and women and men aged 16 to 26 years; 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.
3) demonstration of efficacy against persistent infection and disease related to HPV Types 31, 33, 45, 52 and 58 in girls and women aged 16 to 26 years, and
4) demonstration of non-inferior immunogenicity against the Gardasil 9 HPV Types in boys and girls aged 9 to 15 years and men aged 16 to 26 years and women aged 27 to 45 years, compared to girls and women aged 16 to 26 years.
Clinical studies for Gardasil 9: Efficacy and/or immunogenicity of Gardasil 9 were assessed in ten 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, GDS01C/Protocol 009 and GDS07C/Protocol 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 aged 16 to 26 years (N=14,204: 7,099 receiving Gardasil 9; 7,105 receiving qHPV vaccine).
Protocol 002 evaluated immunogenicity of Gardasil 9 in girls and boys aged 9 to 15 years and women aged 16 to 26 years (N=3,066: 1,932 girls; 666 boys; and 468 women receiving Gardasil 9).
Protocol 003 evaluated immunogenicity of Gardasil 9 in men aged 16 to 26 years and women aged 16 to 26 years (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 aged 16 to 45 years (N=1,210: 640 women aged 27 to 45 years and 570 women aged 16 to 26 years).
Protocols 005 and 007 evaluated Gardasil 9 concomitantly administered with vaccines recommended routinely in girls and boys aged 11 to 15 years (N=2,295).
Protocol 006 evaluated administration of Gardasil 9 to girls and women aged 12 to 26 years 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 aged 9 to 15 years (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 aged 9 to 14 years of age and 3 doses of Gardasil 9 in girls aged 9 to 14 years and women aged 16 to 26 years (N = 1,518; 753 girls; 451 boys and 314 women).
Studies supporting the efficacy of Gardasil 9 against HPV Types 6, 11, 16, 18: Efficacy of qHPV vaccine against HPV Types 6, 11, 16, 18: 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 enrolment 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 enrolment in the base study, PCR negative to the relevant HPV type(s) prior to dose 1 through one month postdose 3 (Month 7).
In 16- through 26- year-old women (N=20,541) efficacy against HPV 16- and 18-related CIN2/3, AIS or cervical cancer was 98.2 % (95 % CI: 93.5, 99.8) based on follow-up to 4 years (median 3.6 years); efficacy against HPV 6, 11, 16 or 18-related diseases was 96.0 % (95 % CI: 92.3, 98.2) for CIN or AIS, 100 % (95 % CI: 67.2, 100) for VIN2/3, 100 % (95 % CI: 55.4, 100) for VaIN2/3, and 99.0 % (95 % CI: 96.2, 99.9) for genital warts.
In 24- through 45- year-old women (N=3,817) efficacy against HPV 6, 11, 16 and 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).
In 16- through 26- year-old men (N=4,055) efficacy against HPV 6, 11, 16 or 18-related diseases was 74.9 % (95 % CI: 8.8, 95.4) for AIN 2/3 (median duration of follow-up of 2.15 years), 100.0 % (95 % CI: -52.1, 100) for penile/perineal/perianal intraepithelial neoplasia (PIN) 1/2/3, and 89.3 % (95 % CI: 65.3, 97.9) for genital warts (median duration of follow-up of 4 years).
In the long-term extension registry study for 16-23 year old women (n = 2,121), no cases of 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, no cases of high-grade intraepithelial neoplasia and no cases of genital warts were observed: 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 = 685), 24-45 years of age at time of vaccination (median follow-up of 8.7 years).
Immunogenicity bridging from qHPV Vaccine to Gardasil 9 for 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 women aged 16 to 26 years from Protocol 001, girls aged 9 to 15 years from GDS01C/Protocol 009 and men aged 16 to 26 years 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 noninferior to immune responses for Gardasil (Table 1). 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. In Protocol 001, GMTs for HPV-6, -11, -16 and -18 were comparable in subjects who received qHPV vaccine or Gardasil 9 for at least 3.5 years. (See Table 1.)
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 women aged 16 to 26 years 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 postdose 3.
Gardasil 9 was efficacious in preventing HPV 31-, 33-, 45-, 52-, and 58-related persistent infection and disease (Table 2). 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 2). (See Table 2.)
Click on icon to see table/diagram/imageAdditional efficacy evaluation of Gardasil 9 against HPV Types: 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 in the PPE: The efficacy of Gardasil 9 against CIN 2 and worse related to HPV types 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 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 in the PPE: The efficacy of Gardasil 9 against cervical biopsy related to HPV types 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 vaccine HPV types 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 11.0 years postdose 3 (median follow-up of 10.0 years) in girls (n = 872) and through 10.6 years postdose 3 (median follow-up of 9.9 years) in boys (n=262) who were aged 9 to 15 years at time of vaccination with Gardasil 9. Incidence rates of vaccine HPV types related 6-month persistent infections in girls and boys observed during the study were 52.4 and 54.6 per 10,000 person-years, respectively, and within ranges of incidence rates expected in vaccinated cohorts of similar age (based on results from previous efficacy studies of Gardasil 9 and qHPV vaccine).
Immunogenicity: The minimum anti-HPV titre 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: 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/Protocol 009. 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 women aged 16 to 26 years, and higher in boys than in girls and women. As expected for women 27 to 45 years of age (Protocol 004), the observed GMTs were lower than those seen in women aged 16 to 26 years.
Anti-HPV responses at Month 7 among girls/boys aged 9 to 15 years were comparable to anti-HPV responses in women aged 16 to 26 years in the combined database of immunogenicity studies for Gardasil 9.
On the basis of this immunogenicity bridging, the efficacy of Gardasil 9 in girls and boys aged 9 to 15 years is inferred.
In Protocol 003, 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 girls and women aged 16 to 26 years for vaccine HPV types. High immunogenicity in MSM aged 16 to 26 years 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 noninferior 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.
Persistence of immune response to Gardasil 9: In long-term follow-up extension of clinical studies Protocols 001 and 002, persistence of antibody responses was observed: for at least 5 years in women who were aged 16 to 26 years at time of vaccination with Gardasil 9, depending on HPV type, 78 to 100 % of subjects were seropositive; however, 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); for at least 10 years in girls and boys who were aged 9 to 15 years at time of vaccination with Gardasil 9; depending on HPV type, 81 to 98 % of subjects were seropositive.
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 (aged 12 to 26 years) 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 vaccine HPV types 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.
Immunogenicity in HIV infected subjects: No clinical study of Gardasil 9 was conducted in HIV-infected individuals.
A study documenting safety and immunogenicity of qHPV vaccine has been performed in 126 HIV infected subjects aged 7 to 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 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.
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 aged 9 to 14 years receiving 2 doses at a 6-month or 12-month interval (+/- 1 month); girls aged 9 to 14 years receiving 3 doses (at 0, 2, 6 months); and women aged 16 to 26 years receiving 3 doses (at 0, 2, 6 months).
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. GMTs were higher in girls and boys who received 2 doses of Gardasil 9 (at either 0, 6 months or 0, 12 months) than in girls and women 16 to 26 years of age 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 girls and boys aged 9 to 14 years is inferred.
In the same study, in girls and boys aged 9 to 14 years, GMTs at one month after the last vaccine dose were numerically lower for some vaccine types after a 2-dose schedule than after a 3-dose schedule (i.e. HPV types 18, 31, 45, and 52 after 0, 6 months and HPV type 45 after 0, 12 months). The clinical relevance of these findings is unknown.
In girls and boys receiving 2 doses at 6- or 12 month interval (+/- 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.
In a clinical trial, persistence of antibody response has been demonstrated for at least 10 years in girls aged 9 to 13 years who received 2 doses of qHPV vaccine.
Duration of protection of a 2-dose schedule of Gardasil 9 has not been established.
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.
