VBI Vaccines Inc. (VBI), a commercial-stage biopharmaceutical company developing next-generation infectious disease and immuno-oncology vaccines, reported top-line data from CONSTANT, the second pivotal Phase 3 study, assessing lot-to-lot manufacturing consistency of Sci-B-Vac®, the company’s trivalent hepatitis B (HBV) vaccine, and comparing safety and immunogenicity of Sci-B-Vac® to GlaxoSmithKline’s currently-marketed HBV vaccine, Engerix-B®. The Phase 3 study, which enrolled 2,838 adults, age 18-45 years, met both the primary and secondary endpoints.
“We are thrilled with the results of the CONSTANT study, which once again demonstrate Sci-B-Vac® is a safe and highly-potent option for vaccination against hepatitis B, and which now enable us to finalize our regulatory package as we work towards submissions in the U.S., Europe, and Canada starting in the second half of 2020,” said Jeff Baxter, VBI’s President and CEO.
The primary endpoint of the study was lot-to-lot consistency for immune response, as measured by geometric mean concentration (GMC) of antibodies across three independent, consecutively-manufactured lots of Sci-B-Vac®, four weeks after the third vaccination. Together with the positive safety and immunogenicity results of the PROTECT Phase 3 study – data which were announced in June 2019 – these data comprise the basis for the regulatory submissions in the U.S., Europe, and Canada, expected to begin in the second half of 2020.
A secondary endpoint of the study was non-inferior immunogenicity as measured by seroprotection rates (SPR) at day 196, one month after completion of the full course of vaccination with either Sci-B-Vac® or Engerix-B®. At day 196, the pooled SPR in subjects who received Sci-B-Vac® was 99.3% compared to 94.8% for those who received Engerix-B® – a difference of 4.49%; 95% Confidence Interval (CI) [2.90%, 6.63%] – up from 90.4% for Sci-B-Vac® and 51.6% for Engerix-B® at day 168, after only two vaccinations. In addition to demonstrating non-inferiority, the SPR achieved with Sci-B-Vac® compared with Engerix-B® was higher after both two and three vaccinations.
The safety and tolerability seen in CONSTANT were consistent with the known safety profile of Sci-B-Vac®. No new safety risks were identified and no safety signals were observed in either cohort. The integrated safety data analysis from both the PROTECT and CONSTANT studies is underway.
An exploratory analysis in CONSTANT also compared the SPR after two doses of Sci-B-Vac® (at day 168) to the SPR after three doses of Engerix-B® (at day 196). At these times points, the SPR was 90.4% for Sci-B-Vac® and 94.8% for Engerix-B® – a difference of -4.3%; 95% CI [-6.48%, -1.90%]. As per the commonly-used statistical margin of non-inferiority for vaccines1, defined as the lower limit of the 95% CI being above -10%, this analysis demonstrated non-inferiority after two doses of Sci-B-Vac® (at day 168) compared with three doses of Engerix-B® (at day 196). Similarly, at these time points, preliminary data from the integrated immunogenicity analysis of both the PROTECT and CONSTANT studies in subjects age 18-45 years demonstrate a difference in SPR of -4.2%; 95% CI [-6.38%, -1.99%]. The two vs. three dose comparison is not part of the regulatory approval process and would not be included in the expected indication the company will seek, but does contribute to the robust immunogenicity profile of Sci-B-Vac®.
Francisco Diaz-Mitoma, M.D., Ph.D., VBI’s Chief Medical Officer commented, “With the completion of the pivotal Phase 3 program, we believe the full data package of Sci-B-Vac® supports its ability to address significant unmet medical needs in North America and in Europe. As demonstrated in the pivotal Phase 3 program, Sci-B-Vac® can safely confer higher rates of protection in older adults and in adults with key immuno-compromising conditions. Moreover, in younger healthy adults who need protection safely and quickly, we believe Sci-B-Vac® has demonstrated its ability to be highly competitive, achieving protection rates of 90% after two vaccinations and 99% after three vaccinations.”
About CONSTANT – Lot-to-Lot Consistency Study
CONSTANT is a double-blind, four-arm, randomized, controlled study that enrolled 2,838 adult subjects, age 18-45 years, who were randomized in a 1:1:1:1 ratio into one of four three-dose cohorts: Lot A of Sci-B-Vac® 10 µg, Lot B of Sci-B-Vac 10 µg, Lot C of Sci-B-Vac 10 µg, or the control vaccine Engerix-B® 20 µg. Under the planned dosing schedule, subjects were vaccinated at months zero, one, and six.
The primary endpoint of this study was:
- To demonstrate lot-to-lot consistency for immune response, as measured by geometric mean concentration (GMC) of antibodies across three independent, consecutive lots of Sci-B-Vac four weeks after the third vaccination.
- This primary endpoint was prospectively defined across two patient sets, with demonstration of lot-to-lot consistency required in only one of the two sets – the detailed study results will be discussed with the FDA as part of the regulatory approval process
The secondary endpoints were to evaluate safety and efficacy of Sci-B-Vac® vs. Engerix-B®.