Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) Takeda announced that The Lancet published two papers related to its dengue vaccine candidate (TAK-003), reporting on results from the 18-month analysis of the ongoing pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study trial and results from the final 48-month analysis of the Phase 2 DEN-204 trial.
The analyses are consistent with previously reported safety, immunogenicity and efficacy data for TAK-003.
The 18-month data analysis from the pivotal Phase 3 TIDES trial includes an update on overall vaccine efficacy (VE) and a formal assessment of secondary efficacy endpoints by serotype, baseline serostatus and disease severity (18 months after the second dose, which was administered three months after the first dose), demonstrating protection against virologically confirmed dengue (VCD) in children ages four to 16 years (overall VE was 73.3% [95% confidence interval (CI): 66.5% to 78.8%].
The TIDES trial met all secondary endpoints for which there were a sufficient number of dengue cases. TAK-003 was generally well tolerated, and there were no important safety risks identified within this analysis.
The 18-month data were previously presented at the American Society of Tropical Medicine & Hygiene (ASTMH) 68th Annual Meeting in November 2019. VE and safety results from the 18-month analysis were generally consistent with the data reported in the previously published 12-month analysis.
“I see first-hand the devastation that dengue can bring to communities and individuals and the pressure it puts on healthcare systems. There is a great need for a vaccine that is safe and effective in reducing not only the incidence and severity of disease but also the hospitalization rate,” said Lulu C. Bravo, M.D., Professor Emeritus, Pediatric Infectious and Tropical Diseases at the University of the Philippines Manila, and an author of The Lancet TIDES paper. “Although long-term data is needed to fully assess the safety and efficacy of this vaccine candidate, the published results from the Phase 3 study indicate that TAK-003 could be an important tool in dengue prevention.”
The TIDES trial is continuing, and safety and efficacy will be assessed over a total of four and a half years.
Takeda plans to share results from the 24-month analysis of TIDES later this year. Takeda’s dengue vaccine candidate is not currently licensed anywhere in the world.
The DEN-204 study enrolled 1,800 participants. In the 48-month data analysis, TAK-003 was shown to elicit antibody responses against all four dengue serotypes in children and adolescents ages two to 17 years, which persisted through four years post-vaccination, regardless of baseline serostatus. Three different dose schedules (one primary dose; one primary dose plus one-year booster dose; or two-dose primary series), and placebo were assessed. In baseline seropositive participants, no clear differences in geometric mean titers (GMTs) – an indication of immune response – were shown between the dosing schedules by Month 48. In the baseline seronegative participants, GMTs were generally lower against all four serotypes in those who received one dose compared with either the two-dose primary series or the one dose plus one-year booster series, further supporting the use of the two-dose primary series studied in the ongoing TIDES trial. No important safety risks were identified throughout the four-year study period, providing insight into the long-term safety profile of TAK-003. While VE was not assessed in this study, there was a significantly lower risk of VCD in the vaccine groups compared with placebo over the four-year study period (relative risk: 0.35; 95% CI: 0.19-0.65). Results of previous interim analyses of the DEN-204 study demonstrated persistence of immunogenicity along with tolerability and safety assessments at six and 18 months.
“Dengue threatens families and communities around the globe, and there remains a critical need for a vaccine that is safe in all people regardless of previous dengue exposure,” said Derek Wallace, VP, Dengue Global Program Leader at Takeda. “We are encouraged by the long-term safety data and immunogenicity profile demonstrated in the Phase 2 trial, and the protection for both seropositive and seronegative individuals, as well as against hospitalized dengue, in our pivotal Phase 3 trial. These data demonstrate the potential for our vaccine candidate to support the global fight against dengue fever."
About the Phase 3 TIDES (DEN-301) Trial
The double-blind, randomized, placebo-controlled Phase 3 TIDES trial is evaluating the safety and efficacy of two doses of TAK-003 in the prevention of laboratory-confirmed symptomatic dengue fever of any severity and due to any of the four dengue virus serotypes in children and adolescents. The TIDES trial is Takeda’s largest interventional clinical trial to date and enrolled over 20,000 healthy children and adolescents ages four to 16 years living in dengue-endemic areas. Study participants were randomly assigned to receive either TAK-003 0.5 mL or placebo by subcutaneous injection on Day 1 and Day 90. The study is comprised of three parts. The primary endpoint analysis evaluated vaccine efficacy (VE) and safety through 15 months after the first dose (12 months after the second dose). The second part of the study continued for an additional six months to complete the assessment of the secondary endpoints of VE by serotype, baseline serostatus and disease severity. The final part of the study is evaluating VE and long-term safety by following participants for an additional three years.
The trial is taking place at sites in dengue-endemic areas in Latin America (Brazil, Colombia, Panama, the Dominican Republic and Nicaragua) and Asia (Philippines, Thailand and Sri Lanka) where there are unmet needs in dengue prevention and where severe dengue is a leading cause of serious illness and death among children. Baseline blood samples were collected from all individuals participating in the trial to allow for evaluation of safety and efficacy based on serostatus. Takeda and an independent Data Monitoring Committee of experts are actively monitoring safety on an ongoing basis.
About the Phase 2 DEN-204 Trial
The Phase 2 DEN-204 study was a randomized, double-blind, placebo-controlled, multi-center trial designed to assess the safety and immunogenicity of either a one- or two-dose schedule of TAK-003 in 1,794 healthy participants living in dengue-endemic areas (the Dominican Republic, Panama and the Philippines). The study was completed in 2019. Participants were ages two through 17 and were randomized to one of four groups, two of which received a one-dose vaccine schedule, one of which received a two-dose vaccine schedule administered three months apart, and one of which received placebo, by the six-month interim analysis timepoint. The primary endpoint of this interim analysis was geometric mean titers (GMTs) of neutralizing antibodies (an indicator of immune response) to the four dengue virus serotypes (DENV-1-4) in the per protocol immunogenicity subset (PPS), a group of participants who had no major protocol violations and for whom valid pre- and post-dosing blood samples were available and immunogenicity was evaluated, at months one, three and six. Secondary endpoints included occurrence of serious adverse events and virologically-confirmed dengue in the safety set (i.e., in all participants who received at least one dose of TAK-003 or placebo), seropositivity rates (percentage of participants who developed antibodies), and occurrence of solicited and unsolicited adverse events in the immunogenicity subset.
