Takeda’s Biologics License Application (BLA) for Dengue Vaccine Candidate (TAK-003) Granted Priority Review by U.S. Food and Drug Administration

Takeda (TSE:4502/NYSE:TAK) today announced that the U.S. Food and Drug Administration (FDA) has accepted and granted priority review of the Biologics License Application (BLA) for TAK-003, the company’s investigational dengue vaccine candidate. In the U.S., TAK-003 is being evaluated for the prevention of dengue disease caused by any dengue virus serotype in individuals 4 years through 60 years of age.

Dengue is a mosquito-borne virus endemic in more than 125 countries, including the U.S. territories of Puerto Rico, the U.S. Virgin Islands and American Samoa.^1,2 Incidence of dengue has increased globally over the past two decades and is a leading cause of fever among travelers returning from Latin America, the Caribbean and Southeast Asia.³

“If approved, we believe TAK-003 has the potential to become an important dengue prevention option for healthcare providers, and we continue to be encouraged by our discussions with the FDA,” said Gary Dubin, M.D., president of the Global Vaccine Business Unit at Takeda. “This year, of the 888 dengue infections in the U.S., 96% were a result of travel to dengue endemic areas. Of the 316 dengue infections in U.S. endemic territories, 97% were locally transmitted.⁴ At Takeda, we are guided by our commitment to serving these affected populations and are fully committed to working with the FDA to advance this filing.”

The TAK-003 BLA is supported by safety and efficacy data from the pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial, where the dengue vaccine candidate met its primary endpoint by preventing 80.2% of symptomatic dengue cases at 12 months.^5,6 In addition, TAK-003 met its secondary endpoint by preventing 90.4% of hospitalizations at 18 months, and in an exploratory analysis, it demonstrated protection against dengue fever through 4.5 years (54 months) after vaccination. The TIDES exploratory analyses showed that throughout the 4.5-year study follow-up, TAK-003 prevented 84% of hospitalized dengue cases and 61% of symptomatic dengue cases in the overall population, including both seropositive and seronegative individuals.

Currently, TAK-003 has not been approved by the FDA or any other health authority outside of Indonesia. Following the approval of TAK-003 in Indonesia, Takeda will continue to progress regulatory filings in other dengue-endemic and non-endemic countries. In October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of Takeda’s dengue vaccine candidate, TAK-003, for the prevention of dengue disease caused by any serotype in individuals four years of age and older in Europe and in dengue-endemic countries participating in the parallel EU-M4all procedure. The final step in the path to approval in Europe is a Marketing Authorization decision from the EMA, which is expected in the coming months. Regulatory reviews will also progress in dengue-endemic countries in Latin America and Asia.

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.⁷ 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.⁸ The pivotal Phase 3 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. Safety results from the studies' integrated analysis showed that the rates of Serious Adverse Events (SAEs) were 6.21% in the TAK-003 Group, and 7.56% in the Placebo Group.⁹ Most frequent unsolicited AEs were nasopharyngitis, upper respiratory tract infection, viral upper respiratory tract infection, viral infection, and pyrexia.

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.¹⁰ Study participants were randomized 2:1 to receive two doses of TAK-003 0.5 mL or placebo on months 0 and 3, administered subcutaneously.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. 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. Part 3 evaluated VE and long-term safety by following participants for an additional two and a half to three years, as per World Health Organization (WHO) recommendations.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.

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.⁵ 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 a mosquito-borne viral disease that spreads rapidly around the world and was one of the WHO’s top 10 threats to global health in 2019.^11,12 Dengue is mainly spread by Aedes aegypti mosquitoes and, to a lesser extent, Aedes albopictus mosquitoes.¹¹ 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.¹³ 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.¹¹

Takeda’s Commitment to Vaccines
Vaccines prevent 3.5 to 5 million deaths each year and have transformed global public health.¹⁴ For more than 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, pandemic flu and Zika. Takeda’s team brings an outstanding track record and a wealth of knowledge in vaccine development and manufacturing to advance a pipeline of vaccines to address some of the world’s most pressing public health needs. For more information, visit www.takeda.com/what-we-do/areas-of-focus/vaccines/.

About Takeda
Takeda 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 Genetics 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 and regions. For more information, visit https://www.takeda.com.

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Medical information
This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development.

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¹ Centers for Disease Control and Prevention. Dengue in the US States and Territories. August 2022. Retrieved August 2022.
² World Health Organization. Feature Stories. WHO Scales Up Response to Worldwide Surge in Dengue. November 2019. Retrieved November 2022.
³ Centers for Disease Control and Prevention. Traveler’s Health: CDC Yellow Book. July 2019. Retrieved October 2021.
⁴ Centers for Disease Control and Prevention. Statistics and Maps – 2022. November 2022. Retrieved November 2022.
⁵ Gov. Efficacy, Safety and Immunogenicity of Takeda’s Tetravalent Dengue Vaccine (TDV) in Healthy Children (TIDES). Retrieved August 2022.
⁶Takeda Pharmaceuticals. Data on File.
⁷ Huang CY-H, et al. Genetic and phenotypic characterization of manufacturing seeds for tetravalent dengue vaccine (DENVax). PLoS Negl Trop Dis. 2013;7:e2243.
⁸ 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.
⁹ Patel et al, Clinical Safety Experience of TAK-003 for Dengue Fever: A New Tetravalent Live Attenuated Vaccine Candidate. Clin Infect Dis. 2022 May 26;ciac418.
¹⁰ Biswal S, et al. Efficacy of a tetravalent dengue vaccine in healthy children and adolescents. N Engl J Med. 2019;2019;381:2009-2019.
¹¹ World Health Organization. Factsheet. Dengue and Severe Dengue. January 2022. Retrieved August 2022.
¹² World Health Organization. Ten threats to global health in 2019. 2019. Retrieved August 2022.
¹³ Guzman MG, et al. Dengue: a continuing global threat. Nature Reviews Microbiology. 2010;8:S7-S16.
¹⁴ World Health Organization. Vaccines and immunization. 2022. Retrieved August 2022.

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