Takeda Completes Enrollment of More Than 20,000 Children and Adolescents in Global Phase 3 Trial of Dengue Vaccine Candidate

Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial evaluates the efficacy of two
doses of vaccine candidate TAK-003, administered three months apart, to protect against all four
strains of dengue virus, regardless of previous dengue exposure

Study includes children and adolescents ages 4 through 16 years in eight dengue-endemic countries
across Latin America and Asia

 - Achieving enrollment demonstrates Takeda’s commitment to advancing global vaccine business and
addressing unmet needs in dengue prevention

Osaka, Japan, April 5, 2017 – Takeda Pharmaceutical Company Limited [TSE: 4502], (“Takeda”) today announced that it has completed enrollment of 20,100 children and adolescents ages 4 through 16in its global, pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial, a double-blind, randomized and placebo-controlled study designed to evaluate the efficacy, safety and immunogenicity of its live-attenuated tetravalent dengue vaccine candidate (TAK-003) [1]Takeda initiated the TIDES trial, the largest vaccine clinical trial for Takeda to date, in September 2016 and completed enrollment in less than seven months.[1]

“The successful enrollment of more than 20,000 children and adolescents in this Phase 3 trial, across several continents, and on an ambitious timeline, while maintaining a clear focus on quality and subject safety, reflects Takeda’s prioritization of dengue and the substantial capabilities of our global organization,” said Rajeev Venkayya, MD, President of the Global Vaccine Business Unit at Takeda.

The study is taking place in eight dengue-endemic countries in Latin America and Asia: Brazil, Colombia, Panama, Dominican Republic, Nicaragua, Philippines, Thailand and Sri Lanka.[1] While dengue can affect people of all ages, it is a leading cause of serious illness among children in some countries in Latin America and Asia.[2] The enrollment of children and adolescents between the ages of 4 and 16 years underscores the significant burden of dengue disease across the entire pediatric age range. Initial results of the TIDES trial are expected in 2018.[1]

TIDES will build on previous studies which have assessed the tolerability, safety and immunogenicity of the vaccine against all four dengue serotypes in multiple age groups to determine whether the vaccine helps prevent symptomatic dengue.[3],[4],[5],[6],[7] In Phase 1 and Phase 2 studies, Takeda’s vaccine candidate induced neutralizing antibody responses against all four dengue virus serotypes across age groups and in both seropositive and seronegative individuals with no observed safety concerns.[3],[4],[5],[6],[7] Interim results of one Phase 2 study (DEN-203) showed the vaccine to be generally safe and well tolerated.[3],[5] Results also showed that adults vaccinated with two doses had a sustained immune response against all four serotypes of the dengue virus, even after two years.[5]  Interim results of another Phase 2 study (DEN-204) showed an acceptable safety profile in endemic pediatric populations, as well as antibody responses against the four dengue serotypes in dengue seropositive and seronegative participants, with a sustained immune response through 180 days.[6],[7]

“This enrollment milestone demonstrates our commitment to a thorough evaluation of the safety and efficacy of our vaccine candidates and, subject to licensure, ensuring that they are available to all populations at risk. It follows Takeda’s recent decision to invest more than 100 million euros to build a new plant for the manufacturing of TAK-003,” said Venkayya. “Beyond dengue, Takeda is pursuing a number of vaccine programs to address high-priority infectious diseases including our Zika program funded by the U.S. Government’s Biomedical Advanced Research and Development Authority (BARDA) and our polio program supported by the Bill & Melinda Gates Foundation.

About the Phase 3 TIDES Study[1]
TIDES is investigating the efficacy, safety and immunogenicity of two doses of TAK-003 administered three months apart. TIDES participants were randomized to receive a two-dose regimen of either TAK-003 or placebo by subcutaneous injection at Day 1 and Day 90. A subset of these participants was randomly selected and stratified by region and age to be included in the safety and immunogenicity subsets. Efficacy assessments will take place once 120 cases of virologically confirmed dengue have accrued and after a minimum subject follow-up period of 12 months, post second vaccination.

The primary outcome measure is vaccine protection against virologically-confirmed dengue of any severity, caused by any of the four dengue virus serotypes, regardless of whether a subject has been previously exposed to dengue. Secondary endpoints include vaccine efficacy in preventing dengue induced by each dengue serotype, vaccine efficacy in preventing hospitalization due to dengue induced by any serotype, vaccine efficacy in preventing severe dengue induced by any serotype, frequency and severity of Adverse Events (AEs) or Serious Adverse Events (SAEs), and seropositivity rate and geometric mean titers (GMTs) of neutralizing antibodies in the immunogenicity subset.

About TAK-003
Takeda’s tetravalent dengue vaccine candidate (TAK-003) is based on a live-attenuated dengue serotype 2 virus (DENV-2), which provides the genetic ‘backbone’ for all four vaccine viruses.[8] Phase 1 and 2 data have supported progression into Phase 3 study, suggesting that TAK-003 is safe and well-tolerated in children and adolescents (no vaccine-related SAEs occurred and reactogenicity was limited) and induced immunogenicity against all four dengue serotypes, even in seronegative participants.[4],[5],[6],[7]

About Dengue
Dengue is the fastest spreading mosquito-borne viral disease.[2] Dengue is spread by Aedes aegypti and Aedes albopictus mosquitoes and is caused by four dengue virus serotypes, each of which can cause dengue fever or severe dengue.[9],[10]The serotypes vary across different geographies, countries, regions, seasons and over time.[11],[12]

Dengue outbreaks are observed in tropical and sub-tropical areas and have recently caused outbreaks in parts of mainland U.S. and Europe.[9],[13],[14]  Forty percent of the world now lives under the threat of dengue, which is responsible for approximately 390 million infections and 20,000 deaths globally each year.[9],[10] 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.[2]

Takeda’s Commitment to Vaccines
Vaccines prevent more than two million deaths each year and have transformed global public health.[15] For 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, norovirus and polio. 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.

About Takeda Pharmaceutical Company Limited
Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.

Contacts:
For media outside of Japan:
Elissa J. Johnsen
TEL: + 1 224-554-3185
elissa.johnsen@takeda.com

For Japanese media:
Tsuyoshi Tada
TEL: +81-3-3278-2417
tsuyoshi.tada@takeda.com

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[2] World Health Organization. Vector-borne Diseases: Dengue. 2015. Retrieved January 2017. 

[3] Osorio, J.E., et al. Development of a Recombinant, Chimeric Tetravalent Dengue Vaccine Candidate. Vaccine. 2015. Retrieved March 2017.

[5] 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 6th Annual Meeting, American Society of Tropical Medicine and Hygiene. 2015.

[6] 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. 2016.

[8] Huang, C. Y.-H., et al. Genetic and Phenotypic Characterization of Manufacturing Seeds for Tetravalent Dengue Vaccine (DENVax). PLoS Neglected Tropical Diseases. 2013. Retrieved May 2016.

[9] World Health Organization. Dengue and Severe Dengue. 2016. Retrieved January 2017.

[10] Centers for Disease Control and Prevention. Clinical Guidance Dengue Virus.  2014. Retrieved January 2017.

[11] Bravo, L., et al. Epidemiology of Dengue Disease in the Philippines (2000-2011): A Systematic Literature Review. PLoS Neglected Tropical Diseases. 2014. Retrieved January 2017. 

[12] Guzman, M.G., et al. Dengue: a continuing global threat. Nature reviews Microbiology. 2010. Retrieved May 2016.

[13] Knowlton, K., et al. NRDC Issue Paper: Mosquito-Borne Dengue Fever Threat Spreading in the Americas. 2009. Retrieved May 2016.

[14] Chan E., et al. Using Web Search Query Data to Monitor Dengue Epidemics: A New Model for Neglected Tropical Disease Surveillance. PLoS Neglected Tropical Diseases. 2011. Retrieved January 2017.

[15] UNICEF. Immunization Facts and Figures. 2013. Retrieved January 2017.