Takeda to Present Data from the ICLUSIG® (ponatinib) Clinical Trial Program that Could Prove Practice-Changing for the Treatment of Chronic-Phase CML

– Oral Presentations of the Phase 2 OPTIC Interim Analysis at the American Society of Clinical Oncology (ASCO) and the European Hematology Association (EHA) Annual Meetings –

– Findings Support Response-Based Dosing Regimens of ICLUSIG Can Optimize Benefit-Risk Profile in Patients with Resistant / Intolerant Chronic-Phase CML –

– Adjudicated Data from Independent Review of Phase 2 PACE Trial in CML and Ph+ ALL Also Featured as Poster Presentations at ASCO and EHA –

CAMBRIDGE, Mass. & OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced that interim analysis data from the Phase 2 OPTIC (Optimizing Ponatinib Treatment In CML) trial will be presented during an oral session at the virtual 56^th American Society of Clinical Oncology (ASCO) Annual Meeting and the 25^th European Hematology Association (EHA) Annual Meeting. The OPTIC trial is an ongoing, randomized, open-label study prospectively evaluating response-based dosing regimens of ICLUSIG^® (ponatinib) over a range of three starting doses (45-, 30-, or 15-mg) with the aim of optimizing its efficacy and safety in patients with chronic-phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy.

With a median follow-up of approximately 21 months, data from the interim analysis of OPTIC show that the optimal benefit-risk profile for ICLUSIG in patients with CP-CML is achieved with a daily starting dose of 45-mg and, upon achieving ≤1% BCR-ABL1, dose reduction to 15-mg. This dosing regimen resulted in an adjudicated arterial occlusive event (AOE) rate of 5.3%.

“These data help revise our understanding of how to treat with ICLUSIG to optimize the benefit-risk in chronic-phase CML patients who are resistant or intolerant to prior TKIs – which was demonstrated in the 45-mg followed by dose reduction to 15-mg regimen – while maintaining a manageable safety profile,” said Jorge Cortes, MD, Georgia Cancer Center at Augusta University, and an OPTIC trial principal investigator. “It is also important to note that clinical benefit was observed in all three starting doses in this population of patients who were resistant to multiple prior TKIs, and the majority had not demonstrated responses better than a complete hematological response to the immediate prior TKI.”

Takeda will be discussing these data with the U.S. Food and Drug Administration (FDA). The complete primary analysis of the OPTIC trial will be conducted and presented at a later date.

“ICLUSIG has been an effective treatment option for appropriate CML patients since its FDA approval in 2012,” said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda. “These data provide additional context around the safety profile of ICLUSIG, a third-generation targeted inhibitor of BCR-ABL1, and may provide further guidance on how to reduce the risk of arterial occlusive events, a concern that we believe has limited patient access to ICLUSIG in the past. We are excited about the OPTIC findings, and we intend to submit these data to the U.S. FDA as quickly as possible as part of a supplemental New Drug Application.”

Interim Analysis (IA) of OPTIC: A Dose Ranging Study of Three Starting Doses of Ponatinib (PON).

Key findings, to be presented by Dr. Jorge Cortes, include:

• By the interim analysis (IA; cutoff date of July 2019) with median follow-up time of approximately 21 months, 77% (n/N=216/282) of patients in the OPTIC trial were evaluable for the primary endpoint.
• The OPTIC IA shows benefit of ponatinib in all three starting doses in a largely resistant population where the majority of patients (>60%) demonstrated a complete hematological response (CHR) or lower response to immediate prior therapy.
• The maximum rates of ≤1% BCR-ABL1^IS at 12 months were achieved in the 45-mg/day starting dose cohort (38.7%), and responses were maintained with the dose reduction to 15-mg/day.
• With the protocol-mandated dose reduction for response in the higher dose cohorts, 75% of patients in the 45-mg cohort and 88% of patients in the 30-mg cohort were able to maintain ≤1% BCR-ABL1^IS response for up to two years.
• Safety data include:
  • As of the OPTIC IA cutoff date (July 2019), among all patients (N=282), the most common treatment emergent adverse events (TEAEs) of any grade (occurring in ≥10% of all patients) were thrombocytopenia (39.4%), neutropenia (25.2%), hypertension (24.1%), anemia (17.4%), headache (17.0%), increased lipase (16.0%), arthralgia (14.2%), constipation (12.4%), platelet count decrease (10.6%) and ALT increase (10.3%).
  • There was a dose-dependent trend in AOE rates:
    • Pre-adjudicated AOEs were reported in (45-, 30-, 15-mg/day starting dose cohorts) 8.5% (n/N = 8/94), 4.3% (n/N = 4/94), and 2.1% (n/N = 2/94).
    • Prospective adjudication of AOEs by independent experts resulted in (45-, 30-, 15-mg/day starting dose cohorts) 5.3% (n/N = 5/94), 4.3% (n/N = 4/94), and 1.1% (n/N = 1/94).
  • At the IA, there were no AOE-related deaths reported.

OPTIC Trial Design

• The Phase 2 OPTIC trial is designed to prospectively evaluate response-based dosing regimens of ICLUSIG over a range of three starting doses, in patients with CP-CML resistant or intolerant to prior TKI therapy.
• The primary endpoint is achieving ≤1% BCR-ABL1 at 12 months.
• The trial enrolled 283 participants around the world, each assigned a daily starting dose of 45-mg, 30-mg or 15-mg at random. Dose reduction at response occurred per study protocol.

In addition to the OPTIC data, a poster featuring data from an independent retrospective review of AOEs in the Phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial will be shared during ASCO and EHA.

About the OPTIC Trial

OPTIC (Optimizing Ponatinib Treatment In CML) is a randomized, dose-ranging trial designed to evaluate three starting doses of ICLUSIG (15 mg, 30 mg, 45 mg) in patients with resistant chronic-phase chronic myeloid leukemia (CP-CML) or who had documented history of presence of T315I mutation after receiving any number of prior TKIs. Dose reduction at response occurred per study protocol. The trial is expected to inform the optimal use of ICLUSIG^® (ponatinib) in these patients. Approximately 283 patients were enrolled at clinical sites around the world. The primary endpoint of the trial is achieving ≤1% BCR-ABL1 at 12 months.

About the PACE Trial

The PACE (Ponatinib Ph+ ALL and CML Evaluation) trial evaluated the efficacy and safety of ICLUSIG in CML and Ph+ ALL patients resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. A total of 449 patients were treated with ponatinib at a starting dose of 45 mg/day. An estimated 93% of patients previously received two or more approved TKIs and 56% of all patients had received three or more approved TKIs. 55% of the overall chronic-phase CML patient population in the PACE trial achieved major cytogenetic response (MCyR) by 12 months – the primary endpoint of the PACE trial for CP-CML patients – and 70% of T315I+ CP-CML patients achieved MCyR. Enrollment in the PACE trial was completed in October 2011.

About CML and Ph+ ALL

CML – a rare malignancy – is one of four main types of leukemia; it is a result of a genetic mutation that takes place in early, immature versions of myeloid cells, which form red blood cells, platelets and most types of white blood cells. Subsequently, an abnormal gene called BCR-ABL1 forms, turning the damaged cell into a CML cell. CML typically progresses slowly, but it can change into a fast-growing acute leukemia that is hard to treat.

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 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 Syndrome: Two patients (<1%, one with AP-CML and one with BP-CML) treated with ICLUSIG developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% of patients. Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with ICLUSIG.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Post-marketing cases of RPLS have been reported in ICLUSIG-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present, and diagnosis is made with supportive findings on magnetic resonance imaging of the brain. If RPLS is diagnosed, interrupt ICLUSIG treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.

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. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the recommended human dose. 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

Most Common Adverse Reactions: The most common non-hematologic adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid concurrent use or reduce ICLUSIG dose if co-administration cannot be avoided.

Strong CYP3A Inducers: Avoid concurrent use.

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential: Ponatinib may impair fertility in females and it is not known if these effects are reversible. Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.

Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 6 days after last dose.

For more information about ICLUSIG, visit www.ICLUSIG.com. For the Prescribing Information including the Boxed Warning for arterial occlusion, venous thromboembolism, heart failure, and hepatoxicity, please visit https://www.iclusig.com/pdf/ICLUSIG-Prescribing-Information.pdf. For more information about ongoing research, please visit www.clinicaltrials.gov.

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 www.takedaoncology.com.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines.

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