MA-TAKEDA

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK ) (“Takeda”) today announced that The Lancet published two papers related to Takeda’s 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 (TIDES) trial and results from the final 48-month analysis of the Phase 2 DEN-204 trial.^1,2 The analyses are consistent with previously reported safety, immunogenicity and efficacy data for TAK-003.^3,4,5,6

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.¹ The 18-month data were previously presented at the American Society of Tropical Medicine & Hygiene (ASTMH) 68th Annual Meeting in November 2019.⁴ VE and safety results from the 18-month analysis were generally consistent with the data reported in the previously published 12-month analysis .^1,3

“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).² Results of previous interim analyses of the DEN-204 study demonstrated persistence of immunogenicity along with tolerability and safety assessments at six⁵ and 18 months.⁶

“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.⁷ 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 90.⁷ 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).⁷ 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.⁷ The final part of the study is evaluating VE and long-term safety by following participants for an additional three years.⁷

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.⁷ 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 2019.⁸ 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.⁸ 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.⁸ 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.⁸

About TAK-003
Takeda's tetravalent dengue vaccine candidate (TAK-003) is based on a live-attenuated dengue serotype 2 virus, which provides the genetic “backbone” for all four vaccine viruses.⁹ Clinical Phase 1 and 2 data in children and adolescents showed that TAK-003 induced immune responses against all four dengue serotypes, in both seropositive and seronegative participants, and the vaccine was found to be generally safe and well tolerated.^5,10,11,12

About Dengue
Dengue is the fastest spreading mosquito-borne viral disease and is one of the World Health Organization’s top 10 threats to global health in 2019.^13,14 Dengue is mainly spread by Aedes aegypti mosquitoes and, to a lesser extent, Aedes albopictus mosquitoes. It is caused by any of four dengue virus serotypes, each of which can cause dengue fever or severe dengue.¹³ The prevalence of individual serotypes varies across different geographies, countries, regions, seasons and over time.^13,15 Recovery from infection by one serotype provides lifelong immunity against only that serotype, and later exposure to any of the remaining serotypes is associated with an increased risk of severe disease.1³

Dengue is pandemic prone, and outbreaks are observed in tropical and sub-tropical areas and have recently caused outbreaks in parts of the continental United States and Europe.^13,16,17 Approximately half of the world now lives under the threat of dengue, which is estimated to cause 390 million infections and around 20,000 deaths globally each year.^13,18 The dengue virus can infect people of all ages and is a leading cause of serious illness among children in some countries in Latin America and Asia.¹³

Takeda’s Commitment to Vaccines
Vaccines prevent 2 to 3 million deaths each year and have transformed global public health.¹⁹ For the past 70 years, Takeda has supplied vaccines to protect the health of people in Japan. Today, Takeda’s global vaccine business is applying innovation to tackle some of the world’s most challenging infectious diseases, such as dengue, Zika and norovirus. Our team brings an outstanding track record and a wealth of knowledge in vaccine development, manufacturing and global access to advance a pipeline of vaccines to address some of the world’s most pressing public health needs. For more information, visit www.TakedaVaccines.com .

About Takeda Pharmaceutical Company Limited
Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK ) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Diseases, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries.
For more information, visit https://www.takeda.com .

References

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¹ Biswal S, et al. Efficacy of a tetravalent dengue vaccine in health children aged 4-16 years: a randomized, placebo-controlled, phase 3 trial . Lancet . 2020. doi:10.1016/S0140-6736(20)30414-1. [epub ahead of print].
² Tricou, V, Sáez-Llorens X, et al. Safety and immunogenicity of a tetravalent dengue vaccine in children aged 2-17 years: a randomised, placebo-controlled, phase 2 trial . Lancet. 2020. doi:10.1016/S0140-6736(20)30556-0. [epub ahead of print].
³ Biswal S, et al. Efficacy of a tetravalent dengue vaccine in healthy children and adolescents . N Engl J Med . 2019;381:2009-2019.
⁴ Biswal S. Efficacy of a tetravalent dengue vaccine in healthy 4 to 16-year-old children. Presented at 68th Annual Meeting, American Society of Tropical Medicine and Hygiene; November 2019; National Harbor, Md.
⁵ Sáez-Llorens X, Tricou V, et al. Safety and immunogenicity of one versus two doses of Takeda's tetravalent dengue vaccine: Interim results of a long-term phase 2, randomized, placebo-controlled pediatric trial in Asia and Latin America . Lancet Infect Dis . 2017;17:615-625.
⁶ Sáez-Llorens X, Tricou V, et al. Immunogenicity and safety of one versus two doses of tetravalent dengue vaccine in healthy children aged 2–17 years in Asia and Latin America: 18-month interim data from a phase 2, randomised, placebo-controlled study. Lancet Infect Dis . 2017;18:P162-170.
⁷ ClinicalTrials.gov. Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children (TIDES) . 2019.
⁸ ClinicalTrials.gov. Safety and Immunogenicity of Different Schedules of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Healthy Participants . 2020.
⁹ Huang CY-H, et al. Genetic and phenotypic characterization of manufacturing seeds for tetravalent dengue vaccine (DENVax). PLoS Negl Trop Dis . 2013;7:e2243.
¹⁰ Osorio, JE, et al. Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study. Lancet Infect Dis . 2014;14:P830-838..
¹¹ Wallace D. Persistence of neutralizing antibodies one year after two doses of a candidate recombinant tetravalent dengue vaccine in subjects aged from 1.5 to 45 years. Presented at 64th Annual Meeting, American Society of Tropical Medicine and Hygiene; October 2016; Philadelphia, Pa.
¹² Saez-Llorens X, et al. Phase II, double-blind, controlled trial to assess the safety and immunogenicity of different schedules of Takeda’s Tetravalent Dengue Vaccine Candidate (TDV) in healthy subjects aged between 2 and <18 years and living in dengue endemic countries in Asia and Latin America. Presented at 5th Pan-American Dengue Research Network Meeting; April 2016; Panama City, Panama.
¹³ World Health Organization. Factsheet. Dengue and Severe Dengue . April 2019. Retrieved November 2019.
¹⁴ World Health Organization. Ten threats to global health in 2019 . 2019. Retrieved November 2019.
¹⁵ Guzman MG, et al. Dengue: a continuing global threat . Nature Reviews Microbiology . 2010;8:S7-S16.
¹⁶ Knowlton K, et al. Mosquito-Borne Dengue Fever Threat Spreading in the Americas . The Natural Resources Defense Council (NRDC). 2009. Retrieved November 2019.
¹⁷ Chan E, et al. Using web search query data to monitor dengue epidemics: a new model for neglected tropical disease surveillance . PLoS Negl Trop Dis . 2011;5:e1206..
¹⁸ Centers for Disease Control and Prevention. About Dengue: What You Need to Know. May 2019. Retrieved March 2020.
¹⁹ UNICEF. Vaccination and Immunization Statistics . 2019. Retrieved November 2019.

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