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Takeda Receives Positive CHMP Opinion Recommending ALUNBRIG® (brigatinib) for the Treatment of ALK+ Non-Small Cell Lung Cancer in Patients Previously Treated with Crizotinib

Opinion  Based on Pivotal Phase 2 ALTA Trial, in which ALUNBRIG Demonstrated an  Objective Response Rate of 56% and Longest Reported Median Progression-Free  Survival of 16.7 months in the Post-Crizotinib Setting

Cambridge, Mass. and Osaka, Japan, September 21, 2018 – Takeda Pharmaceutical  Company Limited (TSE: 4502) today announced  that the European Medicines Agency's (EMA) Committee for Medicinal Products for  Human Use (CHMP) has adopted a positive opinion, recommending the full approval  of ALUNBRIG® (brigatinib) as a monotherapy for the  treatment of adult patients with anaplastic lymphoma kinase-positive (ALK+)  advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.  ALUNBRIG is a tyrosine  kinase inhibitor (TKI) designed to target and inhibit the ALK mutation in NSCLC.  Approximately three to five percent of NSCLC patients globally have the ALK  mutation. If the CHMP opinion is affirmed, and the European Commission approves ALUNBRIG,  it will become the only ALK inhibitor available  in the European Union as a one tablet per day dose that can be taken with or  without food.

The  randomized, global Phase 2 ALTA trial was designed to investigate the efficacy  and safety of ALUNBRIG in patients with locally advanced or metastatic ALK+  NSCLC who had progressed on crizotinib. Patients were randomized to receive one  of two regimens of ALUNBRIG: 90 mg of ALUNBRIG once daily (n=112) or 180 mg  once daily with seven-day lead-in at 90 mg once daily (n=110).

"ALK+  NSCLC is a serious and life-threatening disease that affects approximately  40,000 people worldwide every year, and many patients will progress on or stop  responding to first-line treatment," said Stefania Vallone, President, Lung  Cancer Europe. "For European people with ALK+ NSCLC, there remains a  significant unmet need for new and effective treatment options."

"While ALK inhibitors have demonstrated tremendous growth  in this treatment space over the past decade, having an additional targeted therapy option available  for the treatment of ALK+ NSCLC has been eagerly anticipated," said Enriqueta  Felip, M.D., PhD, Head of the Thoracic Oncology Unit, Oncology Department at  Vall d'Hebron University Hospital in Barcelona. "With a median progression-free  survival of 16.7 months and overall survival of 34.1 months, ALUNBRIG has shown  impressive results, representing new progress for ALK+ NSCLC treatment in this  setting."

"The  ALTA trial has established ALUNBRIG as a potential second-line treatment option  for ALK+ NSCLC, by demonstrating significant efficacy with a manageable safety  profile," said Jesús Gómez-Navarro, M.D., Vice President, Head  of Oncology Clinical Research and Development, Takeda. "With 16.7 months  median progression-free survival, the longest of any ALK inhibitor to be reported in  this setting, ALUNBRIG offers great potential for patients who progressed on  crizotinib. Today's positive opinion brings us closer toward the ultimate goal  of advancing the treatment paradigm for the considerable number of  crizotinib-treated ALK+ NSCLC patients living in Europe. We look forward to the  European Commission's review of the CHMP positive opinion and introducing ALUNBRIG to patients and healthcare professionals in the  European Union if approved."

As  part of this submission, the CHMP also reviewed data from the first interim  analysis of the Phase 3 ALTA-1L trial, which met its primary endpoint, as  supportive evidence. In ALTA-1L, treatment with  ALUNBRIG resulted in a statistically and clinically significant improvement in  PFS versus crizotinib as assessed by a blinded independent review committee. The  safety profile associated with ALUNBRIG was generally consistent with prior  studies and approved U.S. and Canadian labeling.

The CHMP  positive opinion for ALUNBRIG will now be reviewed by the European Commission,  which has the authority to approve medicines for use in the 28 member states of  the European Union, as well as Norway, Liechtenstein and Iceland.

About the ALTA Trial
The Phase 2 ALTA (ALK in Lung Cancer Trial  of AP26113) trial of ALUNBRIG in adults is a global, ongoing,  two-arm, open-label, multicenter trial, which enrolled 222 patients with  locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib.  Patients received either 90 mg of ALUNBRIG once daily (n=112) or 180 mg once  daily with seven-day lead-in at 90 mg once daily regimen (n=110). Investigator-assessed  confirmed objective response rate (ORR) per RECIST v1.1 was the primary  endpoint. Key additional endpoints included Independent Review Committee (IRC)-assessed  ORR, duration of response (DOR), progression-free survival (PFS), intracranial  ORR, intracranial DOR, safety and tolerability.

Results of the ALTA trial demonstrated that of  the patients who received the 180 mg dosing regimen, 56 percent achieved an ORR  as assessed by investigator and 56 percent as assessed by IRC. The median DOR  was 13.8 months as assessed by investigator and 15.7 months by IRC assessment. Median  PFS was 15.6 months as assessed by investigator and 16.7 months by IRC assessment.  Additionally, of the patients with measurable brain metastases at baseline  (n=18), 67 percent achieved an intracranial ORR by IRC assessment; median  duration of intracranial response was 16.6 months by IRC assessment. Median  overall survival was 34.1 months as assessed by investigator.

The most common adverse reactions (≥25%) reported in patients treated  with ALUNBRIG at the 180 mg dosing regimen were increased aspartate  aminotransferase (AST), hyperglycemia, hyperinsulinemia, anemia, increased creatine  phosphokinase (CPK), nausea, increased lipase, decreased lymphocyte count, increased  alanine aminotransferase (ALT), diarrhea, increased amylase, fatigue, cough, headache,  increased alkaline phosphatase, hypophosphatemia, increased abnormal activated  partial thromboplastin time (APTT), rash, vomiting, dyspnea, hypertension,  decreased blood cell count, myalgia, and peripheral neuropathy.

About  the ALTA-1L Trial
The Phase 3  ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib  in 1st Line) trial of ALUNBRIG in adults is a global, ongoing, randomized,  open-label, comparative, multicenter trial, which enrolled 275 patients with  ALK+ locally advanced or metastatic NSCLC who have not received prior treatment  with an ALK inhibitor. Patients received either ALUNBRIG, 180 mg once daily  with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily.  Independent Review Committee (IRC)-assessed progression-free survival (PFS) was  the primary endpoint. Secondary endpoints included objective response rate  (ORR) per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival  (OS), safety and tolerability. A total of approximately 198 PFS events are  planned at the final analysis of the primary endpoint in order to demonstrate a  minimum of six months PFS improvement over crizotinib. The trial is designed  with two pre-specified interim analyses for the primary endpoint – one at  approximately 50 percent of planned PFS events and one at approximately 75  percent of planned PFS events.

About  ALK+ NSCLC
Non-small  cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for  approximately 85 percent 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 three  to five percent 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 targeted  cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired  by Takeda in February 2017. In April 2017, ALUNBRIG received Accelerated  Approval from the U.S. Food and Drug Administration (FDA) for ALK+ metastatic  NSCLC patients who have progressed on or are intolerant to crizotinib. This  indication is approved under Accelerated Approval based on tumor response rate  and duration of response. Continued approval for this indication may be  contingent upon verification and description of clinical benefit in a  confirmatory trial. In July 2018, Health Canada approved ALUNBRIG for the  treatment of adult patients with ALK+ metastatic NSCLC who have progressed on  or who were intolerant to an ALK inhibitor (crizotinib). The FDA and Health Canada approvals of ALUNBRIG were  primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung  Cancer Trial of AP26113) trial. 

ALUNBRIG received  Breakthrough Therapy Designation from the FDA for the treatment of patients  with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan  Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+  NSCLC.

The brigatinib clinical  development program further reinforces Takeda's ongoing commitment to developing  innovative therapies for people living with ALK+ NSCLC worldwide and the  healthcare professionals who treat them. The  comprehensive program includes the following clinical trials: 

  • Phase  1/2 trial, which was designed to evaluate the safety, tolerability,  pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG
  •  
  • Pivotal Phase 2 ALTA trial  investigating the efficacy and safety of ALUNBRIG at two dosing regimens in  patients with ALK+ locally advanced or metastatic NSCLC who had progressed on  crizotinib
  •  
  • Phase 3 ALTA-1L, a global  randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to  crizotinib in patients with ALK+ locally advanced or metastatic  NSCLC who have not received prior treatment with an ALK inhibitor
  •  
  • Phase 2 single-arm, multicenter trial  in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed  on alectinib
  •  
  • Phase 2 global, single arm trial evaluating  ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib  or ceritinib
  •  
  • Phase 3 global randomized trial comparing  the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+  NSCLC who have progressed on crizotinib

For additional  information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.

IMPORTANT  SAFETY INFORMATION (U.S.)
WARNINGS  AND PRECAUTIONS

Interstitial  Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary  adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis  have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in  3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in  the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily).  Adverse reactions consistent with possible ILD/pneumonitis occurred early  (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of  patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or  worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly  during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient  with new or worsening respiratory symptoms, and promptly evaluate for  ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary  embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2  ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to  baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG  for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension  was reported in 11% of patients in the 90 mg group who received ALUNBRIG and  21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9%  of patients overall. Control blood pressure prior to treatment with ALUNBRIG.  Monitor blood pressure after 2 weeks and at least monthly thereafter during  treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite  optimal antihypertensive therapy. Upon resolution or improvement to Grade 1  severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation  of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3  hypertension. Use caution when administering ALUNBRIG in combination with  antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur  with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm)  occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the  90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg  group. Monitor heart rate and blood pressure during treatment with ALUNBRIG.  Monitor patients more frequently if concomitant use of drug known to cause  bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG  and review concomitant medications for those 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. Discontinue ALUNBRIG for  life-threatening bradycardia if no contributing concomitant medication is  identified.

Visual  Disturbance: In  ALTA, adverse reactions leading to visual disturbance including blurred vision,  diplopia, and reduced visual acuity, were reported in 7.3% of patients treated  with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group.  Grade 3 macular edema and cataract occurred in one patient each in the 90→180  mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and  obtain an ophthalmologic evaluation in patients with new or worsening visual  symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3  visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a  reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4  visual disturbances.

Creatine  Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation  occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of  patients in the 90 mg→180 mg group. The incidence of Grade 3‑4 CPK  elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose  reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and  4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle  pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment.  Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery  to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic  Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in  the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations  occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180  mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90  mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase  elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients  in the 90→180 mg group. Monitor lipase and amylase during treatment with  ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon  resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose  or at a reduced dose.

Hyperglycemia: In ALTA, 43% of  patients who received ALUNBRIG experienced new or worsening hyperglycemia.  Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose  levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or  glucose intolerance at baseline required initiation of insulin while receiving  ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and  monitor periodically thereafter. Initiate or optimize anti-hyperglycemic  medications as needed. If adequate hyperglycemic control cannot be achieved  with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic  control is achieved and consider reducing the dose of ALUNBRIG or permanently  discontinuing 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

Serious  adverse reactions occurred in 38% of patients in the 90 mg group and 40% of  patients in the 90→180 mg group. The most common serious adverse reactions were  pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg  group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in  the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and  consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory  failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient  each).

The  most common adverse reactions (≥25%) in the 90 mg group were nausea (33%),  fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group  were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache  (27%).

DRUG  INTERACTIONS

CYP3A  Inhibitors:  Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid  grapefruit or grapefruit juice as it may also increase plasma concentrations of  brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable,  reduce the dose of ALUNBRIG.

CYP3A  Inducers:  Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.

CYP3A  Substrates: Coadministration  of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can  result in decreased concentrations and loss of efficacy of CYP3A substrates.

USE  IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can  cause fetal harm. Advise females of reproductive potential of the potential  risk to a fetus.
Lactation: There are no data regarding the secretion of brigatinib in human milk or  its effects on the breastfed infant or milk production. Because of the  potential adverse reactions in breastfed infants, advise lactating women not to  breastfeed during treatment with ALUNBRIG.

Females  and Males of Reproductive Potential:

ContraceptionAdvise females of  reproductive potential to use effective non-hormonal contraception during  treatment with ALUNBRIG and for at least 4 months after the final dose. Advise  males with female partners of reproductive potential to use effective  contraception during treatment with ALUNBRIG and for at least 3 months after  the final dose.

Infertility: ALUNBRIG may cause  reduced fertility in males.
Pediatric  Use: The  safety and efficacy of ALUNBRIG in pediatric patients have not been  established.

Geriatric  Use: Clinical  studies of ALUNBRIG did not include sufficient numbers of patients aged 65  years and older to determine whether they respond differently from younger  patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75  years or older. No clinically relevant differences in safety or efficacy  were observed between patients ≥65 and younger patients.

Hepatic  or Renal Impairment: No dose adjustment is recommended for patients with mild  hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG  in patients with moderate or severe hepatic impairment or severe renal  impairment has not been studied.

Please  see the full U.S. Prescribing Information for ALUNBRIG at www.ALUNBRIG.com

About  Takeda Pharmaceutical Company 

Takeda  Pharmaceutical Company Limited is a global, research and development-driven  pharmaceutical company committed to bringing better health and a brighter  future to patients by translating science into life-changing medicines. Takeda  focuses its R&D efforts on oncology, gastroenterology and central nervous  system therapeutic areas plus vaccines. Takeda conducts R&D both internally  and with partners to stay at the leading edge of innovation. New innovative  products, especially in oncology and gastroenterology, as well as our presence  in Emerging Markets, fuel the growth of Takeda. More than 30,000 Takeda  employees are committed to improving quality of life for patients, working with  our partners in health care in more than 70 countries. For more information,  visit http://www.takeda.com/news.
Additional information  about Takeda is available through its corporate website, www.takeda.com, and additional  information about Takeda Oncology, the brand for the global oncology business  unit of Takeda Pharmaceutical Company Limited, is available through its  website, www.takedaoncology.com.

Contacts:
Takeda Pharmaceutical Company Limited

           

Japanese Media
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81 3 3 278 2095         

European Media
Kate Burd
kate.burd@takeda.com
+41 79 514 9533

 Media    outside Japan/EU
 Amanda Loder
 Amanda.Loder@takeda.com
 +1-212-259-0491