Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmaco-therapeutic group: Vaccines, Papillomavirus vaccines, ATC code: J07BM02 
Mechanism of action

Cervarix is an adjuvanted non-infectious recombinant vaccine prepared from the highly purified virus- like particles (VLPs) of the major capsid L1 protein of oncogenic HPV types 16 and 18. Since the VLPs contain no viral DNA, they cannot infect cells, reproduce or cause disease. Animal studies have shown that the efficacy of L1 VLP vaccines is largely mediated by the development of a humoral immune response.

HPV-16 and HPV-18 are estimated to be responsible for approximately 70% of cervical cancers and 70% of HPV-related high grade vulvar and vaginal intraepithelial neoplasia. Other oncogenic HPV types can also cause cervical cancer (approximately 30%). HPV 45, -31 and -33 are the 3 most common non-vaccine HPV types identified in squamous cervical carcinoma (12.1%) and adenocarcinoma (8.5%).

The term “premalignant genital lesions” in section 4.1 corresponds to high-grade Cervical Intraepithelial Neoplasia (CIN2/3), high-grade vulvar intraepithelial neoplasia (VIN2/3) and high- grade vaginal intraepithelial neoplasia (VaIN2/3).

Clinical studies

Clinical efficacy in women aged 15 to 25 years
The efficacy of Cervarix was assessed in two controlled, double-blind, randomised Phase II and III clinical trials that included a total of 19,778 women aged 15 to 25 years.

The phase II trial (study 001/007) enrolled only women who:
-      Were tested negative for oncogenic HPV DNA of types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
-      Were seronegative for HPV-16 and HPV-18 and
-      Had normal cytology
The primary efficacy endpoint was incident infection with HPV-16 and/or HPV-18. Twelve-month persistent infection was evaluated as additional efficacy endpoint.

The phase III trial (study 008) enrolled women without pre-screening for the presence of HPV infection, i.e. regardless of baseline cytology and HPV serological and DNA status.
The primary efficacy endpoint was CIN2+ associated with HPV-16 and/or HPV-18 (HPV-16/18).
Cervical Intraepithelial Neoplasia (CIN) grade 2 and 3 (CIN2/3) and cervical adenocarcinoma in situ (AIS) were used in the clinical trials as surrogate markers for cervical cancer.
The secondary endpoints included 6- and 12-month persistent infection.

Persistent infection that lasts for at least 6 months has also been shown to be a relevant surrogate marker for cervical cancer.
Prophylactic efficacy against HPV-16/18 infection in a population naïve to oncogenic HPV types 
Women (N=1,113) were vaccinated in study 001 and evaluated for efficacy up to month 27. A subset of women (N=776) vaccinated in study 001 was followed in study 007 up to 6.4 years (approximately 77 months) after the first dose (mean follow-up of 5.9 years). There were five cases of 12-month persistent HPV-16/18 infection (4 HPV-16; 1 HPV-18) in the control group and one HPV-16 case in the vaccine group in study 001. In study 007 the efficacy of Cervarix against 12-month persistent HPV-16/18 infection was 100% (95% CI: 80.5; 100). There were sixteen cases of persistent HPV-16 infection, and five cases of persistent HPV-18 infection, all in the control group.

In study HPV-023, subjects from the Brazilian cohort (N=437) of study 001/007 were followed up to a mean of 8.9 years (standard deviation 0.4 years) after the first dose. At study completion, there were no cases of infection or histopathological lesions associated with HPV-16 or HPV-18 in the vaccine group in study HPV-023. In the placebo group, there were 4 cases of 6-month persistent infection and 1 case of 12-month persistent infection. The study was not powered to demonstrate a difference between the vaccine and the placebo group for these endpoints.

Prophylactic efficacy against HPV-16/18 in women naïve to HPV-16 and/or HPV-18 
In study HPV-008, the primary analyses of efficacy were performed on the According to Protocol cohort (ATP cohort: including women who received 3 vaccine doses and were DNA negative and seronegative at month 0 and DNA negative at month 6 for the HPV type considered in the analysis) This cohort included women with normal or low-grade cytology at baseline and excluded only women with high-grade cytology (0.5% of the total population). Case counting for the ATP cohort started on day 1 after the third dose of vaccine.

Overall, 74% of women enrolled were naïve to both HPV-16 and HPV-18 (i.e. DNA negative and seronegative at study entry).
Two analyses of study HPV-008 have been performed: an event-triggered analysis performed once at least 36 CIN2+ cases associated with HPV-16/18 were accrued in the ATP cohort and an end-of study analysis.

Vaccine efficacy against the primary endpoint CIN2+at the end of study is presented in Table 1. In a supplemental analysis, the efficacy of Cervarix was evaluated against HPV-16/18-related CIN3+.

Table 1: Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 (ATP cohort)
HPV-16/18 endpoint                              ATP cohort(1)
End of study analysis(3)
Cervarix          Control         % Efficacy (95% CI)
(N = 7338)        (N = 7305) n(2)               n
CIN2+                            5                 97             94.9% (87.7;98.4) CIN3+                            2                 24             91.7% (66.6;99.1) N = number of subjects included in each group n = number of cases
(1)
ATP: includes women who received 3 doses of vaccine, were DNA negative and seronegative at month 0 and DNA negative at month 6 to the relevant HPV type (HPV-16 or HPV-18) (2) including 4 cases of CIN2+ and 2 cases of CIN3+ in which another oncogenic HPV type was identified in the lesion, concomitantly with HPV-16 or HPV-18. These cases are excluded in the HPV type assignment analysis (see under Table).
(3) mean follow-up of 40 months post dose 3

At the event-triggered analysis the efficacy was 92.9% (96.1% CI:79.9;98.3) against CIN2+ and 80% (96.1% CI: 0.3;98.1) against CIN3+. In addition, statistically significant vaccine efficacy against CIN2+ associated with HPV-16 and HPV-18 individually was demonstrated.
Further investigation of the cases with multiple HPV types considered the HPV types detected by Polymerase Chain Reaction (PCR) in at least one of the two preceding cytology samples, in addition to types detected in the lesion to distinguish the HPV type(s) most likely responsible to the lesion (HPV type assignment). This post-hoc analysis excluded cases (in the vaccine group and in the control group) which were not considered to be causally associated with HPV-16 or HPV-18 infections acquired during the trial.
Based on the HPV type assignment post-hoc analysis, there was 1 CIN2+ case in the vaccine group versus 92 cases in the control group (Efficacy 98.9% (95% CI: 93.8;100)) and no CIN3+ case in the vaccine group versus 22 cases in the control group (Efficacy 100% (95% CI: 81.8;100)) at the end of study analysis.

In the event-triggered analysis, vaccine efficacy against CIN1 associated with HPV 16/18 observed in the ATP cohort was 94.1% (96.1% CI: 83.4;98.5). Vaccine efficacy against CIN1+ associated with HPV 16/18 observed in the ATP cohort was 91.7% (96.1% CI: 82.4;96.7). At the end of study analysis, vaccine efficacy against CIN1 associated with HPV 16/18 observed in the ATP cohort was 92.8% (95% CI: 87.1;96.4).

At end of study analysis, there were 2 cases of VIN2+ or VaIN2+ in the vaccine group and 7 cases in the control group in the ATP cohort associated with HPV-16 or HPV-18. The study was not powered to demonstrate a difference between the vaccine and the control group for these endpoints.

Vaccine efficacy against virological endpoints (6-month and 12-month persistent infection) associated with HPV-16/18 observed in the ATP cohort at the end of study is presented in Table 2.

Table 2: Vaccine efficacy against virological endpoints associated with HPV-16/18 (ATP cohort) HPV-16/18 endpoint                            ATP cohort(1)
End of study analysis(2)
Cervarix           Control         % Efficacy
(N = 7338)        (N = 7305)         (95% CI) n/N                n/N
6-month persistent                 35/7182           588/7137            94.3% infection                                                             (92.0;96.1) 12-month persistent                26/7082           354/7038            92.9% infection                                                             (89.4;95.4) N = number of subjects included in each group n = number of cases
(1)
ATP: includes women who received 3 doses of vaccine, were DNA negative and seronegative at month 0 and DNA negative at month 6 to the relevant HPV type (HPV- 16 or HPV-18)
(2) mean follow-up of 40 months post dose 3

The efficacy results at the event-triggered analysis were 94.3% (96.1% CI:91.5;96.3) against 6-month persistent infection and 91.4% (96.1% CI: 89.4;95.4) against 12-month persistent infection.

Efficacy against HPV-16/18 in women with evidence of HPV-16 or HPV-18 infection at study entry.

There was no evidence of protection from disease caused by the HPV types for which subjects were HPV DNA positive at study entry. However, individuals already infected (HPV DNA positive) with one of the vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the other vaccine HPV type.

Efficacy against HPV types 16 and 18 in women with and without prior infection or disease.

The Total Vaccinated Cohort (TVC) included all subjects who received at least one dose of the vaccine, irrespective of their HPV DNA status, cytology and serostatus at baseline. This cohort 
included women with or without current and/or prior HPV infection. Case counting for the TVC started on day 1 after the first dose.
The efficacy estimates are lower in the TVC as this cohort includes women with pre-existing infections/lesions, which are not expected to be impacted by Cervarix.
The TVC may approximate to the general population of women in the age range of 15-25 years.

Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 observed in TVC at end of study is presented in Table 3.

Table 3: Vaccine efficacy against high grade cervical lesions associated with HPV-16/18 (TVC) HPV-                                          TVC(1)
16/18                                 End of study analysis(2) endpoint          Cervarix                Control                % Efficacy (95% CI) (N = 8694)                 (N = 8708) n                          n
CIN2+                   90                        228                       60.7% (49.6;69.5) CIN3+                   51                         94                       45.7% (22.9;62.2) N = number of subjects included in each group n = number of cases
(1)
TVC: includes all vaccinated subjects (who received at least one dose of vaccine) irrespective of HPV DNA status, cytology and serostatus at baseline. This cohort includes women with pre- existing infections/lesions
(2) mean follow-up of 44 months post dose 1

Vaccine efficacy against virological endpoints (6-month and 12-month persistent infection) associated with HPV-16/18 observed in TVC at end of study is presented in Table 4.

Table 4: Vaccine efficacy against virological endpoints associated with HPV-16/18 (TVC) HPV-16/18                                         TVC(1) endpoint                                End of study analysis(2)
Cervarix               Control              % Efficacy (95% CI)
 n/N                    n/N
6-month persistent              504/8863              1227/8870               60.9% (56.6;64.8) infection
12-month persistent             335/8648              767/8671                57.5% (51.7;62.8) infection
N = number of subjects included in each group n = number of cases
(1)
TVC: includes all vaccinated subjects (who received at least one dose of vaccine) irrespective of HPV DNA status, cytology and serostatus at baseline.
(2) mean follow-up of 44 months post dose 1

Overall impact of the vaccine on cervical HPV disease burden

In study HPV-008, the incidence of high grade cervical lesions was compared between the placebo and vaccine group irrespective of the HPV DNA type in the lesion. In the TVC and TVC-naïve cohorts, the vaccine’s efficacy was demonstrated against high-grade cervical lesions at end of study (Table 5).
The TVC-naïve is a subset of the TVC that includes women with normal cytology, and who were HPV DNA negative for 14 oncogenic HPV types and seronegative for HPV-16 and HPV-18 at baseline.


Table 5: Vaccine efficacy against high-grade cervical lesions irrespective of the HPV DNA type in the lesion
End of study analysis(3)
Cervarix              Control           % Efficacy (95% CI)
N     Cases           N     Cases
CIN2+
TVC-naïve(1)       5466       61        5452        172        64.9% (52.7;74.2) TVC(2)             8694       287       8708        428        33.1% (22.2;42.6) CIN3+
TVC-naïve(1)       5466         3       5452         44        93.2% (78.9;98.7) TVC(2)             8694        86       8708        158        45.6% (28.8;58.7) N = number of subjects included in each group
(1)
TVC naïve: includes all vaccinated subjects (who received at least one dose of vaccine) who had normal cytology, were HPV DNA negative for 14 oncogenic HPV types and seronegative for HPV-16 and HPV-18 at baseline.
(2)
TVC: includes all vaccinated subjects (who received at least one dose of vaccine) irrespective of HPV DNA status, cytology and serostatus at baseline.
(3) mean follow-up of 44 months post dose 1

At the end of study analysis, Cervarix reduced definitive cervical therapy procedures (includes loop electrosurgical excision procedure [LEEP], cold-knife Cone, and laser procedures) by 70.2% (95% CI: 57.8;79.3) in TVC-naïve and 33.2% (95% CI: 20.8;43.7) in TVC.

Cross-protective efficacy

The cross-protective efficacy of Cervarix against histopathological and virological endpoints (persistent infection) has been evaluated in study HPV-008 for 12 non-vaccine oncogenic HPV types.
The study was not powered to assess efficacy against disease caused by individual HPV types. The analysis against the primary endpoint was confounded by multiple co-infections in the CIN2+ lesions.
Unlike histopathological endpoints, virological endpoints are less confounded by multiple infections.
HPV-31, 33 and 45 showed consistent cross-protection for 6-month persistent infection and CIN2+ endpoints in all study cohorts.
End of study vaccine efficacy against 6-month persistent infection and CIN2+ associated with individual non-vaccine oncogenic HPV types is presented in Table 6 (ATP cohort).

Table 6: Vaccine efficacy for non-vaccine oncogenic HPV types
ATP(1)
HPV type              6-month persistent infection                                 CIN2+ Cervarix      Control         % Efficacy            Cervarix      Control    % Efficacy n             n            (95% CI)                n            n        (95% CI) HPV-16 related types (A9 species)
HPV-31            58           247              76.8%                 5            40        87.5% (69.0;82.9)                                    (68.3;96.1)
HPV-33            65           117              44.8%                13            41        68.3% (24.6;59.9)                                    (39.7;84.4)
HPV-35            67            56             -19.8%                 3             8        62.5% (<0;17.2)                                      (<0;93.6)
HPV-52           346           374               8.3%                24            33        27.6% (<0;21.0)                                      (<0;59.1)
HPV-58           144           122             -18.3%                15            21        28.5% (<0;7.7)                                      (<0;65.7)
HPV-18 related types (A7 species)
HPV-39           175           184               4.8%                 4            16        74.9% (<0;23.1)                                     (22.3;93.9)
HPV-45            24            90              73.6%                 2            11        81.9% (58.1;83.9)                                    (17.0;98.1)
HPV-59            73            68              -7.5%                 1             5        80.0% (<0;23.8)                                      (<0;99.6)
HPV-68           165           169               2.6%                11            15        26.8% (<0;21.9)                                      (<0;69.6)
Other types
HPV-51           349           416              16.6%                21            46        54.4% (3.6;27.9)                                      (22.0;74.2)
HPV-56              226           215             -5.3%               7            13             46.1% (<0;13.1)                                        (<0;81.8)
HPV-66              211           215              2.3%               7            16             56.4% (<0;19.6)                                        (<0;84.8) n= number of cases
(1)
ATP: includes women who received 3 doses of vaccine, were DNA negative at month 0 and at month 6 to the relevant HPV type.
The limits of the confidence interval around the vaccine efficacy were calculated. When the value zero is included, i.e. when the lower limit of the CI is <0, the efficacy is not considered statistically significant.
The efficacy against CIN3 was only demonstrated for HPV-31 and there was no evidence of protection against AIS for any of the HPV types.

Clinical efficacy in women aged 26 years and older

The efficacy of Cervarix was assessed in a double-blind, randomised Phase III clinical trial (HPV-015) that included a total of 5777 women aged 26 years and older. The study was conducted in North America, Latin America, Asia Pacific and Europe, and allowed women with previous history of HPV disease/infection to be enrolled. An interim analysis was performed when all subjects had completed the month 48 study visit.
The primary analyses of efficacy were performed on the ATP cohort for efficacy and the TVC.

Vaccine efficacy against 6 month persistent infection with HPV-16/18 (relevant surrogate marker for cervical cancer) is summarised in the following table.

Table 7: Vaccine efficacy against 6M PI with HPV 16/18 in ATP and TVC HPV-                            ATP(1)                                              TVC(2) 16/18       Cervarix     Control                                 Cervarix      Control     % Efficacy (97.7% endpoint                             % Efficacy (97.7% CI) n/N         n/N                                     n/N          n/N               CI) 6M PI        6/1859      34/1822       82.9% (53.8; 95.1)        71/2767      132/2776      47% (25.4; 62.7) N= number of subject in each group n= number of subjects reporting at least one event in each group
6M PI = 6-month persistent infection
CI = Confidence Interval
(1)
3 doses of vaccine, DNA negative and seronegative at month 0 and DNA negative at month 6 for the relevant HPV type (HPV-16 and/or HPV-18)
(2) at least one dose of vaccine, irrespective of HPV DNA and serostatus at month 0. Includes 15% of subjects with previous history of HPV disease/infection

Vaccine efficacy against 6-month persistent infection was 79.1% (97.7% CI [27.6; 95.9]) for HPV-31 and 76.9% (97.7% CI [18.5; 95.6]) for HPV-45 in the ATP cohort (3 doses of vaccine, DNA negative at months 0 and 6 for the relevant HPV type).

Vaccine efficacy against 6-month persistent infection was 23.2% (97.7% CI [-23.3; 52.5]) for HPV-31 and 67.7% (97.7% CI [35.9; 84.9]) for HPV-45 in the TVC.

Immunogenicity

Immune response to Cervarix after the primary vaccination course
No minimal antibody level associated with protection against CIN of grade 2 or 3 or against persistent infection associated with vaccine HPV types has been identified for HPV vaccines.

The antibody response to HPV-16 and HPV-18 was measured using a type-specific direct ELISA (version 2, MedImmune methodology, modified by GSK) which was shown to correlate with the pseudovirion-based neutralisation assay (PBNA).

The immunogenicity induced by three doses of Cervarix has been evaluated in 5,465 female subjects from 9 to 55 years of age.

In clinical trials, more than 99% of initially seronegative subjects had seroconverted to both HPV types 16 and 18 one month after the third dose. Vaccine-induced IgG Geometric Mean Titres (GMT) were well above titres observed in women previously infected but who cleared HPV infection (natural infection). Initially seropositive and seronegative subjects reached similar titres after vaccination.

Persistence of Immune Response to Cervarix

Study 001/007, which included women from 15 to 25 years of age at the time of vaccination, evaluated the immune response against HPV-16 and HPV-18 up to 76 months after administration of the first vaccine dose. In study 023 (a subset of study 001/007), the immune response continued to be evaluated up to 113 months. 92 subjects in the vaccine group had immunogenicity data at the [M107- M113] interval after the first vaccine dose with a median follow-up of 8.9 years. Of these subjects, 100% (95% CI: 96.1;100) remained seropositive for HPV-16 and HPV-18 in the ELISA assay.
Vaccine-induced IgG GMTs for both HPV-16 and HPV-18 peaked at month 7 and then declined to reach a plateau from month 18 up to the [M107-M113] interval with ELISA GMTs for both HPV-16 and HPV-18 at least still 10-fold higher than the ELISA GMTs observed in women who cleared a natural HPV infection.
In study 008, immunogenicity up to month 48 was similar to the response observed in study 001. A similar kinetic profile was observed with the neutralising antibodies.

In another clinical trial (study 014) performed in women aged 15 to 55 years, all subjects seroconverted to both HPV types 16 and 18 after the third dose (at month 7). The GMTs were, however, lower in women above 25 years. Nevertheless, all subjects remained seropositive for both types throughout the follow-up phase (up to month 18) maintaining antibody levels at an order of magnitude above those encountered after natural infection.

Evidence of Anamnestic (Immune Memory) Response

In study 024 (a subset of study 001/007), a challenge dose of Cervarix was administered to 65 subjects at a mean interval of 6.8 years after the administration of the first vaccine dose. An anamnestic immune response to HPV-16 and HPV-18 (by ELISA) was observed one week and one month after the challenge dose, GMTs one month after the challenge dose exceeded those observed one month after the primary 3-dose vaccination.

Bridging the efficacy of Cervarix from young adult women to adolescents 
In a pooled analysis (HPV-029,-30 & -48), 99.7% and 100% of females aged 9 years seroconverted to HPV types 16 and 18, respectively after the third dose (at month 7) with GMTs at least 1.4-fold and 2.4-fold higher as compared to females aged 10-14 years and 15 to 25 years, respectively.

In two clinical trials (HPV-012 & -013) performed in girls aged 10 to 14 years, all subjects seroconverted to both HPV types 16 and 18 after the third dose (at month 7) with GMTs at least 2-fold higher as compared to women aged 15 to 25 years.

In ongoing clinical trials (HPV-070 and HPV-048) performed in girls aged 9 to 14 years receiving a 2- dose schedule (0, 6 months) and young women aged 15-25 years receiving Cervarix according to the standard 0, 1, 6 months schedule, all subjects seroconverted to both HPV types 16 and 18 after the second dose (at month 7). The immune response after 2 doses in females aged 9 to 14 years was non- inferior to the response after 3 doses in women aged 15 to 25 years.

On the basis of these immunogenicity data, the efficacy of Cervarix is inferred from 9 to 14 years of age.

Immunogenicity in women aged 26 years and older
In the Phase III study (HPV-015) in women 26 years and older, at the 48-month time point, i.e. 42 months after completion of the full vaccination course, 100% and 99.4% of initially seronegative women remained seropositive for anti-HPV-16 and anti-HPV-18 antibodies, respectively. All initially seropositive women remained seropositive for both anti-HPV-16 and anti-HPV-18 antibodies.
Antibody titers peaked at month 7 then gradually declined up to month 18 and stabilized to reach a plateau up to month 48.

Immunogenicity in HIV infected women

In study HPV-020, conducted in South Africa, 22 HIV uninfected and 42 HIV infected subjects (WHO clinical stage 1; ATP cohort for immunogenicity) received Cervarix. All subjects were seropositive in the ELISA assay to both HPV 16 and 18 one month after the third dose (at Month 7) and the seropositivity for HPV 16 and 18 was maintained up to Month 12. The GMTs appeared to be lower in the HIV infected group (non overlapping 95% confidence interval). The clinical relevance of this observation is unknown. Functional antibodies were not determined. No information exists about protection against persistent infection or precancerous lesions among HIV infected women.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Not applicable.