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Manufacturing and Marketing Approval Received in Japan for ALUNBRIG® in the Treatment of ALK Fusion Gene-positive Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer

January 22, 2021

Osaka, JAPAN, January 22, 2021 -- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced that it has obtained approval from the Japanese Ministry of Health, Labour and Welfare to manufacture and market “ALUNBRIG® Tablets 30 mg, 90 mg" (brigatinib, development code: AP26113) as a first and second-line therapy for the treatment of patients with unresectable, advanced or recurrent ALK fusion gene-positive non-small cell lung cancer (ALK+ NSCLC).

The approval is mainly based on the results of Brigatinib-2001 (J-ALTA), a Phase 2 clinical trial conducted in Japan involving 72 ALK+ patients with unresectable advanced or recurrent NSCLC who progressed after treatment with an ALK tyrosine kinase inhibitor, as well as the AP26113-13-301 (ALTA-1L) global Phase 3 clinical trial focused on ALK+ patients with unresectable advanced or recurrent NSCLC who had not been treated with an ALK tyrosine kinase inhibitor.

“While there have been significant advances in diagnosis, testing and treatment of ALK+ NSCLC, effective treatment with ALK inhibitors can still be a challenge given the unique needs of these patients,” said Makoto Nishio, MD, PhD, Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, the principal investigator in the J-ALTA clinical trial. “ALUNBRIG has been shown to be an effective inhibitor of ALK gene mutations, including in patients with brain metastases, and its approval in Japan is an important milestone for both newly diagnosed and refractory ALK-positive patients.”

Christopher Arendt, Head of the Oncology Therapeutic Area Unit at Takeda added, “As a next-generation ALK inhibitor, ALUNBRIG is backed by extensive clinical evidence, and has been shown to be effective in patients undergoing first and second-line treatment for ALK+ NSCLC including efficacy in patients with brain metastases. With this approval in Japan, we believe that even more patients will be able to benefit from this targeted therapy in NSCLC caused by ALK driver mutations.”

The most common adverse reactions (≥ 25%) reported in Japanese patients treated with ALUNBRIG were increased CPK, diarrhea, hypertension, nausea, increased lipase, increased amylase, increased AST and stomatitis.

About ALK-positive Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately 3–5% of patients with metastatic NSCLC have a rearrangement in the ALK gene. Takeda is committed to continuing research and development in NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.

About ALUNBRIG® (brigatinib)
ALUNBRIG is a potent and selective next-generation tyrosine kinase inhibitor (TKI) that was designed to target anaplastic lymphoma kinase (ALK) molecular alterations.

ALUNBRIG is approved in more than 30 countries including the U.S. and European Union (EU) as a monotherapy for the treatment of adult patients with ALK+ advanced NSCLC previously not treated with an ALK inhibitor. ALUNBRIG is also approved in more than 50 countries for the treatment of people living with ALK+ metastatic NSCLC who have taken the medicine crizotinib, but their NSCLC has worsened or they cannot tolerate taking crizotinib.

Companion Diagnostic Agents
ALUNBRIG should be administered to patients who have been determined to be ALK+. Abbott Japan's Vysis® ALK Break Apart FISH Probe Kit has been approved as a companion diagnostic to assist in the determination of indications for use of ALUNBRIG. Other in vitro diagnostic products and medical devices are also under review.

The Brigatinib-2001 (J-ALTA) Clinical Trial
The purpose of this single-arm, multicenter Phase 2 clinical trial is to evaluate the efficacy and safety of ALUNBRIG in Japanese patients with ALK fusion gene-positive NSCLC. It consists of multiple cohorts, including the main cohort of patients who have become resistant to alectinib or alectinib and crizotinib.

Please see here for details.

The AP26113-13-301 (ALTA-1L) Clinical Trial
The Phase 3 ALTA 1L trial of ALUNBRIG is an international, open label, randomized, controlled trial, which enrolled 275 patients with ALK fusion gene positive unresectable advanced or metastatic NSCLC who had not received prior treatment with an ALK inhibitor. Patients received either ALUNBRIG, 180 mg orally once daily with seven-day lead-in at 90 mg once daily (137 patients), or crizotinib, 250 mg orally twice daily (138 patients).

Please see here for details.


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

ALUNBRIG® (brigatinib): GLOBAL IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients of ALUNBRIG is contraindicated

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Pulmonary Adverse Reactions: Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, has been reported with ALUNBRIG. Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of ALUNBRIG were independently associated with an increased rate of these pulmonary adverse reactions. Consider these factors when initiating treatment with ALUNBRIG. Some patients experienced pneumonitis later in treatment with ALUNBRIG. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.) in the first week of treatment. Promptly investigate signs of pneumonitis in any patient with worsening respiratory symptoms. If pneumonitis is suspected, withhold ALUNBRIG, and evaluate patient for other symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia).

Hypertension has been reported with ALUNBRIG. Monitor blood pressure regularly during treatment with ALUNBRIG. Treat hypertension according to standard guidelines to control blood pressure. Monitor heart rate more frequently in patients if concomitant use of a medicinal product known to cause bradycardia cannot be avoided. For severe hypertension (≥ Grade 3), ALUNBRIG should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly.

Bradycardia has been reported with ALUNBRIG. Use caution when administering ALUNBRIG in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. If symptomatic bradycardia occurs, withhold ALUNBRIG and evaluate concomitant medications known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. In case of life-threatening bradycardia, if no contributing concomitant medication is identified or in case of recurrence, discontinue ALUNBRIG.

Visual Disturbance was reported with ALUNBRIG. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms.

Creatine Phosphokinase (CPK) Elevation has been reported with ALUNBRIG. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels regularly during treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Based on the severity of the CPK elevation, and if associated with muscle pain or weakness, treatment with brigatinib should be withheld, and the dose modified accordingly.

Pancreatic Enzyme Elevation: Elevations of amylase and lipase have been reported with ALUNBRIG. Monitor lipase and amylase regularly. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Based on the severity of the laboratory abnormalities, treatment with brigatinib should be withheld, and the dose modified accordingly.

Hyperglycemia: Elevations of serum glucose have occurred in patients treated with ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Antihyperglycemic medications should be initiated or optimized as needed. If cannot control hyperglycemia with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved. Upon recovery, consider reducing the ALUNBRIG dose or permanently discontinue ALUNBRIG.

Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS
The most common adverse reactions (≥ 25%) reported in patients treated with ALUNBRIG at the recommended dosing regimen were increased AST, increased CPK, hyperglycaemia, increased lipase, hyperinsulinaemia, anaemia, diarrhea, increased ALT, increased amylase, anemia, nausea, fatigue, hypophosphatemia, decreased lymphocyte count, cough, rash, increased alkaline phosphatas, increased APTT, myalgia, headache, hypertension, white blood count decreased, dyspnea and vomiting.

The most common serious adverse reactions (2%) reported in patients treated with ALUNBRIG at the recommended dosing regimen other than events related to neoplasm progression included pneumonitis, pneumonia, and dyspnoea.

DRUG INTERACTIONS
CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG. After discontinuation of strong CYP3A inhibitor, resume ALUNBRIG dose tolerated prior to the initiation of the strong CYP3A inhibitor. No dose adjustment is required for ALUNBRIG in combination with moderate CYP3A inhibitors. Monitor patients closely when coadminister ALUNBRIG with moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of ALUNBRIG. Concomitant use of ALUNBRIG with moderate CYP3A inhibitors should be avoided. If concomitant use of moderate CYP3A inhibitors cannot be avoided, reduce the dose of ALUNBRIG. After discontinuation of a moderate CYP3A inhibitor, resume ALUNBRIG at the dose that was tolerated prior to the initiation of the moderate CYP3A inhibitor.

CYP2C8 Inhibitors: No dose adjustment is required for ALUNBRIG when coadministered with strong CYP2C8 inhibitors

P-gp and BCRP Inhibitors: No dose adjustment is required for ALUNBRIG coadministered with P-gp and BCRP inhibitors.

CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong and moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of ALUNBRIG may be increased in 30 mg increments after 7 days of treatment with the current dose as tolerated, up to a maximum of twice the dose that was tolerated prior to the initiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, resume the dose of ALUNBRIG to the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.

CYP3A Substrates: Clinical drug-drug interaction studies with sensitive CYP3A substrates have not been conducted. ALUNBRIG may reduce plasma concentrations of coadministered and induce other enzymes and transporters (e.g., CYP2C, P-gp).

Transporter Substrates: ALUNBRIG inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Coadministration of ALUNBRIG Transporter substrates may increase their plasma concentrations. Monitored patients closely when coadminister ALUNBRIG with substrates of these transporters with a narrow therapeutic index (e.g., digoxin, dabigatran, methotrexate).

SPECIAL PATIENT POPULATIONS

Women of childbearing potential/Contraception in males and females:
 Advised women of childbearing age not to become pregnant and advise men not to father a child during treatment with ALUNBRIG. Advised women of reproductive potential to use effective non hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advised men with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

Pregnancy: ALUNBRIG can cause fetal harm. There are no clinical data on the use of ALUNBRIG in pregnant women. ALUNBRIG should not be used during pregnancy unless the clinical condition of the mother requires treatment. If used during pregnancy, or if patient becomes pregnant while taking ALUNBRIG, advise patient of the potential harm to fetus.

Breast feeding: There are no data regarding the secretion of ALUNBRIG in human milk. Breastfeed should be stopped during treatment with ALUNBRIG.

Infertility: ALUNBRIG may cause reduced fertility in males.

Elderly Patients: The limited data on the safety and efficacy of ALUNBRIG in patients aged 65 years and older suggest that a dose adjustment is not required in elderly patients. There are no available data on patients over 85 years of age.

Hepatic Impairment: No dose adjustment of ALUNBRIG is required for patients with mild hepatic impairment (Child Pugh class A) or moderate hepatic impairment (Child Pugh class B). Reduce the dose of ALUNBRIG by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment

Renal Impairment: No dose adjustment of ALUNBRIG is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min). The dose of brigatinib should be reduced by approximately 40% (i.e., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh class C

Pediatric Patients: The safety and efficacy of ALUNBRIG in patients less than 18 years of age have not been established.

For US Prescribing Information: https://www.alunbrig.com/assets/pi.pdf
For European Union Summary of Product Characteristics: https://www.ema.europa.eu/en/medicines/human/EPAR/alunbrig
For Canada Product Monograph: https://www.takeda.com/siteassets/en-ca/home/what-we-do/our-medicines/product-monographs/alunbrig/alunbrig-pm-en.pdf

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 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 Genetic 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. For more information, visit https://www.takeda.com.


Contacts:

Japanese Media
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81 (0) 3-3278-2095

Media outside Japan
Lauren Padovan
lauren.padovan@takeda.com
1-617-444-1419


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