Takeda Announces WHO SAGE Recommendation for Dengue Vaccine

• Experts Reviewed Data from QDENGA’s Clinical Program Across 19 Phase 1, 2 and 3 Trials with More Than 28,000 Participants

• WHO Will Consider the SAGE Recommendation and Provide Final Guidance on the Use of QDENGA in Public Vaccination Programs in the Coming Months

• Dengue Poses a Significant and Growing Public Health Burden to People Living in and Traveling to Endemic Countries

OSAKA, Japan, and CAMBRIDGE, Massachusetts, October 3, 2023 – Takeda (TSE:4502/NYSE:TAK) today announced that the World Health Organization’s (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization shared recommendations for use of QDENGA®▼ (Dengue Tetravalent Vaccine [Live, Attenuated]) (TAK-003). In the coming months, the WHO will consider the SAGE recommendation and update its position paper on dengue vaccines to include final guidance on the use of QDENGA in public vaccination programs.

SAGE made the following recommendations:

• The vaccine to be considered for introduction in settings with high dengue disease burden and high transmission intensity to maximize the public health impact and minimize any potential risk in seronegative persons.

• The vaccine to be introduced to children aged 6 to 16 years of age. Within this age range, the vaccine should be introduced about 1-2 years prior to the age-specific peak incidence of dengue-related hospitalizations. The vaccine should be administered in a 2-dose schedule with a 3-month interval between doses.

• The vaccine introduction should be accompanied by a well-designed communication strategy and community engagement.

Dengue fever is among the most common mosquito-borne viral diseases worldwide.¹ It is endemic in more than 100 countries and causes an estimated 390 million infections each year.² While many dengue infections are asymptomatic or produce only mild illness, dengue can occasionally cause more severe disease, and even death.² Dengue is also a leading cause of fever among travelers returning from Latin America, the Caribbean and Southeast Asia.³

“The global impact of dengue cannot be overlooked as the incidence continues to rise. This week, the World Health Organization’s (WHO) Strategic Advisory Group of Experts (SAGE) provided important recommendations for the use of QDENGA in preventing dengue,” said Gary Dubin, M.D., president of the Global Vaccine Business Unit at Takeda. “We’re encouraged by their feedback and look forward to the final position from the WHO in the coming months.”

SAGE reviewed data across 19 Phase 1, 2 and 3 trials with more than 28,000 children and adults, including the pivotal Phase 3 Tetravalent Immunization against Dengue Efficacy Study (TIDES) trial, which was designed according to the WHO’s guidance for a second-generation dengue vaccine. The pivotal TIDES trial met its primary endpoint of overall vaccine efficacy (VE) against virologically-confirmed dengue (VCD) with 80.2% efficacy at 12-months follow-up.⁴ The trial also met all secondary endpoints for which there were a sufficient number of dengue cases at 18-months follow-up.⁵ The VE result in preventing hospitalization due to VCD fever was 90.4%.⁵ Through four and a half years (54 months after the second dose) in an exploratory analysis, QDENGA demonstrated continued overall protection, with sustained overall VE of 61.2% and 84.1% VE against VCD and hospitalized dengue, respectively.⁶ Observations of VE varies by serotype and remained consistent with previously reported results. QDENGA has been generally well tolerated and no important safety risks have been identified in the TIDES trial, to date.

QDENGA is currently available for children and adults in the private market in countries in Europe, Indonesia, Thailand and Brazil, and will be available in Argentina soon.

About QDENGA® ▼ (Dengue Tetravalent Vaccine [Live, Attenuated])

QDENGA® (TAK-003) is a dengue vaccine that is based on a live-attenuated dengue serotype 2 virus, which provides the genetic “backbone” for all four dengue virus serotypes and is designed to protect against any of these serotypes.⁷

In the European Union (EU) Member States, QDENGA is indicated for the prevention of dengue disease in individuals from four years of age and should be administered subcutaneously as a 0.5 mL dose at a two-dose (0 and 3 months) schedule pursuant to approved dosing regimen.⁸

The use of QDENGA should be in accordance with local recommendations.

Important Safety Information

Please consult the Summary of Product Characteristics (SmPC) before prescribing.

Guidance for use: QDENGA should be administered by subcutaneous injection preferably in the upper arm in the region of deltoid. QDENGA must not be injected intravascularly, intradermally or intramuscularly. Vaccination should be postponed in subjects suffering from an acute severe febrile illness. The presence of a minor infection, such as a cold, should not result in a deferral of vaccination. Vaccination should be preceded by a review of the individual’s medical history (especially with regards to previous vaccination and possible hypersensitivity reactions which occurred after vaccination). Appropriate medical treatment and supervision must always be readily available in the event of a rare anaphylactic reaction following administration of the vaccine. Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting. A protective immune response with QDENGA may not be elicited in all vaccinees against all serotypes of dengue virus and may decline over time. It is currently unknown whether a lack of protection could result in an increased severity of dengue. It is recommended to continue personal protection measures against mosquito bites after vaccination. Individuals should seek medical care if they develop dengue symptoms or dengue warning signs.

Contraindications: Hypersensitivity to the active substances or excipients listed, or to previous QDENGA dose. Individuals with congenital or acquired immune deficiency, including immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids (e.g., 20 mg/day or 2 mg/kg body weight/day of prednisone for 2 weeks or more) within 4 weeks prior to vaccination. Individuals with symptomatic HIV infection or asymptomatic HIV infection with impaired immune function. Pregnant and breast-feeding women.

Adverse Reactions: Most frequently reported reactions in subjects 4 to 60 years of age were injection site pain (50%), headache (35%), myalgia (31%), injection site erythema (27%), malaise (24%), asthenia (20%), and fever (11%). Very common: (≥1/10 of subjects): upper respiratory tract infection^a, decreased appetite^c, irritability^c, headache, somnolence^c, myalgia, injection site pain, injection site erythema, malaise, asthenia, fever. Common (≥1/100 to <1/10): nasopharyngitis, pharyngotonsillitis^b, arthralgia, injection site swelling, injection site bruising^e, injection site pruritus^e,

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See Section 4.8 of the SmPC for how to report adverse reactions.

influenza like illness. ^aIncludes upper respiratory tract infection and viral upper respiratory tract infection. ^bIncludes pharyngotonsillitis and tonsillitis. ^cCollected in children below 6 years of age in clinical studies. ^dIncludes rash, viral rash, rash maculopapular, and rash pruritic. ^eReported in adults in clinical studies. Refer to the SmPC for details on full side effect profile and interactions.

For full prescribing information, please see the Summary of Product Characteristics (SmPC) for QDENGA®▼.

Please consult with your local regulatory agency for any approved labeling in your country.

The drug information contained herein is intended to disclose corporate information. Nothing contained in this document should be considered a solicitation, promotion, or indication for any prescription drug, including those currently under development.

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.⁹ 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.⁹ The study is comprised of five parts. Part 1 and the primary endpoint analysis evaluated VE and safety through 12 months after the second dose.⁹ 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.⁹ 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 recommendations.¹⁰ Part 4 is evaluating 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 4.⁹

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.¹¹ 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.^2,12 Dengue is mainly spread by Aedes aegypti mosquitoes and, to a lesser extent, Aedes albopictus mosquitoes.² 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.¹⁴ 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.^2,15

Takeda’s Commitment to Vaccines

Vaccines prevent 3.5 to 5 million deaths each year and have transformed global public health.¹⁶ 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 focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit www.takeda.com.

Media Contacts:

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U.S. and International Media

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Medical Information

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References

1. Bhatt, S., Gething, P., Brady, O. et al. The global distribution and burden of dengue. Nature 496, 504–507 (2013). https://doi.org/10.1038/nature12060.

2. World Health Organization. Dengue and Severe Dengue. Published March 17, 2023.

3. Halstead S, Wilder-Smith A. Severe dengue in travelers: pathogenesis, risk and clinical management. J Travel Med. 2019;26(7).

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

5. 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.

6. Tricou, V. Efficacy and Safety of Takeda’s Tetravalent Dengue Vaccine Candidate (TAK-003) After 4.5 Years of Follow-Up. Presented at the 8th Northern European Conference of Travel Medicine; June 2022.

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. Takeda. QDENGA Summary of Product Characteristics. Retrieved October 2023.

9. ClinicalTrials.Gov. Efficacy, Safety and Immunogenicity of Takeda’s Tetravalent Dengue Vaccine (TDV) in Healthy Children (TIDES). Retrieved July 2023.

10. World Health Organization (WHO) Technical Report Series No. 979, 2013 Annex 2. Guidelines on the quality, safety and efficacy of dengue tetravalent vaccines (live, attenuated). https://cdn.who.int/media/docs/default-source/biologicals/vaccine-standardization/dengue/trs-979-annex-2-dengue.pdf?sfvrsn=bd659777_2&download=true.

11. Murray, et al. Epidemiology of dengue: past, present and future prospects. Clin Epidemiol. 2013 Aug 20;5:299-309. doi: 10.2147/CLEP.S34440.

12. World Health Organization (WHO). Ten threats to global health in 2019. Retrieved July 2023.

13. CDC. About Dengue: What You Need to Know. Published April 13, 2023.

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

15. Reich, et al. Interactions between serotypes of dengue highlight epidemiological impact of cross-immunity. J R Soc Interface 10: 20130414. http://dx.doi.org/10.1098/rsif.2013.0414.

16. World Health Organization. Vaccines and immunization. October 2022. Retrieved July 2023.