Takeda Pharmaceutical Company Limited [TSE: 4502], ("Takeda") today announced that data from a 6-month interim analysis* of the ongoing DEN-204 trial of its live-attenuated tetravalent dengue vaccine candidate, TAK-003 (also referred to as TDV), have been published in The Lancet Infectious Diseases.1
The trial investigated the safety and immunogenicity of TAK-003 in 1,794 participants ages two through 17 living in dengue-endemic areas (the Dominican Republic, Panama and the Philippines). At the time of the analysis, participants had either received one dose of TAK-003, two doses of TAK-003 administered three months apart, or a placebo.
The published data showed that TAK-003 elicited a broad antibody response against all four dengue virus types (called serotypes), regardless of previous exposure to the dengue virus.1 The increased presence of antibodies in the blood against the four serotypes (seropositivity) ranged between 87-100% by Month 1 and was sustained at Month 6 (85-100%) in both the one-dose and two-dose groups.1 This analysis also showed that, in participants who were not previously exposed to dengue infection (seronegative) before vaccination, seropositivity rates against dengue virus types 3 and 4 were improved after a second dose of vaccine.1 For this reason, a two-dose regimen, administered three months apart, was selected for Takeda's ongoing global pivotal Phase 3 efficacy trial.2
This analysis also showed that TAK-003 was safe and well-tolerated in children and adolescents in terms of solicited local reactions and systemic adverse events; no vaccine-related serious adverse events (SAEs) occurred, and the expected immunological responses to the vaccine and associated signs and symptoms (reactogenicity) was limited.1 The number of adverse events reported were similar or lower than those reported for other live attenuated vaccines, and the safety profile was consistent with that observed in earlier Phase 1 and 2 studies of the vaccine candidate.1
Dengue fever is a painful, debilitating mosquito-borne disease caused by any one of four closely related virus serotypes.3 Forty percent of the world lives under the threat of dengue, which can affect people of all ages and is a leading cause of serious illness and death among children throughout the world.4,5
"The levels of immunogenicity induced by TAK-003 against all four dengue serotypes, even in seronegative participants, are encouraging because seropositivity after vaccination may be an important measure of vaccine performance," said Xavier Sáez-Llorens, M.D., primary author of TheLancet Infectious Diseases publication and Head of Infectious Diseases and Director of Clinical Research at the Panama Children's Hospital. "Infection with one dengue serotype makes subsequent infection with a different serotype a major risk factor for severe disease, hence the need for a safe and effective vaccine that simultaneously protects against all four serotypes.6 The durability of these antibody responses and the contribution of cell-mediated immune responses to disease protection warrant further study."
"These and other Phase 1 and Phase 2 safety and immunogenicity data support continued development of this important vaccine candidate,"1,7,8 said Derek Wallace, M.B.B.S., Global Dengue Program Head at Takeda. "We look forward to ongoing studies, which will assess the candidate vaccine's ability to provide protection against all four dengue serotypes in recipients of all ages, whether or not they have been previously exposed to dengue."
In September 2016, Takeda initiated its pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES). The randomized, double-blind, placebo-controlled, multi-center trial is designed to investigate the efficacy, safety and immunogenicity of Takeda's dengue vaccine candidate, administered in two doses, three months apart, in dengue-endemic countries in Latin America and Asia.2 Evaluation of the trial's primary endpoint, vaccine protection against virologically-confirmed dengue of any severity caused by any serotype regardless of previous exposure, is expected in 2018.2 Secondary endpoints include vaccine efficacy in preventing dengue induced by each serotype, vaccine efficacy in preventing dengue caused by any serotype regardless of participants' baseline status, vaccine efficacy in preventing hospitalization due to dengue, and vaccine efficacy in preventing severe dengue induced by any serotype.2
*An interim data analysis is a pre-planned evaluation of data from an ongoing trial before final data collection.
About the Phase 2 DEN-204 Study
The Phase 2 DEN-204 study is 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).1 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 which received placebo, by the 6 month interim analysis timepoint.1 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.1 Secondary endpoints included occurrence of serious adverse events (SAEs), seropositivity rates (percentage of participants who developed antibodies), and adverse events (AEs) in the immunogenicity subset.1
About Takeda's Dengue Vaccine Candidate (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.9 Takeda's dengue vaccine is being developed to support the protection of populations and individuals at risk for dengue across geographies whether or not they have had previous exposure to dengue virus, including children and adults, travelers and those living in endemic areas.
Phase 1 data has been published in the Journal of Infectious Diseases,Lancet Infectious Diseases and Vaccine. Interim results of DEN-203, a Phase 2, placebo-controlled, multi-center, age-descending trial, were presented during the American Society of Tropical Medicine and Hygiene (ASTMH) meeting in October 2015.8 Interim results of DEN-204 were also presented during the 5th Annual Pan-American Dengue Research Network Meeting in May 2016 and ASTMH in November 2016.10,11
Takeda's Commitment to Vaccines
Vaccines prevent more than two million deaths each year and have transformed global public health.12 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.
1 Sáez-Llorens, Tricou, et al. (2017). 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 Infectious Diseases. Retrieved March 2017, from http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30166-4/fulltext?elsca1=tlxpr.
2 ClinicalTrials.gov. Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children (TIDES). (2016) Retrieved May 2016, from https://clinicaltrials.gov/ct2/show/NCT02747927?term=den-301&rank=1.
3 World Health Organization, Vector-borne diseases dengue fact sheet. Retrieved March 2017, from http://www.who.int/mediacentre/factsheets/fs387/en/index2.html.
4 World Health Organization (2016). Dengue and severe dengue. Retrieved May 2016, from http://www.who.int/mediacentre/factsheets/fs117/en/.
5 Centers for Disease Control and Prevention (2014). Dengue homepage: Epidemiology. Retrieved September 2016, from http://www.cdc.gov/dengue/epidemiology/.
6 Scitable by Nature Education. Host Response to the Dengue Virus. Retrieved March 2017, from http://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106.
7 Osorio, J. E., Velez, I. D., Thomson, et al. (2014). 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 Infectious Diseases, 14(9), 830-838. doi:10.1016/s1473-3099(14)70811-4.
8 Wallace, D. (2015). 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.
9 Huang, C. Y.-H., Osorio, J.E., et. Al. (2013). Genetic and Phenotypic Characterization of Manufacturing Seeds for Tetravalent Dengue Vaccine (DENVax). PLoS Neglected Tropical Diseases, 7(5): e2243. doi: 10.1371/journal.pntd.0002243.
10 Saez-Llorens X., et al. (2016). 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.
11 Wallace, D. (2016). Takeda's Tetravalent Dengue Vaccine Candidate. Presented at 65th Annual Meeting, American Society of Tropical Medicine & Hygiene.
12 UNICEF. Immunization Facts and Figures (2013). Retrieved September 2015, from http://www.unicef.org/immunization/files/UNICEF_Key_facts_and_figures_on_Immunization_April_2013(1).pdf.