Superficial Thrombophlebitis

− ICLUSIG Becomes the First and Only Targeted Treatment Approved in the U.S. for Frontline Ph+ Acute Lymphoblastic Leukemia (ALL) in Combination with Chemotherapy − First FDA Approval in Ph+ ALL Based on Novel Primary Endpoint of Minimal Residual Disease (MRD)-negative Complete Remission (CR) − Accelerated Approval Based on Data from the Phase 3 PhALLCON Trial, in which ICLUSIG Demonstrated Superiority in MRD-negative Complete Remission Rates and Comparable Safety to Imatinib OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for ICLUSIG® (ponatinib) for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. This accelerated approval application was granted Priority Review and evaluated under the Real-Time Oncology Review (RTOR) program, an FDA initiative designed to expedite the delivery of cancer medicines by allowing components of an application to be reviewed before submission of the complete application. “This label expansion for ICLUSIG is an incredibly exciting milestone, allowing U.S. adult patients with newly diagnosed Ph+ ALL to have an approved, targeted treatment option in the frontline,” said Awny Farajallah, MD, chief medical officer, oncology at Takeda. “We are thrilled that the FDA has recognized the potential of ICLUSIG to fill a large gap in care for these patients and look forward to seeing the impact this can have on people with this rare and aggressive form of cancer.” The approval was supported by data from the PhALLCON study – the first, global, Phase 3, registrational, head-to-head clinical trial in adults with newly diagnosed Ph+ ALL. The study, in which patients received either ICLUSIG or imatinib, plus reduced-intensity chemotherapy, met its primary endpoint of MRD-negative CR at the end of induction. MRD-negative CR is a composite endpoint defined in alignment with the FDA that reflects deep molecular and clinical responses and is an important prognostic indicator for long-term outcomes for patients with Ph+ ALL. ICLUSIG demonstrated superiority compared to imatinib, with patients who received ICLUSIG achieving a greater than two-fold improvement in the rate of MRD-negative CR at the end of induction (cycle 3). In the trial, the safety pro ICLUSIG was comparable to imatinib, and no new safety signals were identified. “Ph+ ALL is an extremely aggressive cancer and patients with this disease suffer from poor outcomes. There has long been a need for a potent TKI that can suppress mutation development and elicit deep responses in the frontline,” said Elias Jabbour, MD, The University of Texas MD Anderson Cancer Center and lead investigator of the PhALLCON trial. “Ponatinib may help address these factors and impact long-term outcomes.” ICLUSIG is a kinase inhibitor indicated in the U.S. for adult patients with newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on MRD-negative CR at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). In addition, it is approved as monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL, chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated or T315I-positive CML (chronic phase, accelerated phase, or blast phase). ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. About the PhALLCON Trial The PhALLCON study is a Phase 3, randomized, international, open-label multicenter trial evaluating the efficacy and safety of ICLUSIG versus imatinib, in combination with reduced-intensity chemotherapy as a frontline therapy for adult patients with newly diagnosed Ph+ ALL. A total of 245 patients were randomized 2:1 and treated with ICLUSIG or imatinib plus reduced-intensity chemotherapy. The median age of patients was 54 and 52 in the ICLUSIG and imatinib arms, respectively. 164 patients were treated with ICLUSIG receiving a starting dose of 30mg/day and 81 patients were treated with imatinib at a starting dose of 600mg/day. All patients received either ICLUSIG or imatinib with reduced-intensity chemotherapy through induction, consolidation and maintenance phase. After combination therapy, patients continued to receive single-agent ICLUSIG or imatinib until relapse from CR, progressive disease (PD), hematopoietic stem cell transplantation (HSCT), start of alternative therapy or unacceptable toxicity. The primary endpoint of the study was MRD-negative CR rate at the end of induction (3 cycles of treatment). Event-free survival, the key secondary endpoint of the trial, is not yet mature. About Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR::ABL1 and is associated with Ph+ ALL. About ICLUSIG® (ponatinib) tablets ICLUSIG is a kinase inhibitor targeting BCR::ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR::ABL1 and its mutations. ICLUSIG inhibits native BCR::ABL1, as well as all BCR::ABL1 treatment-resistant mutations, including the most resistant T315I mutation. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is a kinase inhibitor indicated in the U.S. for adult patients with newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on MRD-negative CR at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). In addition, it is approved as monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL, chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated, or T315I-positive CML (chronic phase, accelerated phase, or blast phase). ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY See full prescribing information for complete boxed warning. Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity. Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity. WARNINGS AND PRECAUTIONS Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG in PhALLCON, OPTIC and PACE. These included cardiovascular, cerebrovascular, and peripheral vascular events. In PhALLCON, 6% of 163 patients experienced AOEs; 3.7% experienced Grade 3 or 4. The incidence of AOEs in OPTIC (45 mg-> 15 mg) was 14% of 94 patients; 6% experienced Grade 3 or 4. In PACE, the incidence of AOEs was 26% of 449 patients; 14% experienced Grade 3 or 4. Fatal AOEs occurred in 0.6% of patients in PhALLCON, 2.1% of patients in OPTIC, and in 2% of patients in PACE. Some patients in PACE experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed with these events in PACE were history of hypertension, hypercholesterolemia, and non-ischemic cardiac disease. In PhALLCON, OPTIC and PACE, AOEs were more frequent with increasing age. In PhALLCON, patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes were excluded. Patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were also excluded. In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within the 3 months prior to the first dose of ICLUSIG were excluded. Consider whether the benefits of ICLUSIG are expected to exceed the risks. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG. In PhALLCON, VTEs occurred in 12% of 163 patients, including serious or severe (Grade 3 or 4) in 3.1% of patients. One of 94 patients in OPTIC experienced a VTE (Grade 1 retinal vein occlusion). In PACE, VTEs occurred in 6% of 449 patients including serious or severe (Grade 3 or 4) VTEs in 5.8% of patients. In PhALLCON and PACE VTEs included deep venous thrombosis, embolism, pulmonary embolism, superficial vein thrombosis, thrombosis, jugular vein thrombosis, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. The incidence of VTEs in PACE was higher in patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients). Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Heart Failure: Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PhALLCON, heart failure occurred in 6% of 163 patients; 1.2% experienced serious or severe (Grade 3 or 4) heart failure. Heart failure occurred in 13% of 94 patients in OPTIC; 1.1% experienced serious or severe (Grade 3 or 4). In PACE, heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher). In PhALLCON the most frequently reported heart failure event (>1 patient) was increased brain natriuretic peptide (BNP) (2.5%). In OPTIC, the most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and BNP increased (3.2%). In PACE, the most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL treated with monotherapy. Hepatotoxicity occurred in 66% of 163 patients in PhALLCON, in 28% of 94 patients in OPTIC and in 32% of 449 patients in PACE. Grade 3 or 4 hepatotoxicity occurred in PhALLCON (30% of 163 patients), in OPTIC (6% of 94 patients), and in PACE (13% of 449 patients). The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose or discontinue ICLUSIG based on recurrence/severity. Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis. Pancreatitis: Serious or severe pancreatitis has occurred in patients who received ICLUSIG. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2-3 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. Neuropathy: Peripheral and cranial neuropathy occurred in patients in PhALLCON, OPTIC and PACE. Some of these events in PhALLCON and PACE were Grade 3 or 4. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Ocular Toxicity: Serious or severe ocular toxicity leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. The most frequent ocular toxicities occurring in PhALLCON, OPTIC and PACE were dry eye, blurred vision, and eye pain. Retinal toxicities included age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment. Hemorrhage: Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. Fatal hemorrhages occurred in PACE and serious hemorrhages occurred in PhALLCON, OPTIC and PACE. In PACE, the incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Intracranial hemorrhage, gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages. Events often occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Fluid Retention: Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PACE, one instance of brain edema was fatal and serious events included pleural effusion, pericardial effusion, and angioedema. In PhALLCON serious fluid retention included pericardial effusion. The most frequent occurrences of fluid retention in patients who received ICLUSIG were peripheral edema and pleural effusion. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular, atrial arrhythmias, tachycardia, syncope, atrial fibrillation and supraventricular tachycardia occurred in patients in PhALLCON, OPTIC, and PACE. For some patients, events were serious or severe (Grade 3 or 4) and led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Myelosuppression: Grade 3 or 4 events of neutropenia, thrombocytopenia, and anemia occurred in patients in PhALLCON, OPTIC and PACE. In PACE, the incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL treated with monotherapy than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 x 109/L or platelets less than 50 x 109/L, interrupt ICLUSIG until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose. Tumor Lysis Syndrome (TLS): Serious TLS was reported in ICLUSIG-treated patients in PhALLCON, OPTIC and PACE. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Patients may present with neurological signs and symptoms, visual disturbances, and hypertension. Diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown. Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation. Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose. ADVERSE REACTIONS The most common adverse reactions (occurring in >20% of patients) are: ICLUSIG as a single agent: rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. ICLUSIG in combination with chemotherapy: hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase and increased alanine aminotransferase. To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or . DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided. Strong CYP3A Inducers: Avoid coadministration. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 1 week following last dose. Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG. Ponatinib may impair fertility in females, and it is not known if these effects are reversible. Pre-existing Hepatic Impairment: For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG to 30mg orally once daily for patients with pre-existing hepatic impairment as these patients are more likely to experience adverse reactions compared to patients with normal hepatic function. For patients with newly diagnosed Ph+ ALL, no dosage adjustment is recommended. Prescribing Information Takeda’s Commitment to Oncology Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit . 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. 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− Company to Feature 15 Company-Sponsored and Nine Collaborative Abstracts in Oncology and Hematology − Oral Presentations Include Updated Results from Phase 3 OPTIC Trial of ICLUSIG® (ponatinib) and First-In-Human Phase 1/2 Study of Modakafusp Alfa (TAK-573) OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that it will present 15 company-sponsored abstracts at the 64th American Society of Hematology (ASH) Annual Meeting being held December 10-13, 2022 in New Orleans. Takeda’s latest research focuses on improving long-term outcomes for patients with hematologic diseases. Takeda’s presentations will include oral sessions detailing a three-year update of the Phase 3 OPTIC trial demonstrating the efficacy and safety of ICLUSIG® (ponatinib) in patients with resistant chronic-phase chronic myeloid leukemia (CP-CML), and results from a first-in-human Phase 1/2 study evaluating modakafusp alfa (TAK-573) in patients with relapsed / refractory multiple myeloma. “Our latest research is focused on investigating novel mechanisms of action, as well as optimizing approved treatments to improve long-term outcomes and more deeply understand and address unmet needs for patients across a range of hematologic diseases,” said Awny Farajallah, M.D., Head of Global Medical Affairs Oncology at Takeda. “We look forward to sharing our latest clinical trial results and real-world data with the goal of contributing to a more holistic view of the patient experience, and ultimately, profound improvements in care.” A full list of company-sponsored abstracts, which include data in multiple myeloma, lymphoma, leukemia, von Willebrand disease and hemophilia can be found here. Modakafusp alfa (TAK-573) is an investigational compound that has not been approved for use by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or any other regulatory authorities. About ICLUSIG® (ponatinib) tablets ICLUSIG is a kinase inhibitor targeting BCR::ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR::ABL1 and its mutations. ICLUSIG inhibits native BCR::ABL1, as well as all BCR::ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated-phase (AP) or blast-phase (BP) CML or Ph+ ALL for whom no other kinase inhibitor is indicated, and T315I+ CML (CP, AP or BP) or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY See full prescribing information for complete boxed warning. Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity. Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity. WARNINGS AND PRECAUTIONS Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG in OPTIC and PACE. These included cardiovascular, cerebrovascular, and peripheral vascular events. The incidence of AOEs in OPTIC (45 mg->15 mg) was 14% of 94 patients; 6% experienced Grade 3 or 4. In PACE, the incidence of AOEs was 26% of 449 patients; 14% experienced Grade 3 or 4. Fatal AOEs occurred in 2.1% of patients in OPTIC, and in 2% of patients in PACE. Some patients in PACE experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed with these events in PACE were history of hypertension, hypercholesterolemia, and non-ischemic cardiac disease. In OPTIC and PACE, AOEs were more frequent with increasing age. In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within the 3 months prior to the first dose of ICLUSIG were excluded. Consider whether the benefits of ICLUSIG are expected to exceed the risks. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG. In PACE, VTEs occurred in 6% of 449 patients including serious or severe (Grade 3 or 4) VTEs in 5.8% of patients. VTEs included deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. The incidence was higher in patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients). One of 94 patients in OPTIC experienced a VTE (Grade 1 retinal vein occlusion). Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Heart Failure: Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PACE, heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher). Heart failure occurred in 13% of 94 patients in OPTIC; 1.1% experienced serious or severe (Grade 3 or 4). In PACE, the most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). In OPTIC, the most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and BNP increased (3.2%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL. Hepatotoxicity occurred in 28% of 94 patients in OPTIC and 32% of 449 patients in PACE. Grade 3 or 4 hepatotoxicity occurred in OPTIC (6% of 94 patients) and PACE (13% of 449 patients). The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose or discontinue ICLUSIG based on recurrence/severity. Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis. Pancreatitis: Serious or severe pancreatitis has occurred in patients who received ICLUSIG. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. Neuropathy: Peripheral and cranial neuropathy occurred in patients in OPTIC and PACE. Some of these events in PACE were Grade 3 or 4. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Ocular Toxicity: Serious or severe ocular toxicity leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. The most frequent ocular toxicities occurring in OPTIC and PACE were dry eye, blurred vision, and eye pain. Retinal toxicities included age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment. Hemorrhage: Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. Fatal hemorrhages occurred in PACE and serious hemorrhages occurred in OPTIC and PACE. In PACE, the incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages. Events often occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Fluid Retention: Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PACE, one instance of brain edema was fatal and serious events included pleural effusion, pericardial effusion, and angioedema. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular and atrial arrhythmias, occurred in patients in OPTIC and PACE. For some patients, events were serious or severe (Grade 3 or 4) and led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Myelosuppression: Grade 3 or 4 events of neutropenia, thrombocytopenia, and anemia occurred in patients in OPTIC and PACE. The incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 x 109/L or platelets less than 50 x 109/L, interrupt ICLUSIG until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose. Tumor Lysis Syndrome (TLS): Serious TLS was reported in ICLUSIG-treated patients in OPTIC and PACE. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Patients may present with neurological signs and symptoms, visual disturbances, and hypertension. Diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown. Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation. Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose. ADVERSE REACTIONS The most common (>20%) adverse reactions are rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or . DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided. Strong CYP3A Inducers: Avoid coadministration. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 6 days following last dose Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG. Ponatinib may impair fertility in females, and it is not known if these effects are reversible. Pre-existing Hepatic Impairment: Reduce the starting dose of ICLUSIG to 30mg orally once daily for patients with pre-existing hepatic impairment as these patients are more likely to experience adverse reactions compared to patients with normal hepatic function. Takeda’s Commitment to Oncology At Takeda Oncology, we are united by our aspiration to cure cancer and motivated every day to work harder for patients with limited or ineffective treatment options. Our agile structure and deep in-house expertise are complemented by a network of partnerships that optimize our ability to research, develop and deliver transformative medicines to people living with cancer. Building on decades of leadership in oncology and a portfolio of approved medicines for hematologic cancers and solid tumors, we are advancing a cutting-edge pipeline focused on the power of innate immunity. With inspiration from patients and innovation from everywhere, our goal is to introduce new classes of immunotherapies that can lead to deep, durable responses so that more patients can benefit from – and have access to – innovative medicines. Takeda’s Commitment to Hematology Takeda is a leader in hemophilia with the longest heritage and market-leading portfolio, backed by established safety and efficacy profiles with decades of real-world experience. We have 70+ years driving innovation for patients and a broad portfolio of 11 products across multiple bleeding disorders. Our experience as a leader in hematology means we are well prepared to meet today’s needs as we pursue future developments in the care of blood disorders. Together with the hematology community, we are raising expectations for the future, including earlier diagnosis, earlier and full protection against bleeds, and more personalized patient care. 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 . 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. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws. The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies. Forward-Looking Statements This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. 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.

- The PhALLCON Study Is the First Global, Phase 3, Registrational, and Only Head-To-Head Clinical Trial Comparing Two TKIs in Frontline Ph+ ALL - Primary Endpoint Result Shows Superiority Compared to Imatinib as Assessed by MRD-Negative Complete Remission OSAKA, Japan & CAMBRIDGE, Mass--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that the randomized, Phase 3 PhALLCON trial met its primary endpoint, demonstrating that adult patients with newly-diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) treated with ICLUSIG® (ponatinib) plus reduced-intensity chemotherapy achieved higher rates of minimal residual disease (MRD)-negative complete remission (CR) compared to imatinib. MRD-negativity is associated with improvement in long-term outcomes for patients, as reported in literature. ICLUSIG is the only pan-mutational and third-generation tyrosine kinase inhibitor (TKI), targeting BCR::ABL1 and all known single, treatment-resistant mutations, including the most resistant T315I mutation. “Ph+ ALL is a fast-progressing disease with no targeted treatments currently approved in the frontline for patients in the U.S. There is an urgent need for an effective treatment that can suppress the development of difficult-to-treat mutations, which are associated with poor long-term outcomes,” said Awny Farajallah, MD, Head of Global Medical Affairs Oncology at Takeda. “We are excited to see how ICLUSIG may be able to address this gap in care for these patients and look forward to sharing the results.” The PhALLCON study is a Phase 3 randomized, international, open-label multicenter trial evaluating the efficacy and safety of ICLUSIG versus imatinib in combination with reduced-intensity chemotherapy as a frontline therapy for adult patients with newly diagnosed Ph+ ALL. In the trial, no new safety signals were observed. Data from this trial will be discussed with regulatory agencies and shared with the scientific community in the future. About Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR::ABL1 and is associated with Ph+ ALL. About ICLUSIG® (ponatinib) tablets ICLUSIG is a kinase inhibitor targeting BCR::ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR::ABL1 and its mutations. ICLUSIG inhibits native BCR::ABL1, as well as all BCR::ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated-phase (AP) or blast-phase (BP) CML or Ph+ ALL for whom no other kinase inhibitor is indicated, and T315I+ CML (CP, AP or BP) or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY See full prescribing information for complete boxed warning. Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity. Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity. WARNINGS AND PRECAUTIONS Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG in OPTIC and PACE. These included cardiovascular, cerebrovascular, and peripheral vascular events. The incidence of AOEs in OPTIC (45 mg->15 mg) was 14% of 94 patients; 6% experienced Grade 3 or 4. In PACE, the incidence of AOEs was 26% of 449 patients; 14% experienced Grade 3 or 4. Fatal AOEs occurred in 2.1% of patients in OPTIC, and in 2% of patients in PACE. Some patients in PACE experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed with these events in PACE were history of hypertension, hypercholesterolemia, and non-ischemic cardiac disease. In OPTIC and PACE, AOEs were more frequent with increasing age. In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within the 3 months prior to the first dose of ICLUSIG were excluded. Consider whether the benefits of ICLUSIG are expected to exceed the risks. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG. In PACE, VTEs occurred in 6% of 449 patients including serious or severe (Grade 3 or 4) VTEs in 5.8% of patients. VTEs included deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. The incidence was higher in patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients). One of 94 patients in OPTIC experienced a VTE (Grade 1 retinal vein occlusion). Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Heart Failure: Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PACE, heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher). Heart failure occurred in 13% of 94 patients in OPTIC; 1.1% experienced serious or severe (Grade 3 or 4). In PACE, the most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). In OPTIC, the most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and BNP increased (3.2%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL. Hepatotoxicity occurred in 28% of 94 patients in OPTIC and 32% of 449 patients in PACE. Grade 3 or 4 hepatotoxicity occurred in OPTIC (6% of 94 patients) and PACE (13% of 449 patients). The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose or discontinue ICLUSIG based on recurrence/severity. Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis. Pancreatitis: Serious or severe pancreatitis has occurred in patients who received ICLUSIG. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. Neuropathy: Peripheral and cranial neuropathy occurred in patients in OPTIC and PACE. Some of these events in PACE were Grade 3 or 4. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Ocular Toxicity: Serious or severe ocular toxicity leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. The most frequent ocular toxicities occurring in OPTIC and PACE were dry eye, blurred vision, and eye pain. Retinal toxicities included age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment. Hemorrhage: Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. Fatal hemorrhages occurred in PACE and serious hemorrhages occurred in OPTIC and PACE. In PACE, the incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages. Events often occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Fluid Retention: Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PACE, one instance of brain edema was fatal and serious events included pleural effusion, pericardial effusion, and angioedema. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular and atrial arrhythmias, occurred in patients in OPTIC and PACE. For some patients, events were serious or severe (Grade 3 or 4) and led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Myelosuppression: Grade 3 or 4 events of neutropenia, thrombocytopenia, and anemia occurred in patients in OPTIC and PACE. The incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 x 109/L or platelets less than 50 x 109/L, interrupt ICLUSIG until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose. Tumor Lysis Syndrome (TLS): Serious TLS was reported in ICLUSIG-treated patients in OPTIC and PACE. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Patients may present with neurological signs and symptoms, visual disturbances, and hypertension. Diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown. Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation. Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose. ADVERSE REACTIONS The most common (>20%) adverse reactions are rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or . DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided. Strong CYP3A Inducers: Avoid coadministration. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 6 days following last dose Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG. Ponatinib may impair fertility in females, and it is not known if these effects are reversible. Pre-existing Hepatic Impairment: Reduce the starting dose of ICLUSIG to 30mg orally once daily for patients with pre-existing hepatic impairment as these patients are more likely to experience adverse reactions compared to patients with normal hepatic function. Takeda’s Commitment to Oncology Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit . 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 . 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. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws. The companies in which Takeda directly and indirectly owns investments are separate entities. In this press release, “Takeda” is sometimes used for convenience where references are made to Takeda and its subsidiaries in general. Likewise, the words “we”, “us” and “our” are also used to refer to subsidiaries in general or to those who work for them. These expressions are also used where no useful purpose is served by identifying the particular company or companies. Forward-Looking Statements This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. 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. Source: Takeda Pharmaceutical Company Limited