Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Hepatitis B vaccines, purified antigen ATC code J07BC01 
Mechanism of action
Sci-B-Vac contains the full antigenic composition of the hepatitis B virus surface antigen, including the small (S), middle (pre-S2) and large (pre-S1) hepatitis B surface antigens in a virus-like particle structure and confers immunity against all known subtypes of hepatitis B virus infection through the stimulation of a specific immune response, as measured by the induction of anti-HBs antibodies at a level ≥10 mIU/mL.

Clinical immunogenicity
The immunogenicity of Sci-B-Vac was evaluated in comparison with a licensed hepatitis B vaccine (Engerix-B) in two randomised, active controlled, double-blinded, multi-centre Phase 3 clinical trials in adults. Sci-B-Vac and Engerix-B were given as a 3-dose regimen at 0, 1, and 6 months.

Study Sci-B-Vac-001 in adults age ≥18 years
The primary immunogenicity endpoint of the study was the seroprotection rate (SPR), defined as the percentage of subjects with anti-HBs levels of ≥10 mIU/mL The two co-primary analyses, tested hierarchically, were: (1) non-inferiority of Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml compared to Engerix B at Day 196, 4 weeks after receiving the third dose in all adults age ≥18 years and (2) superiority of Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml compared to Engerix-B in subjects ≥45 years old at Day 196.

Non-inferiority was met if the lower bound of the 95% confidence interval (CI) of the difference in SPR (Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml minus Engerix B) was greater than -5%.
Superiority was met if the lower bound of the 95% CI of the difference in SPR (Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml minus Engerix B) was greater than 0%.

The study met both co-primary endpoints. The SPR in subjects ≥18 years of age in the Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml group was non-inferior to the Engerix B group at Study Day 196 (91.4% vs. 76.5%) and the SPR in subjects ≥45 years of age was superior to the Engerix B group at Study Day 196 (89.4% vs. 73.1%). Higher SPR and anti-HBs titres (GMC, geometric mean concentration) were noted for Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml compared with Engerix-B at all time points (Table 2), with peak titres at Day 196 (1424.52 mIU/mL vs.
235.43 mIU/mL) and persistent titres at Day 336 (546.79 mIU/mL vs. 83.48 mIU/mL). Results were consistent across key subgroups based on age, gender, diabetes status, BMI, daily alcohol consumption, and smoking status, with all lower bounds of 95% CIs of the difference in SPR being above the preset margin of non-inferiority and superiority (Table 2).


Table 2:      Seroprotection Rate (SPR) and Geometric Mean Concentration (GMC) of Anti-HBs Titres of Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml and engerix B at Day 196
Difference in SPR
(Hepatitis B vaccine
Hepatitis B vaccine (recombinant,                                             (recombinant, engerix B
Study population             adsorbed) 10µg/1 ml                                                   adsorbed) 10µg/1 and subgroups                                                                                            ml - engerix B)
SPR            GMC                    SPR             GMC           Difference N                                       N
(95% CI)       (mIU/mL)               (95% CI)        (mIU/mL)        (95% CI) 91.36%                                 76.49%                          14.88% Adults (age 18+)         718                        1424.52       723                      235.43 (89.07, 93.32)                         (73.22, 79.53)                  (11.18, 18.63) 99.20%                                 91.11%                          8.09% Age 18-44                125                        4550.39       135                      727.67 (95.62, 99.98)                         (84.99, 95.32)                  (3.40, 14.22) 94.77%                                 80.12%                          14.65% Age 45-64                325                        1558.30       322                      274.80 (91.76, 96.92)                         (75.34, 84.34)                  (9.75, 19.81) 83.58                                 64.66%                          18.92% Age 65+                  268                         414.24       266                       64.31 (78.59, 87.81)                         (58.59, 70.40)                  (11.60, 26.14) 83.33%                                 58.33%                          25.00% Diabetes (age 18+)       54                          448.89       60                        73.68 (70.71, 92.08)                         (44.88, 70.93)                  (8.37, 40.36) BMI >30 kg/m2                        89.22%                                68.11%                            21.11% 269                          1005.16 254                            131.35 (age 18+)                        (84.89, 92.66)                         (61.99, 73.80)                   (14.29, 27.97) N = number of subjects evaluated in the Per-Protocol Set; SPR = Seroprotection Rate defined as anti-HBs titres ≥10 mIU/mL in serum; GMC = Geometric Mean Concentration (adjusted)

Enrolment of subjects in Sci-B-Vac-001 to receive either Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml or Engerix B was stratified by three age groups: age 18-44 years (n=125 vs.
n=135 subjects), age 45-64 years (n=325 vs. n=322, and age 65+ (n=268 vs. n=266. Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml achieved higher seroprotection rates in each of these groups at Day 196, four weeks after the third dose (age 18-44: 99.2% vs. 91.1%; age 45-64: 94.8% vs.
80.1%; age 65+: 83.6% vs. 64.7%).

Study Sci-B-Vac-002 in adults age 18-45 years
The primary endpoint of the study was to compare 3 lots of Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml and Engerix-B for immune response assessed by measuring GMC of anti-HBs.
The data from the three lots were combined (pooled) to demonstrate that the SPR on Study Day 196, 4 weeks after completion of the 3-dose regimen of Hepatitis B vaccine (recombinant, adsorbed)
10µg/1 ml was non-inferior to Engerix-B. Non-inferiority of Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml compared to Engerix B was based on the difference in SPR and the lower bound of the 2-sided 95% CI, using the preset margin of -5%.

The GMC of anti-HBs titres in the Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml groups were consistent across all three lots and higher than Engerix B at all time points, including at peak at Study Day 196 (Lot A: 5979.5 mIU/mL; Lot B: 4855.3 mIU/mL; Lot C: 5553.2 mIU/mL vs.
1526.3 mIU/mL). The SPR in the pooled Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml group was also higher at each time point than Engerix B and demonstrated non-inferiority at Day 196 (99.3 vs. 94.8) after the required 3-dose course (Table 3).



Table 3:       Seroprotection Rate (SPR) and Geometric Mean Concentration (GMC) of Anti-HBs Titres of Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml and Engerix B in Adults Age 18-45
Difference in SPR
( Hepatitis B vaccine
Hepatitis B vaccine (recombinant,
Engerix B                     (recombinant,
adsorbed) 10µg/1 ml Pooled
Timepoint                                                                                           adsorbed) 10µg/1 ml – Engerix B)
SPR              GMC                        SPR              GMC             Difference N                                           N
(95% CI)          (mIU/mL)                  (95% CI)         (mIU/mL)           (95% CI) 99.26%                                      94.76%                                4.49 Day 196      1753                             5443.07     592                             1526.26 (98.74. 99.60)                              (92.65, 96.41)                       (2.90, 6.63) 98.66%                                      92.41%                                6.25 Day 336      1718                             2093.80     580                              473.02 (98.00, 99.15)                              (89.95, 94.43)                       (4.26, 8.74) N = number of subjects in the Per-Protocol Set 2 (received all 3 doses at months 0, 1 and 6); SPR = Seroprotection Rate defined as % of subjects with anti-HBs titers
≥10 mIU/mL in serum; Pooled Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml includes the Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml Lots A, B, and C

The safety and immunogenicity of Hepatitis B vaccine (recombinant, adsorbed) 10µg/1 ml observed in the two pivotal studies, Sci-B-Vac 001 and Sci-B-Vac 002, are supportive of that observed in 11 adult legacy studies.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

The pharmacokinetic properties of the hepatitis B surface antigen used in Sci-B-Vac have not been assessed.