Takeda to Showcase Growing Pipeline and Diversified Portfolio of Oncology Products at Upcoming Scientific Congresses

Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.

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Health, Biotechnology, Clinical trials, Genetics, Oncology, Pharmaceutical, Research, Science, Medicine, Clinical medicine, Organ systems, Takeda Pharmaceutical Company, Neurological disorders, Brentuximab vedotin, Hypoesthesia, Peripheral neuropathy, Paresthesia, Dysesthesia, Hyperesthesia
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Summary
Key Points: 
  • Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.
  • Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia.
  • There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity.
  • Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience and Rare Diseases.


Takeda Pharmaceutical Company Limited (TSE:
4502/NYSE:TAK) today announced that the company will present data at
the 55th Annual Meeting of the American Society of Clinical
Oncology (ASCO), May 31-June 4 in Chicago and the 24th
Congress of the European Hematology Association (EHA), June 13-16 in
Amsterdam.

“We look forward to presenting data at ASCO and EHA that illustrate the
continued progress of our portfolio in both clinical research and
real-world settings in solid tumors and blood cancers,” said Phil
Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. “These
data demonstrate our continued commitment to the discovery, development
and delivery of medicines for patients with cancers.”

At ASCO, Takeda will present data from both its lung portfolio and
hematology portfolio. Results from a Phase 1/2 first-in-human,
open-label, multicenter study of TAK-788 will be presented orally. The
ongoing study is investigating the antitumor activity and safety of
TAK-788 in patients with locally advanced or metastatic non-small cell
lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor
(EGFR) exon 20 insertion mutations. Takeda also will present three
posters that demonstrate our commitment to furthering the understanding
of patients with anaplastic lymphoma kinase-positive (ALK+) NSCLC
treated with ALUNBRIG® (brigatinib). The Phase 3 PhALLCON
trial – an ongoing efficacy study of ICLUSIG® (ponatinib) in
combination with reduced-intensity chemotherapy in patients with newly
diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia
(Ph+ ALL) – will be featured in a poster presentation. Additional data
from the ECHELON-1 and ECHELON-2 trials evaluating ADCETRIS®
(brentuximab vedotin) as a frontline treatment option in patients with
newly diagnosed Stage III and IV Hodgkin lymphoma and in CD30+
peripheral T-cell lymphoma, respectively, will also be shared in
partnership with Seattle Genetics.

At EHA, additional analyses from the TOURMALINE-MM3 trial, which is
investigating NINLARO™ (ixazomib) as a post-transplant
maintenance therapy in adult patients with multiple myeloma, will be
presented, including quality of life and outcomes in patients who
deepened their responses while on ixazomib maintenance. Furthermore,
preliminary demographics, baseline characteristics and electronic
patient-reported outcomes of patients enrolled in the US MM-6 trial, a
study of multiple myeloma patients who transitioned from treatment with
VELCADE® (bortezomib) to treatment with NINLARO, will be
presented. Real-world findings will also be featured at the meeting,
including results from INSIGHT-MM, a global, prospective,
non-interventional, observational study of presentation, treatment
patterns and outcomes in multiple myeloma by age and geographical
region. ADCETRIS will be featured in encore presentations including
three-year results from the ECHELON-1 trial, which will be presented
during an oral, as well as results from the ECHELON-2 trial.

The eight Takeda-sponsored abstracts accepted for presentation during
ASCO 2019 and 11 abstracts at EHA 2019 include:

ASCO Annual Meeting 2019

Note: All times listed are in Central Daylight Time

TAK-788

ALUNBRIG (brigatinib)

ICLUSIG (ponatinib)

ADCETRIS (brentuximab vedotin)

EHA 24th Congress

Note: All times listed are in Central European Time

Multiple Myeloma / NINLARO (ixazomib)

ADCETRIS (brentuximab vedotin)

For more information, please see ASCO (https://meetings.asco.org/am/program)
and EHA (http://www.eha-2019.org/)
online programs.

About ADCETRIS

ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30
monoclonal antibody attached by a protease-cleavable linker to a
microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing
Seattle Genetics' proprietary technology. The ADC employs a linker
system that is designed to be stable in the bloodstream but to release
MMAE upon internalization into CD30-positive tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval
for six indications in adult patients with: (1) previously untreated
systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing
peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell
lymphoma and PTCL not otherwise specified, in combination with
cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated
Stage III or IV classical Hodgkin lymphoma (cHL), in combination with
doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of
relapse or progression as post-autologous hematopoietic stem cell
transplantation (auto-HSCT) consolidation, (4) cHL after failure of
auto-HSCT or failure of at least two prior multi-agent chemotherapy
regimens in patients who are not auto-HSCT candidates, (5) sALCL after
failure of at least one prior multi-agent chemotherapy regimen, and (6)
primary cutaneous anaplastic large cell lymphoma (pcALCL) or
CD30-expressing mycosis fungoides (MF) who have received prior systemic
therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or
refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional
approval for post-autologous stem cell transplantation (ASCT)
consolidation treatment of Hodgkin lymphoma patients at increased risk
of relapse or progression in 2017, adults with pcALCL or CD30-expressing
MF who have had prior systemic therapy in 2018, and for previously
untreated Stage IV Hodgkin lymphoma in combination with doxorubicin,
vinblastine, and dacarbazine in 2019.

ADCETRIS received conditional marketing authorization from the European
Commission in October 2012. The approved indications in Europe are: (1)
for the treatment of adult patients with relapsed or refractory
CD30-positive Hodgkin lymphoma following ASCT, or following at least two
prior therapies when ASCT or multi-agent chemotherapy is not a treatment
option, (2) for the treatment of adult patients with relapsed or
refractory sALCL, (3) for the treatment of adult patients with
CD30-positive Hodgkin lymphoma at increased risk of relapse or
progression following ASCT, (4) for the treatment of adult patients with
CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior
systemic therapy and (5) for the treatment of adult patients with
previously untreated CD30-positive Stage IV Hodgkin lymphoma in
combination with AVD.

ADCETRIS has received marketing authorization by regulatory authorities
in more than 70 countries for relapsed or refractory Hodgkin lymphoma
and sALCL. See important safety information below.

ADCETRIS is being evaluated broadly in more than 70 clinical trials,
including a Phase 3 study in first-line Hodgkin lymphoma (ECHELON-1) and
another Phase 3 study in first-line CD30-positive peripheral T-cell
lymphomas (ECHELON-2), as well as trials in many additional types of
CD30-positive malignancies.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the
terms of the collaboration agreement, Seattle Genetics has U.S. and
Canadian commercialization rights and Takeda has rights to commercialize
ADCETRIS in the rest of the world. Seattle Genetics and Takeda are
funding joint development costs for ADCETRIS on a 50:50 basis, except
in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) Important Safety Information (European
Union)

Please refer to Summary of Product Characteristics (SmPC) before
prescribing.

CONTRAINDICATIONS

ADCETRIS is contraindicated for patients with hypersensitivity to
brentuximab vedotin and its excipients. In addition, combined use of
ADCETRIS with bleomycin causes pulmonary toxicity.

SPECIAL WARNINGS & PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): John Cunningham
virus (JCV) reactivation resulting in progressive multifocal
leukoencephalopathy (PML) and death can occur in patients treated with
ADCETRIS. PML has been reported in patients who received ADCETRIS after
receiving multiple prior chemotherapy regimens. PML is a rare
demyelinating disease of the central nervous system that results from
reactivation of latent JCV and is often fatal.

Closely monitor patients for new or worsening neurological, cognitive,
or behavioral signs or symptoms, which may be suggestive of PML.
Suggested evaluation of PML includes neurology consultation,
gadolinium-enhanced magnetic resonance imaging of the brain, and
cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or
a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude
PML. Additional follow up and evaluation may be warranted if no
alternative diagnosis can be established Hold dosing for any suspected
case of PML and permanently discontinue ADCETRIS if a diagnosis of PML
is confirmed.

Be alert to PML symptoms that the patient may not notice (e.g.,
cognitive, neurological, or psychiatric symptoms).

Pancreatitis: Acute pancreatitis has been observed in
patients treated with ADCETRIS. Fatal outcomes have been reported.
Closely monitor patients for new or worsening abdominal pain, which may
be suggestive of acute pancreatitis. Patient evaluation may include
physical examination, laboratory evaluation for serum amylase and serum
lipase, and abdominal imaging, such as ultrasound and other appropriate
diagnostic measures. Hold ADCETRIS for any suspected case of acute
pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute
pancreatitis is confirmed.

Pulmonary Toxicity: Cases of pulmonary toxicity, some with
fatal outcomes, including pneumonitis, interstitial lung disease, and
acute respiratory distress syndrome (ARDS), have been reported in
patients receiving ADCETRIS. Although a causal association with ADCETRIS
has not been established, the risk of pulmonary toxicity cannot be ruled
out. Promptly evaluate and treat new or worsening pulmonary symptoms
(e.g., cough, dyspnoea) appropriately. Consider holding dosing during
evaluation and until symptomatic improvement.

Serious infections and opportunistic infections: Serious
infections such as pneumonia, staphylococcal bacteremia, sepsis/septic
shock (including fatal outcomes), and herpes zoster, and opportunistic
infections such as Pneumocystis jiroveci pneumonia and
oral candidiasis have been reported in patients treated with ADCETRIS.
Carefully monitor patients during treatment for emergence of possible
serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as
well as anaphylaxis, have been reported with ADCETRIS. Carefully monitor
patients during and after an infusion. If anaphylaxis occurs,
immediately and permanently discontinue administration of ADCETRIS and
administer appropriate medical therapy. If an IRR occurs, interrupt the
infusion and institute appropriate medical management. The infusion may
be restarted at a slower rate after symptom resolution. Patients who
have experienced a prior IRR should be premedicated for subsequent
infusions. IRRs are more frequent and more severe in patients with
antibodies to ADCETRIS.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS.
Patients with rapidly proliferating tumor and high tumor burden are at
risk of TLS. Monitor these patients closely and manage according to best
medical practice.

Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both
sensory and motor. ADCETRIS-induced PN is typically an effect of
cumulative exposure to ADCETRIS and is reversible in most cases. Monitor
patients for symptoms of neuropathy, such as hypoesthesia,
hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic
pain, or weakness. Patients experiencing new or worsening PN may require
a delay and a dose reduction or discontinuation of ADCETRIS.

Hematological toxicities: Grade 3 or Grade 4 anemia,
thrombocytopenia, and prolonged (equal to or greater than one week)
Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete
blood counts prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported with
ADCETRIS. Complete blood counts should be monitored prior to
administration of each dose of treatment. Closely monitor patients for
fever and manage according to best medical practice if febrile
neutropenia develops.

When ADCETRIS is administered in combination with AVD, primary
prophylaxis with G-CSF is recommended for all patients beginning with
the first dose.

Stevens-Johnson syndrome (SJS): SJS and toxic epidermal
necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have
been reported. Discontinue treatment with ADCETRIS if SJS or TEN occurs
and administer appropriate medical therapy.

Gastrointestinal (GI) Complications: GI complications, some with
fatal outcomes, including intestinal obstruction, ileus, enterocolitis,
neutropenic colitis, erosion, ulcer, perforation and haemorrhage, have
been reported with ADCETRIS. Promptly evaluate and treat patients if new
or worsening GI symptoms occur.

Hepatotoxicity: Elevations in alanine aminotransferase (ALT)
and aspartate aminotransferase (AST) have been reported with ADCETRIS.
Serious cases of hepatotoxicity, including fatal outcomes, have also
occurred. Pre-existing liver disease, comorbidities, and concomitant
medications may also increase the risk. Test liver function prior to
treatment initiation and routinely monitor during treatment. Patients
experiencing hepatotoxicity may require a delay, dose modification, or
discontinuation of ADCETRIS.

Hyperglycemia: Hyperglycemia has been reported during trials in
patients with an elevated body mass index (BMI) with or without a
history of diabetes mellitus. Closely monitor serum glucose for patients
who experiences an event of hyperglycemia. Administer anti-diabetic
treatment as appropriate.

Renal and Hepatic Impairment: There is limited experience in
patients with renal and hepatic impairment. Available data indicate that
MMAE clearance might be affected by severe renal impairment, hepatic
impairment, and by low serum albumin concentrations.

CD30+ CTCL: The size of the treatment effect in CD30 + CTCL
subtypes other than mycosis fungoides (MF) and primary cutaneous
anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high
level evidence. In two single arm phase II studies of ADCETRIS, disease
activity has been shown in the subtypes Sézary syndrome (SS),
lymphomatoid papulosis (LyP) and mixed CTCL histology. These data
suggest that efficacy and safety can be extrapolated to other CTCL CD30+
subtypes. Carefully consider the benefit-risk per patient and use with
caution in other CD30+ CTCL patient types.

Sodium content in excipients: This medicinal product contains
13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended
maximum daily intake of 2 g sodium for an adult.

INTERACTIONS

Patients who are receiving a strong CYP3A4 and P-gp inhibitor,
concomitantly with ADCETRIS may have an increased risk of neutropenia.
If neutropenia develops, refer to dosing recommendations for neutropenia
(see SmPC section 4.2). Co-administration of ADCETRIS with a CYP3A4
inducer did not alter the plasma exposure of ADCETRIS, but it appeared
to reduce plasma concentrations of MMAE metabolites that could be
assayed. ADCETRIS is not expected to alter the exposure to drugs that
are metabolized by CYP3A4 enzymes.

PREGNANCY: Advise women of childbearing potential to use two
methods of effective contraception during treatment with ADCETRIS and
until 6 months after treatment. There are no data from the use of
ADCETRIS in pregnant women, although studies in animals have shown
reproductive toxicity. Do not use ADCETRIS during pregnancy unless the
benefit to the mother outweighs the potential risks to the fetus.

LACTATION (breast-feeding): There are no data as to whether
ADCETRIS or its metabolites are excreted in human milk, therefore a risk
to the newborn/infant cannot be excluded. With the potential risk, a
decision should be made whether to discontinue breast-feeding or
discontinue/abstain from therapy with ADCETRIS.

FERTILITY: In nonclinical studies, ADCETRIS treatment has
resulted in testicular toxicity, and may alter male fertility. Advise
men being treated with ADCETRIS not to father a child during treatment
and for up to 6 months following the last dose.

Effects on ability to drive and use machines: ADCETRIS may have a
moderate influence on the ability to drive and use machines.

UNDESIRABLE EFFECTS

Monotherapy: The most frequent adverse reactions (≥10%) were
infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea,
pyrexia, upper respiratory tract infection, neutropenia, rash, cough,
vomiting, arthralgia, peripheral motor neuropathy, infusion-related
reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia
and abdominal pain. Serious adverse drug reactions occurred in 12% of
patients. The frequency of unique serious adverse drug reactions was
≤1%. Adverse events led to treatment discontinuation in 24% of patients.

Combination Therapy: In the study of ADCETRIS as combination
therapy with AVD in 662 patients with previously untreated advanced HL,
the most common adverse reactions (≥ 10%) were: neutropenia, nausea,
constipation, vomiting, fatigue, peripheral sensory neuropathy,
diarrhoea, pyrexia, alopecia, peripheral motor neuropathy, decreased
weight, abdominal pain, anaemia, stomatitis, febrile neutropenia, bone
pain, insomnia, decreased appetite, cough, headache, arthralgia, back
pain, dyspnoea, myalgia, upper respiratory tract infection, alanine
aminotransferase increased. Serious adverse reactions occurred in 36% of
patients. Serious adverse reactions occurring in ≥ 3% of patients
included febrile neutropenia (17%), pyrexia (6%), and neutropenia (3%).
Adverse events led to treatment discontinuation in 13% of patients.

ADCETRIS (brentuximab vedotin) Important Safety Information (U.S.)

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection
resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g.,
interstitial infiltration and/or inflammation).

Warnings and Precautions

  • Peripheral neuropathy (PN): ADCETRIS causes PN that is
    predominantly sensory. Cases of motor PN have also been reported.
    ADCETRIS-induced PN is cumulative. Monitor for symptoms such as
    hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning
    sensation, neuropathic pain, or weakness. Institute dose modifications
    accordingly.
  • Anaphylaxis and infusion reactions: Infusion-related reactions
    (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor
    patients during infusion. If an IRR occurs, interrupt the infusion and
    institute appropriate medical management. If anaphylaxis occurs,
    immediately and permanently discontinue the infusion and administer
    appropriate medical therapy. Premedicate patients with a prior IRR
    before subsequent infusions. Premedication may include acetaminophen,
    an antihistamine, and a corticosteroid.
  • Hematologic toxicities: Fatal and serious cases of febrile
    neutropenia have been reported with ADCETRIS. Prolonged (≥1 week)
    severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can
    occur with ADCETRIS.

    Administer G-CSF primary prophylaxis
    beginning with Cycle 1 for patients who receive ADCETRIS in
    combination with chemotherapy for previously untreated Stage III/IV
    cHL or previously untreated PTCL.

    Monitor complete blood
    counts prior to each ADCETRIS dose. Monitor more frequently for
    patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If
    Grade 3 or 4 neutropenia develops, consider dose delays, reductions,
    discontinuation, or G-CSF prophylaxis with subsequent doses.
  • Serious infections and opportunistic infections: Infections
    such as pneumonia, bacteremia, and sepsis or septic shock (including
    fatal outcomes) have been reported in ADCETRIS-treated patients.
    Closely monitor patients during treatment for bacterial, fungal, or
    viral infections.
  • Tumor lysis syndrome: Closely monitor patients with rapidly
    proliferating tumor and high tumor burden.
  • Increased toxicity in the presence of severe renal impairment: The
    frequency of ≥Grade 3 adverse reactions and deaths was greater in
    patients with severe renal impairment compared to patients with normal
    renal function. Avoid use in patients with severe renal impairment.
  • Increased toxicity in the presence of moderate or severe hepatic
    impairment:     The frequency of ≥Grade 3 adverse reactions and deaths
    was greater in patients with moderate or severe hepatic impairment
    compared to patients with normal hepatic function. Avoid use in
    patients with moderate or severe hepatic impairment.
  • Hepatotoxicity: Fatal and serious cases have occurred in
    ADCETRIS-treated patients. Cases were consistent with hepatocellular
    injury, including elevations of transaminases and/or bilirubin, and
    occurred after the first ADCETRIS dose or rechallenge. Preexisting
    liver disease, elevated baseline liver enzymes, and concomitant
    medications may increase the risk. Monitor liver enzymes and
    bilirubin. Patients with new, worsening, or recurrent hepatotoxicity
    may require a delay, change in dose, or discontinuation of ADCETRIS.
  • PML: Fatal cases of JC virus infection resulting in PML have
    been reported in ADCETRIS-treated patients. First onset of symptoms
    occurred at various times from initiation of ADCETRIS, with some cases
    occurring within 3 months of initial exposure. In addition to ADCETRIS
    therapy, other possible contributory factors include prior therapies
    and underlying disease that may cause immunosuppression. Consider PML
    diagnosis in patients with new-onset signs and symptoms of central
    nervous system abnormalities. Hold ADCETRIS if PML is suspected and
    discontinue ADCETRIS if PML is confirmed.
  • Pulmonary toxicity: Fatal and serious events of noninfectious
    pulmonary toxicity, including pneumonitis, interstitial lung disease,
    and acute respiratory distress syndrome, have been reported. Monitor
    patients for signs and symptoms, including cough and dyspnea. In the
    event of new or worsening pulmonary symptoms, hold ADCETRIS dosing
    during evaluation and until symptomatic improvement.
  • Serious dermatologic reactions: Fatal and serious cases of
    Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
    have been reported with ADCETRIS. If SJS or TEN occurs, discontinue
    ADCETRIS and administer appropriate medical therapy.
  • Gastrointestinal (GI) complications: Fatal and serious cases of
    acute pancreatitis have been reported. Other fatal and serious GI
    complications include perforation, hemorrhage, erosion, ulcer,
    intestinal obstruction, enterocolitis, neutropenic colitis, and ileus.
    Lymphoma with preexisting GI involvement may increase the risk of
    perforation. In the event of new or worsening GI symptoms, including
    severe abdominal pain, perform a prompt diagnostic evaluation and
    treat appropriately.
  • Embryo-fetal toxicity: Based on the mechanism of action and
    animal studies, ADCETRIS can cause fetal harm. Advise females of
    reproductive potential of the potential risk to the fetus, and to
    avoid pregnancy during ADCETRIS treatment and for at least 6 months
    after the final dose of ADCETRIS.

Most Common (≥20% in any study) Adverse Reactions

Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper
respiratory tract infection, pyrexia, constipation, vomiting, alopecia,
decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and
mucositis.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the
potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE
exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to
use effective contraception during ADCETRIS treatment and for at least 6
months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding
while receiving ADCETRIS.

For additional Important Safety Information, including BOXED WARNING,
please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or http://www.ADCETRIS.com.

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.
  • In November 2018, the European Commission (EC) granted marketing
    authorization for ALUNBRIG as a monotherapy for the treatment of adult
    patients with ALK+ advanced NSCLC previously treated with crizotinib.

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

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 coadministration of
ALUNBRIG with strong or moderate CYP3A inhibitors. Avoid grapefruit or
grapefruit juice as it may also increase plasma concentrations of
brigatinib. If coadministration of a strong or moderate CYP3A inhibitor
cannot be avoided, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid coadministration of
ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of
moderate CYP3A inducers cannot be avoided, increase the dose of ALUNBRIG

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

Pregnancy Testing: Verify pregnancy status
in females of reproductive potential prior to initiating ALUNBRIG

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 effectiveness 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.

Hepatic or Renal Impairment: No dose adjustment is recommended
for patients with mild or moderate hepatic impairment or mild or
moderate renal impairment. Reduce the dose of ALUNBRIG for patients with
severe hepatic impairment or severe renal impairment.

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

About ICLUSIG® (ponatinib) tablets

ICLUSIG is a kinase inhibitor primarily 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 targets
native BCR-ABL1, as well as 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 which received full
approval from the FDA in November 2016, is also approved in the EU,
Australia, Switzerland, Israel, Canada and Japan.

In the U.S., ICLUSIG is indicated for:

  • Treatment of adult patients with chronic-phase, accelerated-phase or
    blast-phase CML (CP-CML, AP-CML or BP-CML) or Ph+ ALL for whom no
    other tyrosine kinase inhibitor (TKI) therapy is indicated.
  • Treatment for adult patients with T315I-positive CML (CP, AP or BP) or
    T315I-positive Ph+ ALL.

Limitations of Use: ICLUSIG is not
indicated and is not recommended for the treatment of patients with
newly diagnosed CP-CML.

ICLUSIG (ponatinib) 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: Arterial occlusions, including fatal
myocardial infarction, stroke, stenosis of large arterial vessels of the
brain, severe peripheral vascular disease have occurred in at least 35%
of ICLUSIG-treated patients from the phase 1 and phase 2 trials. In the
phase 2 trial, 33% (150/449) 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 multi-site vascular occlusion. Patients have
required revascularization procedures. The median time to onset of the
first cardiac vascular, cerebrovascular, and peripheral vascular
arterial occlusive events was 193, 526, and 478 days, respectively.
Patients with and without cardiovascular risk factors, some age 50 years
or younger, experienced these events. The most common risk factors
observed with these events were hypertension, hyperlipidemia, and
history of cardiac disease. Arterial occlusive events were more frequent
with increasing age and in patients with a history of ischemia,
hypertension, diabetes, or hyperlipidemia. In patients suspected of
developing arterial occlusive events, interrupt or stop ICLUSIG.

Venous Thromboembolism: Venous thromboembolic events occurred in
6% (25/449) of ICLUSIG-treated patients with an incidence rate of 5%
(13/270 CP-CML), 4% (3/85 AP-CML), 10% (6/62 BP-CML) and 9% (3/32 Ph+
ALL). Events included: deep venous thrombosis, pulmonary embolism,
superficial thrombophlebitis, and retinal vein thrombosis with vision
loss. 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 ICLUSIG-treated patients (29/449). Nine
percent of patients (39/449) experienced any grade of heart failure or
left ventricular dysfunction. The most frequently reported heart failure
events were congestive cardiac failure and decreased ejection fraction
(14 patients each; 3%). 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: ICLUSIG can cause hepatotoxicity, including liver
failure and death. Fulminant hepatic failure leading to death occurred
in a patient within one week of starting ICLUSIG. Two additional fatal
cases of acute liver failure also occurred. The fatal cases occurred in
patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all
disease cohorts, with 11% (50/449) experiencing grade 3 or 4
hepatotoxicity. The most common forms of hepatotoxicity 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. Hepatotoxic events were
observed in 29% of patients. The median time to onset of hepatotoxicity
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% (306/449) of
ICLUSIG-treated patients. Fifty-three patients (12%) experienced
treatment-emergent symptomatic hypertension as a serious adverse
reaction, including hypertensive crisis. Patients may require urgent
clinical intervention for hypertension associated with confusion,
headache, chest pain, or shortness of breath. In patients with baseline
systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285)
experienced treatment-emergent hypertension; 44% (124/285) developed
Stage 1 hypertension, 37% developed Stage 2 hypertension. In 132
patients with Stage 1 hypertension at baseline, 67% (88/132) developed
Stage 2 hypertension. Monitor and manage blood pressure elevations
during ICLUSIG use and treat hypertension to normalize blood pressure.
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 occurred in 7% (31/449, 6%
serious or grade 3/4) of ICLUSIG-treated patients. The incidence of
treatment-emergent lipase elevation was 42% (16% grade 3 or greater).
Pancreatitis resulted in discontinuation or treatment interruption in 6%
of patients (26/449). The median time to onset of pancreatitis was 14
days. Twenty-three of the 31 cases of pancreatitis resolved within 2
weeks with dose interruption or reduction. Check serum lipase every 2
weeks for the first 2 months and then 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 less than 1.5 x ULN.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In
a prospective randomized clinical trial in the first-line treatment of
newly diagnosed patients with chronic phase (CP) CML, single agent
ICLUSIG 45 mg once-daily increased the risk of serious adverse reactions
2-fold compared to single agent 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-treated patients, ICLUSIG-treated
patients 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: Peripheral and cranial neuropathy have occurred
in ICLUSIG-treated patients. Overall, 20% (90/449) of ICLUSIG-treated
patients experienced a peripheral neuropathy event of any grade (2%,
grade 3/4). The most common peripheral neuropathies reported were
paresthesia (5%, 23/449), neuropathy peripheral (4%, 19/449),
hypoesthesia (3%, 15/449), dysgeusia (2%, 10/449), muscular weakness
(2%, 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed
in 2% (10/449) of ICLUSIG-treated patients (<1%, 3/449 - grade 3/4). Of
the patients who developed neuropathy, 26% (23/90) 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 ICLUSIG-treated patients.
Retinal toxicities including macular edema, retinal vein occlusion, and
retinal hemorrhage occurred in 2% of ICLUSIG-treated patients.
Conjunctival irritation, corneal erosion or abrasion, dry eye,
conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye
pain occurred in 14% of patients. Visual blurring occurred in 6% of
patients. 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: Serious hemorrhage events including fatalities,
occurred in 6% (28/449) of patients treated with ICLUSIG. Hemorrhage
occurred in 28% (124/449) of patients. The incidence of serious bleeding
events was higher in patients with AP-CML, BP-CML, and Ph+ ALL.
Gastrointestinal hemorrhage and subdural hematoma were the most commonly
reported serious bleeding events occurring in 1% (4/449) each. Most
hemorrhagic events, but not all, occurred in patients with grade 4
thrombocytopenia. Interrupt ICLUSIG for serious or severe hemorrhage and
evaluate.

Fluid Retention: Fluid retention events judged as serious
occurred in 4% (18/449) of patients treated with ICLUSIG. One instance
of brain edema was fatal. For fluid retention events occurring in >2% of
the patients (treatment-emergent), serious cases included: pleural
effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema
peripheral (2/449, <1%).

In total, fluid retention occurred in 31% of the patients. The most
common fluid retention events were peripheral edema (17%), pleural
effusion (8%), pericardial effusion (4%) and peripheral swelling (3%).

Monitor patients for fluid retention and manage patients as clinically
indicated. Interrupt, reduce, or discontinue ICLUSIG as clinically
indicated.

Cardiac Arrhythmias: Arrhythmias occurred in 19%
(86/449) of ICLUSIG-treated patients, of which 7% (33/449) were grade 3
or greater. Arrhythmia of ventricular origin was reported in 3% (3/86)
of all arrhythmias, with one case being grade 3 or greater. Symptomatic
bradyarrhythmias that led to pacemaker implantation occurred in 1%
(3/449) of ICLUSIG-treated patients.

Atrial fibrillation was the most common arrhythmia and occurred in 7%
(31/449) of patients, approximately half of which were grade 3 or 4.
Other grade 3 or 4 arrhythmia events included syncope (9 patients;
2.0%), tachycardia and bradycardia (2 patients 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 (1 patient 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 as an adverse
reaction in 59% (266/449) of ICLUSIG-treated patients and grade 3/4
myelosuppression occurred in 50% (226/449) of patients. The incidence of
these events was greater in patients with AP-CML, 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% (31/449) 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): Postmarketing
cases of reversible posterior leukoencephalopathy syndrome (RPLS—also
known as Posterior Reversible Encephalopathy Syndrome (PRES)) 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
(MRI) 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.

Compromised Wound Healing and Gastrointestinal Perforation: Since
ICLUSIG may compromise wound healing, interrupt ICLUSIG for at least 1
week prior to major surgery. Serious gastrointestinal perforation
(fistula) occurred in one patient 38 days post-cholecystectomy.

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: Overall, 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-T-1POINT (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: ICLUSIG can
cause fetal harm when administered to pregnant women. Advise females to
use effective contraception during treatment with ICLUSIG and for 3
weeks after the last dose. 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 six days after last dose.

For US Prescribing Information: http://www.iclusig.com/pi

About NINLARO™ (ixazomib) capsules

NINLARO™ (ixazomib) is an oral proteasome inhibitor which is being
studied across the continuum of multiple myeloma treatment settings as
well as systemic light-chain (AL) amyloidosis. NINLARO was approved by
the U.S. Food and Drug Administration (FDA) in November 2015 following a
priority review and by the European Commission in November 2016. In the
U.S. and Europe, NINLARO is indicated in combination with lenalidomide
and dexamethasone for the treatment of patients with multiple myeloma
who have received at least one prior therapy. NINLARO is currently
approved in more than 60 countries, including the United States, Japan
and in the European Union, with more than 10 regulatory filings
currently under review. It was the first oral proteasome inhibitor to
enter Phase 3 clinical trials and to receive approval.

Ixazomib was granted orphan drug designation in multiple myeloma in both
the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and
Europe in 2012. Ixazomib received Breakthrough Therapy status by the
U.S. FDA for relapsed or refractory AL amyloidosis, a related ultra
orphan disease, in 2014. The Japanese Ministry of Health, Labour and
Welfare granted Orphan Drug designation to ixazomib in 2016 and granted
SAKIGAKE designation to ixazomib for AL amyloidosis in 2019.

The comprehensive ixazomib clinical development program, TOURMALINE,
includes a total of five ongoing pivotal trials, which together are
investigating major multiple myeloma patient populations, and one in AL
amyloidosis:

  • TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with
    lenalidomide and dexamethasone in relapsed and/or refractory multiple
    myeloma
  • TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with
    lenalidomide and dexamethasone in patients with newly diagnosed
    multiple myeloma
  • TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance
    therapy in patients with newly diagnosed multiple myeloma following
    induction therapy and autologous stem cell transplant (ASCT)
  • TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance
    therapy in patients with newly diagnosed multiple myeloma who have not
    undergone ASCT; this study is currently enrolling
  • TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs.
    physician choice of selected regimens in patients with relapsed or
    refractory AL amyloidosis; this study is currently enrolling

For more information about actively enrolling TOURMALINE studies please
visit: https://www.tourmalinetrials.com/

In addition to the TOURMALINE program, ixazomib is being evaluated in
multiple therapeutic combinations for various patient populations in
investigator initiated studies globally.

NINLARO™ (ixazomib) capsules: Global
Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO (28% vs. 14% in
the NINLARO and placebo regimens, respectively) with platelet nadirs
typically occurring between Days 14-21 of each 28-day cycle and recovery
to baseline by the start of the next cycle. It did not result in an
increase in hemorrhagic events or platelet transfusions. Monitor
platelet counts at least monthly during treatment with NINLARO and
consider more frequent monitoring during the first three cycles. Manage
with dose modifications and platelet transfusions as per standard
medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and
placebo regimens respectively, such as diarrhea (42% vs. 36%),
constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs.
11%), occasionally requiring use of antiemetic and anti-diarrheal
medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the
NINLARO and placebo regimens, respectively). The most commonly reported
reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO
and placebo regimens, respectively). Peripheral motor neuropathy was not
commonly reported in either regimen (< 1%). Monitor patients for
symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25% vs. 18% in
the NINLARO and placebo regimens, respectively). Evaluate patients for
underlying causes and provide supportive care, as necessary. Adjust the
dose of dexamethasone per its prescribing information or the dose of
NINLARO for severe symptoms.

Cutaneous reactions occurred in 19% of patients in the NINLARO
regimen compared to 11% of patients in the placebo regimen. The most
common type of rash reported in both regimens was maculo-papular and
macular rash. Manage rash with supportive care, dose modification or
discontinuation.

Hepatotoxicity, drug-induced liver injury,
hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have
been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly
and adjust dose for Grade 3 or 4 symptoms.

Pregnancy- NINLARO can cause fetal harm. Advise male and females
patients of reproductive potential to use contraceptive measures during
treatment and for an additional 90 days after the final dose of NINLARO.
Women of childbearing potential should avoid becoming pregnant while
taking NINLARO due to potential hazard to the fetus. Women using
hormonal contraceptives should use an additional barrier method of
contraception.

Lactation- It is not known whether NINLARO or its metabolites are
excreted in human milk. There could be potential adverse events in
nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT POPULATIONS

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in
patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting
dose to 3 mg in patients with severe renal impairment or end-stage renal
disease (ESRD) requiring dialysis. NINLARO is not dialyzable and,
therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS

Co-administration of strong CYP3A inducers with NINLARO is not
recommended.

ADVERSE REACTIONS

The most frequently reported adverse reactions (≥ 20%) in the NINLARO
regimen, and greater than in the placebo regimen, were diarrhea (42% vs.
36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%),
peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral
edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs.
16%). Serious adverse reactions reported in ≥ 2% of patients included
thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one
or more of the three drugs was discontinued in ≤ 1% of patients in the
NINLARO regimen.

For European Union Summary of Product Characteristics: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003844/WC500217620.pdf

For US Prescribing Information: https://www.ninlarohcp.com/pdf/prescribing-information.pdf

For Canada Product Monograph: http://www.takedacanada.com/ninlaropm

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. Takeda focuses its R&D efforts on four
therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience and
Rare Diseases. 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 and regions.

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

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