Potential Impact of Takeda’s Dengue Vaccine Candidate Reinforced by Long-Term Safety and Efficacy Results

− Takeda’s dengue vaccine candidate (TAK-003) prevented 83.6% of hospitalizations and 62.0% of dengue illness overall, with no identified important safety risks through three years following vaccination in ongoing pivotal Phase 3 TIDES trial

− Regulatory filings for TAK-003 progressing in European Union and in many dengue-endemic countries; filing in United States planned for later this year

− Dengue is the fastest-spreading mosquito-borne viral disease with an estimated 390 million cases and 500,000 hospitalizations per year globally, with limited options for prevention

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that its dengue vaccine candidate (TAK-003) demonstrated continued protection against dengue illness and hospitalization, regardless of an individual’s previous dengue exposure, with no important safety risks identified through three years after vaccination in the ongoing pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial. TIDES enrolled more than 20,000 healthy children and adolescents ages four to 16 years in dengue-endemic countries in Latin America and Asia.

“Dengue epidemics occur suddenly, and hospitals can become overwhelmed with severe disease cases and people seeking testing,” said LakKumar Fernandoⁱ, M.D., Center for Clinical Management of Dengue and Dengue Haemorrhagic Fever, Negombo General Hospital, Sri Lanka and a primary investigator of the TIDES trial. “Results from the long-term analysis of Takeda’s dengue vaccine candidate suggest that it could help with outbreak prevention, reduce rates of hospitalization and protect people from dengue regardless of their previous exposure. Importantly, no important safety risks were identified.”

Safety and efficacy results from the 36-month follow-up exploratory analysis of TIDES were presented on May 22, 2021, at the 17th Conference of the International Society of Travel Medicine (CISTM). Through three years (36 months after the second dose), TAK-003 demonstrated overall vaccine efficacy (VE) of 62.0% (95% CI: 56.6% to 66.7%) against virologically-confirmed dengue (VCD), with 65.0% VE (95% CI: 58.9% to 70.1%) in seropositive individuals and 54.3% VE (95% CI: 41.9% to 64.1%) in seronegative individuals. TAK-003 also demonstrated 83.6% VE (95% CI: 76.8% to 88.4%) against hospitalized dengue, with 86.0% VE (95% CI: 78.4% to 91.0%) in seropositive individuals and 77.1% VE (95% CI: 58.6% to 87.3%) in seronegative individuals. Observations of varied VE by serotype remained consistent with previously reported results. No evidence of disease enhancement was observed. TAK-003 was generally well tolerated, and there were no important safety risks observed. The results reinforce the potential of TAK-003 to help protect those who are living in or traveling to dengue-endemic countries.

“Our dengue vaccine candidate continued to provide protection against dengue throughout three years, and was especially robust in preventing hospitalization,” said Derek Wallace, VP, Dengue Global Program Leader at Takeda. "These results reinforce my confidence that TAK-003 can help address the significant global burden of dengue.”

As previously reported, the TIDES trial met its primary endpoint of overall VE against VCD at 12-months follow-up (VE: 80.2%; 95% CI: 73.3% to 85.3%; p<0.001) and all secondary endpoints for which there were a sufficient number of dengue cases (measured at 18-months follow-up). The TIDES trial has been amended to include the evaluation of a booster dose to address the waning of overall VE observed over time (from 12 through 36 months after the second dose), largely driven by outpatient dengue. Takeda intends to publish results of the 36-month exploratory analysis in a peer-reviewed journal this year.

TIDES safety and efficacy data through 36-months follow-up was included in regulatory submissions to the European Union and dengue-endemic countries and will be part of additional filings planned for 2021, including in the United States. Takeda will seek an indication for TAK-003 for the prevention of dengue disease in individuals four to 60 years of age, regardless of previous virus exposure, based on data in both adults and children. There remains a need for dengue vaccines that can be used in both dengue-naïve and dengue-exposed adults and children.

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.¹ Clinical Phase 2 data in children and adolescents showed that TAK-003 induced immune responses against all four dengue serotypes, in both seropositive and seronegative participants, which persisted through 48 months after vaccination, and the vaccine was found to be generally safe and well tolerated.² The pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial met its primary endpoint of overall vaccine efficacy (VE) against virologically-confirmed dengue (VCD) at 12-months follow-up and all secondary endpoints at 18-months follow-up for which there were a sufficient number of dengue cases, including VE against hospitalized dengue and VE in baseline seropositive and baseline seronegative individuals.^3,4 Efficacy varied by serotype. The results demonstrated TAK-003 was generally well tolerated, and there have been no important safety risks observed to date.

About the Phase 3 TIDES (DEN-301) Trial

The double-blind, randomized, placebo-controlled Phase 3 Tetravalent Immunization against Dengue Efficacy Study (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.⁴ 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 90.⁴ The study is comprised of five parts. Part 1 and the primary endpoint analysis evaluated vaccine efficacy (VE) and safety through 12 months after the second dose.⁴ Part 2 continued for an additional six months to complete the assessment of the secondary endpoints of VE by serotype, baseline serostatus and disease severity, including VE against hospitalized dengue.⁴ Part 3 is evaluating VE and long-term safety by following participants for an additional two and a half to three years.⁵ Part 4 will evaluate efficacy and safety for 13 months following booster vaccination and Part 5 will evaluate long-term efficacy and safety for one year after completion of Part 4.⁵

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.⁴ 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 Dengue

Dengue is the fastest spreading mosquito-borne viral disease and was one of the WHO’s top 10 threats to global health in 2019.^6,7 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. The prevalence of individual serotypes varies across different geographies, countries, regions, seasons and over time.⁸ 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.

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.^9,10 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.^10,11 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.¹⁰

Takeda’s Commitment to Vaccines

Vaccines prevent 2 to 3 million deaths each year and have transformed global public health.¹² 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, COVID-19, Zika and norovirus. Takeda’s 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 discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetic and Hematology, 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.

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ⁱ Dr. LakKumar Fernando did not receive compensation for his statement.

¹ Huang CY-H, et al. Genetic and phenotypic characterization of manufacturing seeds for tetravalent dengue vaccine (DENVax). PLoS Negl Trop Dis. 2013;7:e2243.

²Tricou, 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.

³ Biswal S, et al. Efficacy of a tetravalent dengue vaccine in healthy children and adolescents. N Engl J Med. 2019; 2019;381:2009-2019.

⁴ Biswal S, et al. Efficacy of a tetravalent dengue vaccine in healthy children aged 4-16 years: a randomized, placebo controlled, phase 3 trial. Lancet. 2020. 2020;395:1423-1433.

⁵ ClinicalTrials.Gov. Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children (TIDES). Retrieved March 2021.

⁶ World Health Organization. Factsheet. Dengue and Severe Dengue. April 2019. Retrieved February 2021.

⁷ World Health Organization. Ten threats to global health in 2019. 2019. Retrieved February 2021.

⁸ Guzman MG, et al. Dengue: a continuing global threat. Nature Reviews Microbiology. 2010;8:S7-S16.

⁹ Knowlton K, et al. Mosquito-Borne Dengue Fever Threat Spreading in the Americas. The Natural Resources Defense Council (NRDC). 2009. Retrieved February 2021.

¹⁰ 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.

¹¹ Centers for Disease Control and Prevention. About Dengue: What You Need to Know. May 2019. Retrieved February 2021.

¹² UNICEF. Vaccination and Immunization Statistics. 2019. Retrieved February 2021.

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