Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: vaccines; ATC code: J07AH09

Mechanism of action
Trumenba is a vaccine composed of 2 recombinant lipidated factor H binding protein (fHbp) variants. fHbp is found on the surface of meningococcal bacteria and helps bacteria to avoid host immune defenses. fHbp variants segregate into 2 immunologically distinct subfamilies, A and B, and over 96% of meningococcal serogroup B isolates in Europe express fHbp variants from either subfamily on the bacterial surface.

Immunisation with Trumenba, which contains one fHbp variant each from subfamily A and B, is intended to stimulate the production of bactericidal antibodies that recognize fHbp expressed by meningococci. The Meningococcal Antigen Surface Expression (MEASURE) assay was developed to relate the level of fHbp surface expression to killing of meningococcal serogroup B strains in serum bactericidal assays with human complement (hSBAs). A survey of over 2,150 different invasive meningococcal serogroup B isolates collected from 2000-2014 in 7 European countries, the US and Canada demonstrated that over 91% of all meningococcal serogroup B isolates expressed sufficient levels of fHbp to be susceptible to bactericidal killing by vaccine-induced antibodies.

Clinical efficacy

The efficacy of Trumenba has not been evaluated through clinical trials. Vaccine efficacy has been inferred by demonstrating the induction of serum bactericidal antibody responses to 4 meningococcal serogroup B test strains (see the Immunogenicity section). The 4 test strains express fHbp variants representing the 2 subfamilies (A and B) and, when taken together, are representative of meningococcal serogroup B strains causing invasive disease.

Immunogenicity

Protection against invasive meningococcal disease is mediated by serum bactericidal antibodies to bacterial surface antigens. Bactericidal antibodies act in concert with human complement to kill meningococci. This process is measured in vitro with hSBA for meningococcal serogroup B. An hSBA titre of ≥1:4 is assumed to be protective against meningococcal disease. In the immunogenicity analysis for Trumenba, a more conservative hSBA titre threshold of ≥ 1:8 or 1:16 was applied, depending on the hSBA strain.



Vaccine coverage was investigated using four primary representative meningococcal serogroup B test strains: two expressing subfamily A fHbp (variants A22 and A56) and two expressing subfamily B fHbp (variants B24 and B44). To support and further extend the breadth of vaccine coverage, an additional 10 meningococcal serogroup B test strains were used; these included six expressing subfamily A fHbp (variants A06, A07, A12, A15, A19 and A29) and four expressing subfamily B fHbp (variants B03, B09, B15 and B16).

Immunogenicity in subjects 10 years of age and older

The immunogenicity of Trumenba described in this section includes results from Phase 2 and Phase 3 clinical studies:
• Following the 2-dose schedule (0 and 6 months) in subjects 10 to 25 years of age in the US and Europe (Study B1971057);
• Following the 3-dose schedule (0, 2, and 6 months) in subjects 10 to 25 years of age globally (Studies B1971009 and B1971016); and
• Following the 2-dose (0 and 6 months) and 3-dose schedules (0, 1-2, and 6 months) in subjects 11 to 18 years of age in Europe (Study B1971012).

Study B1971057 is a Phase 3, randomised, active-controlled, observer-blinded, multicentre trial in which subjects 10 to 25 years of age received Trumenba at months 0 and 6 (coadministered with MenACWY-CRM for the first dose) or an investigational pentavalent meningococcal vaccine at months 0 and 6. A total of 1,057 subjects received Trumenba and 543 subjects received the investigational control. The hSBA titres for primary test strains are presented in Table 1. Table 2 presents the hSBA titres against the additional 10 test strains which support and extend the breadth of vaccine coverage demonstrated by the 4 representative primary strains.

Table 1: hSBA titres among subjects 10 to 25 years of age receiving Trumenba on a 0- and 6-month schedule for primary strains 1 month post-dose 2 (Study B1971057) Composite(4)
≥ 4-fold rise (1)
Titre ≥ 1:8 (2)
GMT   (3)
Pre-vaccination    Post-dose 2
1
%                   %           GMT         N         %       N        % N                  N
Strain          (95% CI)           (95% CI)      (95% CI)           (95% CI)          (95% CI) 73.8                91.0          49.3
A22     827                852
(70.6, 76.7)        (88.8, 92.8) (46.2, 52.6)
95.0                99.4         139.5
A56     823                854                                                           74.3 (93.3, 96.4)        (98.6, 99.8) (130.6, 149.1)           1.8
799               814     (71.2,
67.4                79.3          21.2             (1.0, 2.9)
B24     835                842                                                          77.3) (64.1, 70.6)        (76.4, 82.0) (19.6, 22.9)
86.4                94.5          37.8
B44     850                853
(83.9, 88.6)        (92.7, 95.9) (35.1, 40.8)
Abbreviations: GMT=geometric mean titre; hSBA=serum bactericidal assay using human complement.
(1) A ≥ 4-fold rise is defined as (i) A hSBA titre ≥ 1:16 for subjects with a baseline hSBA titre < 1:4. (ii) Four  times the 1:8 or 16 threshold or four times the baseline hSBA titre, whichever is higher for subjects with a baseline hSBA titre ≥ 1:4.
(2) All strains used a 1:8 titre threshold except A22 which was 1:16.
(3) N for GMT is the same as that presented in preceding titre ≥ 1:8 or 16 column.
(4) Proportion of subjects with a composite of hSBA titres ≥ 1:8 or 16 for all four primary strains combined.



Table 2: hSBA titres among subjects 10 to 25 years of age receiving Trumenba on a 0- and 6-month schedule for additional strains 1 month post-dose 2 (Study B1971057)
N               % titre ≥ 1:8(1)                       95% CI
A06                         159                    89.3                             83.4, 93.6 A07                         157                    96.8                             92.7, 99.0 A12                         157                    83.4                             76.7, 88.9 A15                         165                    89.1                             83.3, 93.4 A19                         167                    90.4                             84.9, 94.4 A29                         166                    95.2                             90.7, 97.9 B03                         164                    74.4                             67.0, 80.9 B09                         166                    71.1                             63.6, 77.8 B15                         167                    85.0                             78.7, 90.1 B16                         164                    77.4                             70.3, 83.6 Abbreviations: hSBA=serum bactericidal assay using human complement.
(1) All strains used a 1:8 titre threshold except A06, A12 and A19 which were 1:16.


Study B1971009 was a Phase 3, randomised, active-controlled, observer-blinded, multicentre trial in which subjects 10 to 18 years of age received 1 of 3 lots of Trumenba or the active control hepatitis A virus (HAV) vaccine/saline (control). A total of 2,693 subjects received at least 1 dose of Trumenba and 897 received at least 1 dose of HAV vaccine/saline. The study assessed the safety, tolerability, immunogenicity, and demonstration of manufacturability of 3 lots of Trumenba administered on a 0-, 2-, and 6-month schedule. The hSBA titres for primary test strains observed after the third dose in lot 1 and the control are presented in Table 3. Results from lots 2 and 3 are not presented, as only 2 representative strains were evaluated.
Similar results were observed for lots 2 and 3 as observed for lot 1.

Study B1971016 was a Phase 3, randomised, placebo-controlled, observer-blinded, multicentre trial in which subjects 18 to 25 years of age were assigned to receive either Trumenba at months 0, 2, and 6 or saline at months 0, 2, and 6 in a 3:1 ratio. A total of 2,471 subjects received Trumenba and 822 received saline. The hSBA titres for primary test strains observed after the third dose are presented in Table 3.



Table 3. hSBA titres among subjects 10 to 25 years of age receiving Trumenba 1 month post- dose 3 of Trumenba or control on a 0-, 2-, 6-month schedule for primary strains (Study B1971009 and Study B1971016)
Study B1971009                       Study B1971016
(10-18 years of age)                 (18-25 years of age)
Trumenba          HAV/saline        Trumenba             Saline
% or                    % or                % or
% or GMT
Strain                             N        GMT         N           GMT         N       GMT        N (95% CI)
(95% CI)                (95% CI)            (95% CI)
80.5
83.2                  9.6                              56       6.3
≥ 4-fold rise(1)       1225                  730               1695          (78.6, (81.0, 85.2)         (7.6, 12.0)                          8     (4.5, 8.7) 82.4)
97.8                   34.0                 93.5
57      36.6
A22         hSBA ≥ 1:16           1266      (96.8,      749        (30.7,      1714     (92.2, 7    (32.6, 40.6)
98.5)                  37.6)                94.6)
12.6                 74.3
86.8                   (12.0,                          57      13.2 hSBA GMT              1266                  749                    1714     (70.2, (82.3, 91.5)                                              7    (12.4, 14.1) 13.4)                78.6)
90.0
90.2                 11.3                              53      10.3
≥ 4-fold rise(1)       1128                  337               1642          (88.4, (88.4, 91.9)         (8.1, 15.1)                          3    (7.9, 13.2) 91.4)
27.5                 99.4
99.5                                                   55      34.2
A56          hSBA ≥ 1:8           1229                  363        (23.0,      1708     (98.9, (98.9, 99.8)                                              2    (30.3, 38.4) 32.5)                99.7)
222.5                                       176.7
8.8                              55       9.1 hSBA GMT              1229     (210.1,      363               1708         (167.8, (7.6, 10.1)                          2    (8.2, 10.1)
235.6)                                      186.1)
79.3               5.5
79.8                     2.7                           56
≥ 4-fold rise(1)      1235                  752                    1675     (77.3,           (3.8, 7.7) (77.4, 82.0)             (1.6, 4.1)                       2
81.2)
95.1
87.1                     7.0                           57      30.2
B24         hSBA ≥ 1:8            1250                  762                    1702     (93.9, (85.1, 88.9)             (5.3, 9.0)                       3    (26.5, 34.1) 96.0)
49.5
24.1                     4.5                           57       7.2 hSBA GMT              1250                  762                    1702     (46.8, (22.7, 25.5)             (4.4, 4.7)                       3     (6.6, 7.8) 52.4)
79.6               1.6
85.9                       1.0                           57
≥ 4-fold rise   (1)
1203                  391                    1696     (77.6,           (0.7, 3.0) (83.8, 87.8)               (0.3, 2.6)                       3
81.5)
87.4
89.3                     5.3                           57      11.4
B44         hSBA ≥ 1:8            1210                  393                    1703     (85.8, (87.4, 90.9)             (3.3, 8.1)                       7    (9.0, 14.3) 89.0)
47.6
50.9                     4.4                           57       4.8 hSBA GMT              1210                  393                    1703     (44.2, (47.0, 55.2)             (4.2, 4.6)                        7    (4.6, 5.1) 51.3)
Composite(2)
1.1                     2.0                  7.3      54       6.1
Pre-vaccination 1               1088                  354                    1612 (0.6, 1.9)              (0.8, 4.0)          (6.0, 8.6)    1    (4.2, 8.5) 84.9               7.5
83.5                     2.8                           53
Post-dose 3                      1170                  353                    1664     (83.1,          (5.4, 10.0) (81.3, 85.6)             (1.4, 5.1)                        5
86.6)
Abbreviations: GMT=geometric mean titre; hSBA=serum bactericidal assay using human complement; HAV=hepatitis A virus vaccine.
Table 3. hSBA titres among subjects 10 to 25 years of age receiving Trumenba 1 month post- dose 3 of Trumenba or control on a 0-, 2-, 6-month schedule for primary strains (Study B1971009 and Study B1971016)
Study B1971009                       Study B1971016
(10-18 years of age)                 (18-25 years of age)
Trumenba          HAV/saline        Trumenba             Saline
% or                      % or                 % or
% or GMT
Strain                             N        GMT            N          GMT         N        GMT           N (95% CI)
(95% CI)                  (95% CI)             (95% CI)
(1) A ≥ 4-fold rise is defined as (i) A hSBA titre ≥ 1:16 for subjects with a baseline hSBA titre < 1:4. (ii) Four times the 1:8/16 threshold or four times the baseline hSBA titre, whichever is higher for subjects with a baseline hSBA titre ≥ 1:4.
(2) Proportion of subjects with a composite of hSBA titres ≥ 1:8 or 16 for all four primary strains combined.


In Studies B1971009 and B1971016, the proportion of subjects achieving a hSBA titre ≥ 1:8 (variants A07, A15, A29, B03, B09, B15, B16) or 1:16 (variants A06, A12, A19) against the 10 additional test strains after 3 doses of Trumenba, administered on a 0-, 2-, and 6-month schedule, was determined. Across the two studies, the majority of subjects, ranging from 71.3% to 99.3% for the 6 subfamily A fHbp strains and 77.0% to 98.2% for the 4 subfamily B fHbp strains, achieved a hSBA titre ≥ 1:8 or 16, consistent with the results observed with the       4 primary test strains.

In Study B1971012, a Phase 2 study in subjects 11 to 18 years of age in Europe, hSBA titres following completion of two 3-dose schedules (0, 1, and 6 months and 0, 2, and 6 months) and a 2-dose schedule (0, 6 months) were determined against the 4 primary test strains. At 1 month after the third dose, similar robust and broad immune responses were observed for both 3-dose schedules with 86.1% to 99.4% achieving hSBA titres ≥ 1:8 or 16 and 74.6% to 94.2% achieving a 4-fold increase in hSBA titre. At 1 month after completion of the 2-dose schedule (0, 6 months), 77.5% to 98.4% achieved hSBA titres ≥ 1:8 or 16 and 65.5% to 90.4% achieved a 4-fold increase in hSBA titre.

Study B1971033 was an open-label, follow-up study of subjects previously enrolled in a primary study, including Study B1971012. Subjects attended visits over 4 years for collection of blood samples and received a single booster dose of Trumenba approximately 4 years after receipt of a primary series of 2 or 3 doses of Trumenba. hSBA titres 4 years after the primary series and 26 months after the booster dose for subjects enrolled from primary Study B1971012 Group 1 (0-, 1-, 6-Month Schedule), Group 2 (0-, 2-, 6-Month), and Group 3 (0-, 6-Month) are presented in Table 4. A booster response was observed as measured by hSBA at 1 month following a dose of Trumenba approximately 4 years after a primary series of 2 doses (Group 3) or 3 doses (Groups 1 and 2).



Table 4:     hSBA titres among subjects 11 to 18 years of age receiving Trumenba on a 0-, 1-, 6- month; 0-, 2-, 6-month; and 0-, 6-month schedules and a booster 4 years after primary series completion (Study B1971033)
Primary Study B1971012 Vaccine Groups (as Randomised)
0, 1, and 6 months           0, 2, and 6 months           0 and 6 months %        GMT            % ≥ 1:8   (1)
GMT         % ≥ 1:8(1) GMT
≥ 1:8 (95% CI)
(1)
(95% CI) (95% CI)           (95% CI) (95% CI)
(95%
Strain      Timepoint     N      CI)                  N                           N 89.8       53.0              91.2        59.5           98.4
55.8 month 1 59 (79.2,          (40.4,     57     (80.7,      (45.5,   61    (91.2, 46.2, 67.4)
96.2)        69.6)            97.1)       77.8)          100.0)
Post-primary



41.4       14.9              45.0        15.8           36.3 month                                                                              15.6 99 (31.6,         (12.6, 111 (35.6,             (13.4, 113     (27.4, 12                                                                               13.0, 18.8) 51.8)        17.7)            54.8)       18.6)          45.9)
49.2       16.6              56.1        20.7           55.7 month                                                                              16.6 59 (35.9,         (13.0,     57     (42.4,      (15.6,   61    (42.4,                48                                                                               13.4, 20.5)
62.5)        21.1)            69.3)       27.4)          68.5)
A22
100.0      126.5             100.0       176.7           96.7     142.0 month 1 59 (93.9, (102.7, 58                 (93.8,     (137.8, 60      (88.5, (102.9, 100.0)       155.8)            100.0)     226.7)          99.6)     196.1) Post-booster



74.1       33.6              77.8        44.1           80.0      31.6 month
58 (61.0,         (24.5,     54      (64.4,      (31.2, 60      (67.7,     (23.5, 12
84.7)        46.1)            88.0)       62.4)          89.2)      42.5) 73.5        34.7           61.9      27.1 month
0     NE(2)       NE(2)     34      (55.6,      (23.0, 42      (45.6,     (18.6,                26
87.1)       52.4)          76.4)      39.6)
100.0      158.7              98.2       191.2           98.4     143.1 month 1 58 (93.8, (121.5, 57                 (90.6,     (145.8, 62      (91.3, (109.6, 100.0)       207.3)            100.0)     250.8)          100.0)    187.0) Post-primary



73.5       25.7              76.1        27.3           60.4 month                                                                              18.5 98 (63.6,         (19.4, 109 (67.0,             (21.0, 106     (50.4, 12                                                                               13.8, 24.7) 81.9)        34.0)            83.8)       35.4)          69.7)
43.4                         56.4        15.0           43.5 month                       10.7                                                   10.8 53 (29.8,                    55     (42.3,      (10.2,   62    (31.0,                48                        (7.4, 15.3)                                            (7.6, 15.3)
57.7)                         69.7)       22.2)          56.7)
A56
100.0      359.8             100.0       414.8           98.4     313.1 month 1 57 (93.7, (278.7, 56                 (93.6,     (298.8, 62      (91.3, (221.3, 100.0)       464.7)            100.0)     575.9)          100.0)    442.8) Post-booster



90.9       47.3              89.1        64.0           81.4      41.0 month
55 (80.0,          (34.3, 55         (77.8,      (42.6, 59      (69.1,     (26.7, 12
97.0)        65.3)            95.9)       96.2)          90.3)      62.7) 82.8        37.8           57.5      16.0 month
0     NE(2)       NE(2)     29      (64.2,      (21.3, 40      (40.9,      (9.9,                26
94.2)       67.2)          73.0)      25.8)
88.1       25.6              91.4        30.5           85.0
29.2
Post-primary


 month 1 59 (77.1,          (19.7,     58     (81.0,      (23.8,   60    (73.4, 21.5, 39.6)
95.1)        33.3)            97.1)       39.1)          92.9)
B24
40.8                         49.1        11.5           36.9 month                        9.7                                                    8.4 98 (31.0,                   108 (39.3,           (9.0,  103    (27.6, 12                        (7.5, 12.4)                                            (6.7, 10.6) 51.2)                         58.9)       14.6)          47.0)


Table 4:  hSBA titres among subjects 11 to 18 years of age receiving Trumenba on a 0-, 1-, 6- month; 0-, 2-, 6-month; and 0-, 6-month schedules and a booster 4 years after primary series completion (Study B1971033)
Primary Study B1971012 Vaccine Groups (as Randomised)
0, 1, and 6 months           0, 2, and 6 months             0 and 6 months %        GMT           % ≥ 1:8   (1)
GMT           % ≥ 1:8(1) GMT
≥ 1:8 (95% CI)
(1)
(95% CI) (95% CI)             (95% CI) (95% CI)
(95%
Strain Timepoint        N       CI)                 N                             N 40.7                         49.1         11.4              40.3 month                       10.7                                                        8.9 59 (28.1,                   57     (35.6,        (8.2,    62      (28.1,               48                       (7.6, 15.1)                                                (6.8, 11.8)
54.3)                         62.7)        15.9)             53.6)
100.0        94.9            100.0        101.6              96.8       79.1 month 1 58 (93.8,          (74.6,    57     (93.7,       (83.1,    62      (88.8,     (60.6, 100.0)        120.9)           100.0)      124.2)             99.6)      103.5) Post-booster



65.5        21.1             74.1         25.7              77.4      22.4 month
58 (51.9,          (14.2, 54        (60.3,       (17.7, 62         (65.0,     (16.4, 12
77.5)         31.3)           85.0)        37.5)             87.1)      30.5) 78.8         24.4              59.5       14.5 month
0     NE(2)       NE(2)     33      (61.1,       (16.1, 42         (43.3,      (9.9,               26
91.0)        36.8)             74.4)       21.3)
86.2        46.3             89.5         50.2     60       81.7
35.5 month 1 58 (74.6,          (31.7,    57     (78.5,       (35.3,            (69.6, 24.5, 51.4)
93.9)        67.8)           96.0)        71.3)             90.5)
Post-primary



24.0                         22.5                           16.5 month                        6.4                           6.0                          5.6 100 (16.0,                  111 (15.1,                    115      (10.3, 12                        (5.2, 7.8)                    (5.1, 7.2)                   (4.8, 6.5) 33.6)                         31.4)                          24.6)
36.8                         35.1          7.6 month                        8.3                                            12.9        4.6 57 (24.4,                   57     (22.9,        (5.8,    62
48                       (6.3, 11.0)                                     (5.7, 23.9) (4.1, 5.1)
50.7)                         48.9)        10.0)
B44
100.0       137.3            100.0        135.9              93.4       74.2 month 1 59 (93.9, (100.3, 58                (93.8,      (108.0, 61         (84.1,     (51.6, 100.0)        188.0)           100.0)      171.0)             98.2)      106.8) Post-booster



75.0        23.2             81.1         24.3              59.0       13.3 month
56 (61.6,          (16.2, 53        (68.0,       (17.8, 61         (45.7,      (9.7, 12
85.6)         33.2)           90.6)        33.3)             71.4)       18.3) 66.7         16.0              62.8       13.6 month
0     NE(2)       NE(2)     33      (48.2,       (10.4, 43         (46.7,      (9.8,               26
82.0)        24.7)             77.0)       18.9)
Composite(3)
80.7                         87.3                         77.2 month 1 57 (68.1,            NE     55      (75.5,         NE     57      (64.2,        NE 90.0)                        94.7)                          87.3)
Post-primary



10.9 month                                        13.7                         20.4 55     (4.1,        NE     51                     NE     49                    NE 12                                        (5.7, 26.3)                  10.2, 34.3) 22.2)
19.6                         30.2 month                                                                      9.8 51     (9.8,        NE     53      (18.3,         NE     61                    NE               48                                                                     (3.7, 20.2)
33.1)                        44.3) ost-booste



100                        100.0
91.5 month 1 56 (93.6,            NE     55      (93.5,         NE     59                    NE 81.3, 97.2)
100.0)                        100.0)

Table 4:     hSBA titres among subjects 11 to 18 years of age receiving Trumenba on a 0-, 1-, 6- month; 0-, 2-, 6-month; and 0-, 6-month schedules and a booster 4 years after primary series completion (Study B1971033)
Primary Study B1971012 Vaccine Groups (as Randomised)
0, 1, and 6 months      0, 2, and 6 months        0 and 6 months
%      GMT         % ≥ 1:8  (1)
GMT         % ≥ 1:8(1) GMT
≥ 1:8 (95% CI)
(1)
(95% CI) (95% CI)        (95% CI) (95% CI)
(95%
Strain         Timepoint     N      CI)              N                        N 52.8                    64.6                    61.4 month
53     (38.6,    NE     48      (49.5,    NE     57     (47.6,     NE 12
66.7)                   77.8)                    74.0)
48.1                    44.4 month
0     NE(2)     NE     27      (28.7,    NE     36     (27.9,     NE
26
68.1)                    61.9)
Abbreviations: hSBA=serum bactericidal assay using human complement; NE=not evaluated; GMT=geometric mean titre.
(1) All strains used a 1:8 titre threshold except A22 which was 1:16.
(2) Subjects were not followed beyond 12 months post booster.
(3) Proportion of subjects with a composite of hSBA titres ≥ 1:8 or 16 for all four primary strains combined.

Serum samples were analysed concurrently in the same serology campaign for all time points except the 12 months post-primary dose time point for which results are from the interim analysis.

Pharmacokinetic Properties

5.2         Pharmacokinetic properties

Not applicable.