13 January 2020 - - US-based commercial-stage biopharmaceutical company VBI Vaccines Inc. (NASDAQ: VBIV) has 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 vaccine, and comparing safety and immunogenicity of Sci-B-Vac to GlaxoSmithKline's currently-marketed HBV vaccine, Engerix-B, the company said.

The Phase 3 study, which enrolled 2,838 adults, age 18-45 years, met both the primary and secondary endpoints.

The primary endpoint of the study was lot-to-lot consistency for immune response, as measured by geometric mean concentration 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 US, 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 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 [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.

CONSTANT is a double-blind, four-arm, randomised, 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 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.