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Takeda Oncology Demonstrates Leadership in Hematologic Cancers at 62nd American Society of Hematology (ASH) Annual Meeting

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? Company to Present 22 Abstracts in Oncology, Including 5 Oral Presentations, Demonstrating Takeda�s Enduring Commitment to Improving the Lives of Patients with Blood Cancers

CAMBRIDGE, Mass. & OSAKA, Japan--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (�Takeda�) today announced that it will present 22 company-sponsored abstracts at the 62nd American Society of Hematology (ASH) Annual Meeting, being held virtually December 5-8, 2020. The company�s scientific research at ASH will identify unique approaches in advancing the treatment of hematologic cancers, illustrative of its commitment to developing and providing transformative solutions for patient needs. Takeda will also be presenting data from its broader hematology portfolio and pipeline at the conference.

�At this year�s ASH, Takeda�s Oncology Research and Development updates underscore our commitment to transform existing treatment paradigms and investigate truly novel approaches that address critical needs for patients living with blood cancers, such as leukemias, lymphomas and myeloma,� said Chris Arendt, Head, Oncology Therapeutic Area Unit, Takeda. �Our pursuit to cure cancer is driven by our commitment to provide life-saving medicines to all patients, including those with limited or ineffective treatment options.�

Key data to be presented include:

  • Pevonedistat: A sub-analysis from the Phase 2 Pevonedistat-2001 trial will be presented in an oral session. The analysis, which focused on outcomes of the higher-risk myelodysplastic syndromes (MDS) subgroup of the study, showed that the combination of pevonedistat and azacitidine resulted in longer event-free survival, longer duration of response and delayed transformation to acute myeloid leukemia without increasing myelosuppression, compared to treatment with azacitidine alone. Additionally, the safety profile of pevonedistat and azacitidine in combination was comparable to azacitidine alone. Despite poor outcomes, there have been no novel advances in higher-risk MDS treatment in over 10 years and new, effective therapies with favorable safety profiles that do not worsen myelosuppression are needed.
  • ICLUSIG� (ponatinib): Data from the interim analysis of the OPTIC trial of ICLUSIG will be presented in an oral session. The data highlighted the revised benefit-risk of ICLUSIG, a third-generation tyrosine kinase inhibitor (TKI), with the use of a response-based dosing regimen in resistant chronic-phase chronic myeloid leukemia (CP-CML) patients, with or without mutations, who have experienced treatment failure with second-generation (2G) TKIs. Another oral presentation will feature a pooled sub-analysis highlighting patients from the PACE and OPTIC trials, comprising the largest patient population evaluation in a post-2G TKI setting. While CP-CML is often manageable, patients who have experienced treatment failure with prior 2G TKI therapy, especially those who are resistant to therapy, suffer from poor long-term outcomes, underscoring that there are still gaps in care for people living with CP-CML.
  • NINLARO� (ixazomib): Results from the TOURMALINE-MM2 trial will be presented in an oral session. The study was designed to evaluate the addition of NINLARO to lenalidomide and dexamethasone in newly diagnosed transplant ineligible multiple myeloma patients. While the trial did not meet the threshold for statistical significance and the primary endpoint of progression-free survival (PFS) was not met, the study found the addition of NINLARO resulted in a 13.5 month increase in median PFS overall. In the prespecified expanded high-risk cytogenetics subgroup, the addition of NINLARO resulted in a median PFS of 23.8 months versus 18.0 months in the placebo arm. Newly diagnosed multiple myeloma patients are in need of additional proteasome inhibitor-based treatment options, as there are currently no approved options that are all-oral.
  • ADCETRIS� (brentuximab vedotin): Five-year follow up data from two Phase 3 frontline lymphoma studies will be featured as poster presentations. Data from the ECHELON-1 trial, which evaluated ADCETRIS in combination with doxorubicin, vinblastine and dacarbazine (ADCETRIS+AVD) for previously untreated, stage III/IV Hodgkin lymphoma shows that, with extended follow-up time, the addition of ADCETRIS to AVD demonstrates a robust and sustained treatment benefit, independent of disease stage, International Prognostic Index risk factor score and PET2 status compared to ABVD, the current standard of care. Positive final analyses from ECHELON-2 which evaluated ADCETRIS in combination with CHP (cyclophosphamide, doxorubicin, prednisone) (ADCETRIS+CHP) versus a standard care treatment in frontline treatment of patients with CD30-positive peripheral T-cell lymphoma will also be presented. The safety profile of ADCETRIS in the ECHELON-1 and ECHELON-2 trials were consistent with the established safety profile of ADCETRIS in combination with chemotherapy.

Accepted oncology abstracts include:

Note: all times listed are in Pacific Time

Pevonedistat

ICLUSIG� (ponatinib)

Multiple Myeloma

ADCETRIS� (brentuximab vedotin) and Lymphoma

About Pevonedistat

Pevonedistat is a first in class NEDD8-activating enzyme (NAE) inhibitor, which blocks modifications of select proteins. Pevonedistat treatment disrupts cell cycle progression and cell survival, leading to cell death in cancers including leukemias. Pevonedistat in combination with azacitidine demonstrated antitumor activity in preclinical studies and was well tolerated, with promising clinical activity, in a Phase 1 study of patients with AML. Pevonedistat is currently being evaluated in Phase 3 studies as a first-line treatment for patients with HR-MDS, HR-CMML, and AML, who are ineligible (unfit) for transplant or intensive induction chemotherapy and is also being explored in a Phase 2 study in unfit AML in a triple combination with azacitidine and venetoclax.

About ICLUSIG� (ponatinib) tablets

ICLUSIG is a kinase inhibitor targeting BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (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 is the only approved TKI that demonstrates activity against the T315I gatekeeper mutation of BCR-ABL1. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with CP, accelerated phase, or blast phase CML or Ph+ ALL for whom no other TKI therapy is indicated, and treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.

IMPORTANT SAFETY INFORMATION (U.S.)

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning.

  • Arterial occlusion has occurred in at least 35% of ICLUSIG� (ponatinib)-treated patients including 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 less than 50 years old, experienced these events. Interrupt or stop ICLUSIG immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ICLUSIG.
  • Venous Thromboembolism has occurred in 6% of ICLUSIG-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.
  • Heart Failure, including fatalities occurred in 9% of ICLUSIG-treated patients. Monitor cardiac function. Interrupt or stop ICLUSIG for new or worsening heart failure.
  • Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor hepatic function. Interrupt ICLUSIG if hepatotoxicity is suspected.

WARNINGS AND PRECAUTIONS

Arterial Occlusions: The 35% of patients reported to have arterial occlusive events (AOEs) in the boxed warning included patients from both phase 1 and phase 2 trials. In the phase 2 trial, 33% of ICLUSIG-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event. Some patients experienced more than 1 type of event. Fatal and life-threatening events have occurred within 2 weeks of starting treatment, with doses as low as 15 mg per day. ICLUSIG can also cause recurrent or multisite vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first AOE ranged from 193-526 days. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. AOEs were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing AOEs, interrupt or stop ICLUSIG.

Venous Thromboembolism: Venous thromboembolic events, including deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss, occurred in 6% of patients with an incidence rate of 5% (CP-CML), 4% (AP-CML), 10% (BP-CML), and 9% (Ph+ ALL). Consider dose modification or discontinuation of ICLUSIG in patients who develop serious venous thromboembolism.

Heart Failure: Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of patients in the phase 2 trial. The most common heart failure events (each 3%) were congestive cardiac failure and decreased ejection fraction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of ICLUSIG. Consider discontinuation if serious heart failure develops.

Hepatotoxicity: Hepatotoxic events were observed in 29% of patients (11% were grade 3 or 4). Severe hepatotoxicity occurred in all disease cohorts. Three patients with BP-CML or Ph+ ALL died: one with fulminant hepatic failure within one week of starting ICLUSIG and two with acute liver failure. The most common forms were elevations of AST or ALT (54% all grades, 8% grade 3 or 4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase. The median time to onset of event was 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue ICLUSIG as clinically indicated.

Hypertension: Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% of patients, of which 12% were serious and included hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline BP <140/90 mm Hg, 80% developed treatment-emergent hypertension (44% Stage 1 and 37% Stage 2). In 132 patients with Stage 1 hypertension at baseline, 67% developed Stage 2. Monitor and manage BP elevations during ICLUSIG use and treat hypertension to normalize BP. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Pancreatitis was reported in 7% of patients (6% were serious or grade 3/4). Many of these cases resolved within 2 weeks with dose interruption or reduction of ICLUSIG. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater). Check serum lipase every 2 weeks for the first 2 months and monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with ICLUSIG and evaluate patients for pancreatitis. Do not consider restarting ICLUSIG until patients have complete resolution of symptoms and lipase levels are <1.5 x ULN.

Increased Toxicity in Newly Diagnosed CP-CML: In a prospective, randomized clinical trial in the first-line treatment of newly diagnosed patients with CP-CML, ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib, ICLUSIG 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: Overall, 20% of patients experienced a peripheral neuropathy event of any grade (2% were grade 3/4). The most common were paresthesia (5%), neuropathy peripheral (4%), hypoesthesia (3%), dysgeusia (2%), muscular weakness (2%), and hyperesthesia (1%). Cranial neuropathy developed in 2% of patients (<1% grade 3/4). Of the patients who developed neuropathy, 26% developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting ICLUSIG and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2%. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14%. Visual blurring occurred in 6%. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Hemorrhage occurred in 28% of patients (6% serious, including fatalities). The incidence of serious bleeding events was higher in patients with AP- or BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% each. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and evaluate.

Fluid Retention: Fluid retention occurred in 31% of patients. The most common events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%). Serious events occurred in 4%. One instance of brain edema was fatal. Serious treatment-emergent events included: pleural effusion (2%), pericardial effusion (1%), and edema peripheral (<1%). Monitor patients for fluid retention and manage as clinically indicated. Interrupt, reduce, or discontinue ICLUSIG as clinically indicated.

Cardiac Arrhythmias: Arrhythmias occurred in 19% of patients (7% were grade ?3). Arrhythmia of ventricular origin was reported in 3% of all arrhythmias, with one case being grade ?3. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% of patients. Atrial fibrillation was the most common arrhythmia (7%), approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (2%), tachycardia and bradycardia (each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (each 0.2%). For 27 patients, the event led to hospitalization. In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt ICLUSIG and evaluate.

Myelosuppression: Myelosuppression was reported in 59% of patients (50% were grade 3/4). The incidence of these events was greater in patients with AP- or BP-CML, and Ph+ ALL than in patients with CP-CML. Severe myelosuppression (grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range <1-40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated and adjust the dose as recommended

Tumor Lysis Sy

Contacts

Japanese Media
Kazumi Kobayashi

[email protected]
+81 (0) 3-3278-2095

Media Outside Japan
Emy Gruppo

[email protected]
+1 617 444 2252

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