Merck & Co has announced that in the pivotal phase III efficacy study, its investigational 9-valent HPV vaccine ( V503 ) prevented approximately 97% of cervical, vaginal and vulvar pre-cancers caused by HPV types 31, 33, 45, 52, and 58.
V503 has also generated immune responses to HPV types 6, 11, 16, and 18 that were non-inferior to those generated by Gardasil [ Human Papillomavirus Quadrivalent ( types 6, 11, 16, and 18 ) Vaccine, Recombinant ].
V503 includes five more HPV types ( 31, 33, 45, 52, 58 ) in addition to the four original HPV types ( 6, 11, 16, 18 ) in Gardasil.
Results from the pivotal phase III efficacy study
The pivotal phase III study ( Protocol 001 ) has evaluated the efficacy, safety and immunogenicity of V503 ( n=7,099 ) compared to Gardasil ( n=7,105 ) in 16-26-year old females. The primary efficacy analysis was conducted in those who received all three doses of vaccine within one year, who were not infected with the relevant HPV types at enrollment and who remained free of infection with the relevant HPV types through Month 7 ( per-protocol population ).
The results were as follows:
a) 96.7% reduction ( 95% CI; 80.9, 99.8 ) in the combined incidence of high-grade cervical / vulvar / vaginal disease [ CIN ( cervical intraepithelial neoplasia ) 2/3+, VIN ( vulvar intraepithelial neoplasia ) 2/3+, and VaIN ( vaginal intraepithelial neoplasia ) 2/3+ ] caused by HPV types 31, 33, 45, 52, 58 ( 1 case in the group that received V503 vs 30 cases in the group that received Gardasil, papillomavirus quadrivalent ( types 6, 11, 16, and 18 ) vaccine, recombinant );
b) 97.1% reduction ( 95% CI; 91.8, 99.2 ) in the combined incidence of cervical / vulvar / vaginal disease of any grade ( all CIN, VIN, VaIN ) caused by HPV types 31, 33, 45, 52, 58 ( 3 cases in the group that received V503 vs 103 cases in the group that received Gardasil );
c) 96.0% efficacy ( 95% CI; 94.4, 97.2 ) against six-month persistent HPV infection with HPV types 31, 33, 45, 52, 58 ( 35 cases in the group that received V503 vs 810 cases in the group that received Gardasil ).
Because Gardasil does not contain the five additional HPV types in V503, cases of disease caused by these five types in the study group that received Gardasil were expected.
Non-inferior immunogenicity for the four HPV types ( 6, 11, 16, 18 ) also in Gardasil was a second primary endpoint in this study. Because Gardasil has been shown in clinical studies to be highly effective against certain diseases caused by HPV types 6, 11, 16, and 18, few disease endpoints caused by these HPV types were expected, making it difficult to directly assess efficacy of V503 for these four types. Therefore, antibody levels were evaluated for these four HPV types common to both vaccines.
V503 generated immune responses for HPV 6, 11, 16, and 18 ( measured by geometric mean titers and seroconversion rates at month 7 ) that were non-inferior to those generated by Gardasil.
In the study, the seroconversion rates were 99.8% for HPV types 6 and 18 and 100 percent for HPV types 11 and 16 in the V503 group. The corresponding numbers in the group that received Gardasil were 99.8, 99.9, 100, and 99.7% for HPV types 6, 11, 16 and 18, respectively. These results are to support the bridging of the efficacy findings for Gardasil for HPV types 6, 11, 16, 18 to V503.
Safety of V503 in pivotal efficacy study
In this study, the frequencies of adverse event reports were generally comparable between V503 and Gardasil; however, there was a higher frequency of injection-site adverse effects ( 90.8% vs 85.1% ), including swelling, pain and erythema in the V503 group.
Injection-site pain was mostly reported as mild or moderate in intensity with both vaccines. The majority of injection-site swelling and erythema cases were of small size ( less than or equal to one inch ).
The most frequently reported vaccine-related systemic adverse reactions ( frequency greater than or equal to 2% ) for V503 compared to Gardasil, respectively, were: headache ( 14.6% vs 13.7% ), pyrexia ( 5.0% vs 4.3% ), nausea ( 4.4% vs 3.7% ), dizziness ( 3.0% vs 2.8% ), and fatigue ( 2.3% vs 2.1% ).
Results of adolescent immunobridging studies for V503
The results from two open-label immunobridging studies for V503 in adolescents were presented. Immunobridging studies were used for the adolescent population because adolescents are not likely to have been exposed to HPV, and therefore, efficacy against disease endpoints cannot be studied directly.
Immunogenicity bridging data is an accepted surrogate for efficacy and is an approach that is accepted by major regulatory agencies.
In Protocol 002, which is aimed at extending the pivotal efficacy study findings in females 16-26 years of age to males and females 9-15 years of age ( adolescents ), 3,074 subjects were divided into three groups: 669 male 9-15-year olds, 1,935 female 9-15-year olds and 470 female 16-26-year olds. Immune responses to V503 were compared among the groups.
All study participants in the per-protocol population received three doses of V503 over a six-month period and were evaluated at month 7 for geometric mean titers and seroconversion rates.
Results from this study showed non-inferior immunogenicity of V503 in adolescent males and females compared with females 16-26 years old for all nine vaccine HPV types: 99.8-100% of adolescent females and 99.8-100% of adolescent males seroconverted, or developed antibodies, against the nine HPV types at month 7 compared to 99.5-100% of 16-26-year old females.
The safety profile of V503 was similar or slightly more favorable in adolescent males compared to adolescent females and females 16-26 years old; the overall safety and tolerability findings were consistent with those reported in previous studies with Gardasil.
In Protocol 009, 600 adolescent females who had not yet received a prophylactic HPV vaccine were randomized into two groups, 300 who received V503 and 300 who received Gardasil, to compare the immune responses in adolescent girls for HPV types 6, 11, 16 and 18.
All study participants in the per-protocol population received three doses of Gardasil or V503 over a six-month period and were evaluated at month 7 for GMTs and seroconversion rates.
In this study, immunogenicity of V503 was non-inferior compared to Gardasil in adolescent females for HPV types 6, 11, 16 and 18: 100% of adolescent females in both study groups seroconverted against HPV types 6, 11, 16 and 18 at month 7.
The overall safety profile of V503 was generally similar to Gardasil, with higher frequency of injection-site swelling with V503. ( Xagena )
Source: Merck, 2014