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Takeda’s dengue vaccine candidate demonstrates protection in children aged four to 16 years, regardless of previous dengue exposure

Takeda’s dengue vaccine candidate was generally well-tolerated, and no important safety risks have been observed to date

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Takeda has announced that results from the primary endpoint analysis of the ongoing pivotal phase 3 Tetravalent Immunisation Against Dengue Efficacy Study (TIDES) trial of its dengue vaccine candidate (TAK-003) were published in the New England Journal of Medicine. The company’s dengue vaccine candidate demonstrated protection against virologically-confirmed dengue (VCD), the trial primary endpoint, in children aged four to 16 years. Vaccine efficacy (VE) was 80.2 per cent in the 12-month period after the second dose, which was administered three months after the first dose. Similar degrees of protection were seen in individuals who had and had not been previously infected with dengue based on planned exploratory analyses of secondary endpoints. Other exploratory analyses showed a 95.4 per cent reduction in dengue-associated hospitalisations. Efficacy against severe disease could not be assessed due to the limited number of cases. Onset of protection was seen after the first dose, with 81 per cent VE between the first and second doses.

Takeda’s dengue vaccine candidate was generally well-tolerated, and no important safety risks have been observed to date. The observed safety profile was consistent with results reported in previous studies of TAK-003.1,2,3,4 The TIDES trial will continue to assess safety and efficacy in study subjects for a total of four-and-a-half years.

“The results of this first analysis are very encouraging, indicating that the vaccine could potentially provide important public health benefits against dengue fever and hospitalization,” said Humberto Reynales, MD, PhD, a lead author of the New England Journal of Medicine paper. “It will be important to further analyze the trial results over time in order to assess the long-term efficacy and safety of the vaccine. If longer follow-up data confirm this initial observation, we are looking at a significant step forward in the global fight against dengue.”

“According to the World Health Organization, dengue represents one of the ten biggest global health threats, and it is critical that we have access to a safe and effective vaccine candidate that can reduce the devastating impact dengue fever has in endemic regions,” said In-Kyu Yoon, MD, Senior Advisor, International Vaccine Institute. “Historically, vaccine development against dengue has been challenging, especially for people who haven’t previously been exposed to dengue, and these results demonstrate protection from dengue fever, including among many participants without prior dengue.”

Serotype-Specific Efficacy

Dengue virus infections caused by all four serotypes were observed in the global TIDES trial. Exploratory analyses of secondary endpoints showed efficacy varied by serotype: VE was 73.7 per cent for serotype 1 (95% CI: 51.7% to 85.7%), 97.7 per cent for serotype 2 (95% CI: 92.7% to 99.3%), and 62.6 per cent for serotype 3 (95% CI: 43.3% to 75.4%). There were too few dengue serotype four virus cases to fully assess efficacy at this time (VE: 63.2% [95% CI: -64.6% to 91.8%]).

Further analyses of exploratory endpoints also showed that, for both serotypes 1 and 2, efficacy levels among seropositives and seronegatives were similar. For dengue serotype 3, VE in baseline seropositives was 71.3 per cent (95% CI: 54.2% to 82.0%), and in seronegatives, results were inconclusive but suggested a lack of efficacy (VE: -38.7% [95% CI: –335.7% to 55.8%]). No dengue serotype 4 cases were observed in seronegative participants.

Ongoing Analysis

While in the process of publishing the primary endpoint data, Takeda received additional data from the ongoing TIDES trial, which adds six months of follow-up and provides formal assessment of the secondary efficacy endpoints. Both the primary endpoint analysis and formal assessment of secondary endpoints will be presented at the American Society of Tropical Medicine and Hygiene (ASTMH) 68th Annual Meeting, November 20-24, 2019, in National Harbour, Md, and submitted to a peer-reviewed journal.

“We are excited to share this long-anticipated data from our TIDES trial, which is evaluating the performance of our dengue vaccine candidate in a diverse set of countries across Asia and Latin America, and in a study population that intentionally includes a large proportion of children who had never been exposed to dengue,” said Rajeev Venkayya, MD, President, Global Vaccine Business Unit, Takeda. “While more data is needed to fully understand the safety and efficacy profile of TAK-003, these findings strongly suggest that it could help address the massive global burden of dengue in all populations. We look forward to sharing more data in the coming weeks, and engaging health authorities and the scientific, public health and medical communities on these findings, priorities for future evidence generation, and ways we can work together to maximise the reach and impact of this vaccine upon licensure.”

The Phase 3 TIDES trial is ongoing, and longer-term data will be important in determining the efficacy and safety profile, particularly in baseline seronegative participants with dengue serotype 3 virus. Takeda is engaging global health experts to provide insights into the burden of dengue in endemic regions and analyses of results from the trial. Takeda’s dengue vaccine candidate is not currently licensed anywhere in the world.

About the Phase 3 TIDES (DEN-301) Trial

The double-blind, randomised, 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. 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 severity. The final part of the study evaluates 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, 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.

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