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Takeda Announces Phase 3 Trial of ALUNBRIG® (brigatinib) Met Primary Endpoint Demonstrating Superiority in Progression-Free Survival Versus Crizotinib in Patients with ALK+ Advanced NSCLC Who are ALK Inhibitor Naïve

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Takeda Pharmaceutical Company Limited (TSE:
4502
) today announced that the global, randomized, Phase 3 ALTA-1L (ALK
in Lung Cancer Trial of AP26113 in 1st
Line) trial met its primary endpoint at the first pre-specified
interim analysis, with ALUNBRIG® (brigatinib) demonstrating a
statistically significant improvement in progression-free survival (PFS)
compared to crizotinib in adults with anaplastic lymphoma
kinase-positive (ALK+) locally advanced or metastatic non-small cell
lung cancer (NSCLC) who had not received a prior ALK inhibitor. The
trial was designed to assess the efficacy and safety of ALUNBRIG in
comparison to crizotinib based on evaluation of the primary endpoint of
PFS, or length of time from the start of treatment that a patient lives
without the disease getting worse. ALUNBRIG is currently not approved as
frontline therapy.

"This represents a major milestone for the ALUNBRIG program. Our goal
with ALUNBRIG is to improve the lives of patients with ALK+ NSCLC by
furthering the available therapeutic options," said Jesús Gomez-Navarro,
M.D., Vice President, Head of Oncology Clinical Research and
Development, Takeda. "We are encouraged by the data, which demonstrated
a statistically significant improvement in progression-free survival
versus crizotinib in patients with ALK+ advanced NSCLC, and look forward
to beginning discussions with regulatory authorities as we seek to
expand ALUNBRIG's indication into the frontline setting."

The safety profile associated with ALUNBRIG from the ALTA-1L trial was
generally consistent with the existing prescribing information, with no
new safety concerns.

The results from this interim analysis will be submitted for
presentation at an upcoming medical meeting.

About the ALTA-1L Trial

The Phase 3 ALTA-1L (ALK in Lung Cancer Trial
of AP26113 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 50 percent of planned PFS events and one at 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.

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. A Marketing
Authorization Application (MAA) for ALUNBRIG was submitted to the
European Medicines Agency (EMA) in February 2017.

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 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 study in Japanese patients with ALK+
    NSCLC, focusing on patients who have progressed on alectinib
  • Phase 2 global study evaluating ALUNBRIG in patients with advanced
    ALK+ NSCLC who have progressed on alectinib or ceritinib

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:

Contraception: Advise 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 (TSE: 4502) 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 neuroscience therapeutic areas plus
vaccines. Takeda conducts R&D both internally and with partners to stay
at the leading edge of innovation. Innovative products, especially in
oncology and gastroenterology, as well as Takeda's presence in emerging
markets, are currently fueling the growth of Takeda. Approximately
30,000 Takeda employees are committed to improving quality of life for
patients, working with Takeda's partners in health care in more than 70
countries. For more information, visit https://www.takeda.com/newsroom/.

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.

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