Enterobiasis

— 12 Weeks of Treatment with EOHILIA May Address Significant Unmet Needs of Patients 11 Years of Age and Older — EoE Is a Chronic Disease That Can Significantly Impact Patients, with Esophageal Inflammation and Intermittent Symptoms of Choking and Difficult or Painful Swallowing OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Takeda (TSE:4502/NYSE:TAK) today announced that the U.S. Food and Drug Administration (FDA) has approved EOHILIA (budesonide oral suspension), the first and only FDA-approved oral therapy for people 11 years and older with eosinophilic esophagitis (EoE).1 It will be available in 2 mg/10 mL convenient, single-dose stick packs by the end of February. EOHILIA is a corticosteroid indicated for 12 weeks of treatment in patients 11 years and older with EoE.1 Developed specifically for EoE, EOHILIA’s novel formulation of budesonide confers thixotropic properties – flowing more freely when shaken and returning to a more viscous state when swallowed.1,2 “Various formulations of corticosteroids have been used in the past to manage EoE, but in an off-label capacity and using multiple delivery options. With EOHILIA, it’s gratifying to now have an FDA-approved treatment specifically formulated for a consistent dose delivery with demonstrated ability to address esophageal inflammation and EoE dysphagia symptoms,” said Ikuo Hirano, MD, professor of medicine and director of the Kenneth C. Griffin Esophageal Center in the Division of Gastroenterology and Hepatology at Northwestern University Feinberg School of Medicine. “As the treatment needs and goals of patients with EoE can vary, I welcome the flexibility that EOHILIA offers as an oral medication.” The FDA approval of EOHILIA 2 mg twice daily is based on efficacy and safety data from two multicenter, randomized, double-blind, parallel-group, placebo-controlled 12-week studies (Study 1 and Study 2) in patients (ages 11 to 56 and 11 to 42, respectively) with EoE.1 In both studies, patients received at least one dose of either EOHILIA 2 mg twice daily or placebo orally twice daily. Efficacy endpoints included histologic remission (peak eosinophil count of ≤6 per high-powered field across all available esophageal levels) and the absolute change from baseline in patient-reported Dysphagia Symptom Questionnaire (DSQ) combined score after 12 weeks of treatment. The DSQ measures how often a patient with EoE has trouble swallowing and the behavioral adaptations they subsequently use, as reported directly by patients.3 Significantly more patients receiving EOHILIA achieved histologic remission vs. placebo in Study 1 (53.1% vs. 1%).1 In Study 2, 38% of EOHILIA patients achieved histologic remission vs. 2.4% of those in the placebo group. Absolute change from baseline in DSQ combined score in the EOHILIA vs. placebo groups in Study 1 was -10.2 (1.5) vs. -6.5 (1.8) and in Study 2, -14.5 (1.8) vs. -5.9 (2.1). During the last two weeks of each study, more patients receiving EOHILIA experienced no dysphagia or only experienced dysphagia that “got better or cleared up on its own” as compared to placebo, as measured by the DSQ. EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks. The most common adverse reactions (≥2% of patients receiving EOHILIA and at a rate greater than placebo) in Study 1 included: respiratory tract infection (13%), gastrointestinal mucosal candidiasis (8%), headache (5%), gastroenteritis (3%), throat irritation (3%), adrenal suppression (2%) and erosive esophagitis (2%). The safety pro EOHILIA in Study 2 was generally similar to Study 1.1 “For most of us, eating is a simple experience. But for people living with eosinophilic esophagitis, sitting down for a meal can include painful and difficult swallowing, chest pain and a choking sensation,” said Brandon Monk, senior vice president and head, U.S. Gastroenterology Business Unit, Takeda. “With EOHILIA, patients and their physicians now have the first and only FDA-approved oral treatment option for EoE that was shown during two 12-week clinical studies to reduce esophageal inflammation and improve the ability to swallow.” EoE is a chronic, immune-mediated, inflammatory disease localized in the esophagus.4 Although the exact cause is unknown, it is believed to be triggered by a variety of stimuli including certain foods and environmental allergens.5,6 The chronic inflammation of EoE can lead to a range of symptoms, which can vary by person and age, and include difficulty swallowing, vomiting and pain.7 Identifying EoE can be complex and delayed diagnosis is common among patients. If left untreated, the inflammation of EoE can worsen and narrow the esophagus, which can lead to food impaction (when food becomes stuck in the esophagus).8,9 In fact, EoE is the leading cause of emergency room visits for food impaction.10 Takeda is assessing the financial impacts of the approval, including a reversal of impairment loss for intangible assets, on the fiscal year ending on March 31, 2024 (FY2023), but does not anticipate the impact to be material. Indication and Limitations of Use EOHILIA is indicated for 12 weeks of treatment in adult and pediatric patients 11 years of age and older with eosinophilic esophagitis (EoE). EOHILIA has not been shown to be safe and effective for the treatment of EoE for longer than 12 weeks. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS EOHILIA is contraindicated in patients with hypersensitivity to budesonide. Serious hypersensitivity reactions, including anaphylaxis, have occurred with oral budesonide products. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression Systemic effects such as hypercorticism and adrenal axis suppression may occur. Monitor patients for signs and symptoms and consider reducing the dosage of EOHILIA. Use is not recommended in patients with severe hepatic impairment (Child‑Pugh Class C) and monitoring for signs and/or symptoms of hypercorticism is recommended in patients with moderate hepatic impairment (Child‑Pugh Class B). Corticosteroids, including EOHILIA, can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to trauma, surgery, infection, or other stress situations, supplementation with a systemic corticosteroid is recommended. Immunosuppression and Increased Risk of Infection Corticosteroids, including EOHILIA, suppress the immune system and increase the risk of infection with any pathogen. Corticosteroid-associated infections can be mild, severe, and at times fatal. Monitor patients and consider discontinuation of EOHILIA if the patient develops an infection. Tuberculosis reactivation may occur. Closely monitor patients with latent tuberculosis or tuberculin reactivity while receiving EOHILIA. Varicella Zoster and Measles can be serious or fatal in non-immune patients taking corticosteroids. Avoid exposure. If a patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered. If a patient is exposed to measles, prophylaxis with immunoglobulin may be indicated. Hepatitis B Virus Reactivation can occur. Prior to starting EOHILIA for patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy. Amebiasis: It is recommended that latent or active amebiasis be ruled out before starting EOHILIA in patients who have spent time in the tropics or have unexplained diarrhea. Avoid EOHILIA in patients with: systemic fungal infections, known or suspected Strongyloides (threadworm) infection, cerebral malaria, and active ocular herpes simplex. Localized Infections: In clinical trials, some patients developed Candida albicans infections in the mouth, throat, and esophagus. Instruct patients: do not eat or drink for 30 minutes after taking EOHILIA; after 30 minutes rinse mouth with water and spit without swallowing. If oropharyngeal or esophageal candidiasis develops, treat with appropriate antifungal therapy and consider discontinuing EOHILIA. Erosive Esophagitis Erosive esophagitis occurred in subjects who received EOHILIA in a 12-week clinical trial. None of the subjects had erosions at baseline esophagogastroduodenoscopy (EGD), and most were receiving concomitant therapy with a proton pump inhibitor (PPI). Advise patients or caregivers to report new onset or worsening signs or symptoms of erosive esophagitis to their healthcare provider. Consider endoscopic evaluation as appropriate. Effect on Growth Use of corticosteroids may cause a reduction of growth velocity in pediatric patients. Monitor the growth of pediatric patients on EOHILIA. The maximum recommended duration of treatment with EOHILIA is 12 weeks. Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids Monitor patients who are transferred from corticosteroids with high systemic effects to corticosteroids with lower systemic availability, such as EOHILIA, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously. Replacement of systemic corticosteroids with EOHILIA may unmask allergies (e.g., rhinitis and eczema) previously controlled by the systemic drug. Other Corticosteroid Effects Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, or cataracts, or with family history of diabetes, glaucoma, or with other conditions where corticosteroids may have unwanted effects. Kaposi’s Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma. The maximum recommended duration of treatment with EOHILIA is 12 weeks. ADVERSE REACTIONS Most common adverse reactions (≥2%) are: respiratory tract infection, gastrointestinal mucosal candidiasis, headache, gastroenteritis, throat irritation, adrenal suppression, and erosive esophagitis. DRUG INTERACTIONS Budesonide is a substrate for CYP3A4. Avoid concomitant use with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine, and grapefruit juice), which can increase systemic budesonide concentrations. USE IN SPECIFIC POPULATIONS Pregnancy: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism and managed accordingly. Lactation: Lactation studies have not been conducted with EOHILIA. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EOHILIA and any potential adverse effects on the breastfed infant from EOHILIA, or from the underlying maternal condition. Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), monitor for signs and/or symptoms of hypercorticism. Please click here for full Prescribing Information. Takeda’s Commitment to Gastroenterology With this latest milestone, Takeda continues to demonstrate a commitment to meeting the very real needs of those living with gastrointestinal (GI) diseases. We believe that GI and liver diseases are life-disrupting conditions. Beyond a fundamental need for effective treatment options, we understand that improving patients’ lives also depends on their needs being recognized. With more than 35 years of experience in gastroenterology, Takeda has made significant strides in addressing patient needs with treatments for inflammatory bowel disease (IBD), acid-related diseases, short bowel syndrome (SBS) and motility disorders. We are making significant strides toward closing the gap on new areas of unmet need. Together with researchers, patient groups and more, we are working to advance scientific research and clinical medicine in GI. 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 . Important Notice For the purposes of this notice, “press release” means this document, any oral presentation, any question-and-answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. 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These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: or at . Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results. 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. References 1 EOHILIA (budesonide oral suspension) Prescribing Information. Takeda Pharmaceuticals U.S.A., Inc. 2 Mewis J, Wagner NJ. Advances in Colloid and Interface Science. 2009; 214–227. 3 Hudgens S, Evans C, Phillips E, et al. J Patient Rep Outcomes. 2017;1(1):3. 4 Furuta GT, Katzka DA. N Engl J Med. 2015;373(17):1640-1648. 5 Clayton F, Peterson K. Gastrointest Endosc Clin N Am. 2018;28(1):1-14. 6 O’Shea KM, Aceves SS, Dellon ES, et al. Gastroenterology. 2018;154(2):333-345. 7 Muir AB, Brown-Whitehorn T, Gowin B, et al. Clin Exp Gastroenterol. 2019;12:391-399. 8 Shaheen NJ, Mukkada V, Eichinger CS, et al. Dis Esophagus. 2018;31(8):1-14. 9 Hirano I, Furuta GT. Gastroenterology. 2020;158(4):840-851. 10 Dellon ES, Hirano I. Gastroenterology. 2018;154(2):319-332.e3. US-BOS-0537v1.0 02/24

A study published Monday in Nature Climate Change showed that climate change is making more than half of hundreds of known infectious diseases worse. These include diseases such as malaria, hantavirus and cholera. The researchers, from the University of Hawaii and the University of Wisconsin-Madison, ran a systematic search for examples of the impacts of 10 climatic hazards sensitive to greenhouse gas emissions on each known human pathogenic disease. They found that 58%, or 218 out of 375 infectious diseases that affect people globally have been at some point aggravated by climate hazards - flooding, heat waves and drought. Of those, 16% had their impact lessened. The researchers identified and mapped 1,006 unique pathways where climatic hazards, “via different transmission types, led to pathogenic diseases.” “If the climate is changing, the risk of these diseases is changing,” Jonathan Patz, M.D. MPH., co-author and director of the Global Health Institute at the University of Wisconsin-Madison, wrote in the study. He added that physicians need to think of these diseases as symptoms of a sick Earth. Dr. Carlos del Rio, M.D., an Emory University infectious disease researcher who was not part of the study, told AP News, “The findings of this study are terrifying and illustrate well the enormous consequences of climate change on human pathogens. Those of us in infectious diseases and microbiology need to make climate change one of our priorities, and we need to all work together to prevent what will be without doubt a catastrophe as a result of climate change.” Effects Not Limited to Infectious Diseases The research team didn’t limit their study to infectious diseases. They also looked at illnesses such as asthma, allergies and animal bites. They identified 286 unique illnesses, of which 223 appeared to be made worse by climate hazards, nine decreased by climate hazards and 54 were both aggravated and minimized. Camilo Mora, Ph.D., a climate data analyst at the University of Hawaii, said the study doesn’t predict future cases. “There is no speculation here whatsoever. These are things that have already happened.” One example is a case that occurred in Siberia in 2016. A reindeer that had died from anthrax decades earlier and been frozen in permafrost, thawed. A child touched it, caught anthrax and started an outbreak. The researchers discovered 3,213 empirical case examples in which climatic hazards were implicated in pathogenic diseases. They were associated with 286 unique pathogenic diseases. These included anaphylaxis, black fly bites, conjunctivitis, Diptera, enterobiasis, insect bites, swimmer’s itch, trichinellosis, Anthrax, Bacillus cereus food poisoning, chlamydia, cholera, leprosy, Lyme disease, plague, Queensland Tick Typus, Q fever and many others. Jessica Leibler, DrPH, ScM, an environmental epidemiologist at the Boston University School of Public Health who wasn’t involved in the study, told NBC News that 58% “seems like a really high number, but it reflects the reality that infectious diseases are driven by what’s going on in our environment. Climate drives habitat change and disruption around the world. That also brings humans into contact with animal species in ways that we were not in contact with them historically or haven’t been in the recent past. Our recent pandemic is an example to the extent that the leading hypothesis is that bats might have played a role.” Animal-to-Human Transmission Increased Animals that commonly spread infectious diseases to humans include mosquitos, snakes, birds and rodents. One example, Mora noted, is voles, which use snow cover for winter habitat. But as snowpacks decrease, the small rodents seek shelter in homes, where he said they have been documented to transmit hantavirus. Increased environmental temperatures have also increased the range of many animals and insects, such as ticks, fleas and mosquitoes, which carry West Nile virus, Zika and dengue fever. A study published in Nature in April noted there were about 10,000 viruses with the potential to infect humans, and most are “circulating silently in wild mammals.” Climate change and shifts in land-use patterns increase the possibility of cross-species viral transmission as animals that rarely had contact with people have increased contact. The authors wrote, “Whereas most studies agree that climate change mitigation through reducing greenhouse gas emissions will prevent extinctions and minimize harmful ecosystem impacts, our results suggest that mitigation alone cannot reduce the likelihood of climate-driven viral sharing. Instead, the mildest scenarios for global warming appear likely to produce at least as much or even more cross-species viral transmission.” They project the possibility of more than 4,000 viruses that could be shared between different species that have never met. And that the sharing could be one virus or all of their viruses, “So when we’re saying 4,000, what we mean is there are going to be 4,000 pairs of species sharing viruses for the first time, and that could be 4,000 cross-species transmission,” Colin J. Carlson, Ph.D., an assistant professor of biology at Georgetown University and one of the co-authors of the April Nature study, said. “It could be 400,000. We just don’t know.” Dr. Aaron Bernstein, M.D., MPH, interim director of the Center for Climate, Health, and the Global Environment at Harvard T.H. Chan School of Public Health, added, “It’s not entirely surprising that as habitats shrink and the climate warms, you see greater chances for animals to bump into each other - especially animals that have not historically been in contact with each other- and that creates interfaces where pathogens can move from one species to another. What it means for us is that we have to really think hard about how we approach emerging infections like COVID-19. And part of that has to take seriously the need to prevent spillover rather than trying to play catch-up.”