Market Overview

Takeda Showcases Broadened Oncology Portfolio Through Data Presentations at Upcoming Medical Meetings

Share:





Takeda Pharmaceutical Company Limited (TSE:
4502
) today announced that the company will feature new clinical
analyses and outcomes research during three upcoming medical meetings:
the 53rd Annual Meeting of the American Society of Clinical Oncology
(ASCO), June 2-6 in Chicago, the 22nd Congress of the European
Hematology Association (EHA), June 22-25 in Madrid, and the
International Conference on Malignant Lymphoma 2017 (ICML), June 14-17
in Lugano, Switzerland. Presentations at this year's meetings will
highlight Takeda's ongoing commitment to patients with hematologic
cancers, while demonstrating a broadened portfolio with the recent
addition of new targeted therapies and pipeline assets in solid tumors.

"Takeda Oncology's presence at these upcoming medical meetings
demonstrates our relentless pursuit to deliver innovations for patients
with cancer," said Christophe Bianchi, M.D., President, Takeda Oncology.
"The data we are presenting highlight the depth and breadth of our
recently expanded portfolio, now including both hematological
malignancies and solid tumors with the recent approval of ALUNBRIG™
(brigatinib) for metastatic non-small cell lung cancer, and brings us
one step closer to our aspiration to cure cancer."

At ASCO, Takeda will present patient-reported outcomes and quality of
life findings from the pivotal Phase 2 ALTA (ALK in Lung
Cancer Trial of AP26113) trial of ALUNBRIG™,
which recently received Accelerated Approval from the U.S. Food and Drug
Administration for the treatment of patients with anaplastic lymphoma
kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who
have progressed on or are intolerant to crizotinib. Approximately two to
eight percent of patients with metastatic NSCLC have a rearrangement in
the ALK gene. Results from an analysis of the drug's activity in
crizotinib-resistant ALK+ NSCLC patients according to ALK plasma
mutation status will also be featured.

Both ASCO and EHA will feature findings from studies of Takeda medicines
for the treatment of a variety of blood cancers, including lymphoma,
multiple myeloma and chronic myeloid leukemia. Data from the Phase 3
ALCANZA study of ADCETRIS (brentuximab vedotin) in CD30-positive
cutaneous T-cell lymphoma will be presented at both ASCO and EHA.
Several Phase 1 and 2 studies investigating NINLARO (ixazomib) in
patients with newly diagnosed multiple myeloma will be presented at EHA,
including two oral presentations which evaluated ixazomib plus
lenalidomide and dexamethasone followed by maintenance with single-agent
ixazomib. In addition, ASCO and EHA will highlight five-year data from
the Phase 2 PACE trial of ICLUSIG® (ponatinib) in heavily
pretreated chronic phase chronic myeloid leukemia.

Among the nine Takeda-sponsored abstracts accepted for presentation
during ASCO 2017 and 15 abstracts at EHA 2017, selected highlights
include:

ASCO Annual Meeting 2017

ADCETRIS (brentuximab vedotin):

ALUNBRIG (brigatinib):

ICLUSIG (ponatinib):

EHA 22nd Congress

ADCETRIS (brentuximab vedotin):

NINLARO (ixazomib):

ICLUSIG (ponatinib):

For more information, please see ASCO (https://am.asco.org/program)
and EHA (http://www.eha-2017.org/)
online programs. Abstracts for ICML will be released on June 7.

About ADCETRIS® (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 ongoing clinical
trials, including three Phase 3 studies, the ongoing ECHELON-1 trial in
frontline classical Hodgkin lymphoma and the ongoing ECHELON-2 trial in
frontline mature T-cell lymphomas, as well as the completed ALCANZA
trial in cutaneous T-cell lymphoma for which a supplemental BLA is
planned in mid-2017.

ADCETRIS is an 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 for intravenous injection has received approval from the FDA
for three indications: (1) regular approval for the treatment of
patients with classical Hodgkin lymphoma after failure of autologous
hematopoietic stem cell transplantation (auto-HSCT) or after failure of
at least two prior multi-agent chemotherapy regimens in patients who are
not auto-HSCT candidates, (2) regular approval for the treatment of
classical Hodgkin lymphoma patients at high risk of relapse or
progression as post-auto-HSCT consolidation, and (3) accelerated
approval for the treatment of patients with systemic anaplastic large
cell lymphoma (sALCL) after failure of at least one prior multi-agent
chemotherapy regimen. The sALCL indication is approved under accelerated
approval based on overall response rate. Continued approval for the
sALCL indication may be contingent upon verification and description of
clinical benefit in confirmatory trials. Health Canada granted ADCETRIS
approval with conditions for relapsed or refractory Hodgkin lymphoma and
sALCL.

ADCETRIS was granted conditional marketing authorization by the European
Commission in October 2012 for two indications: (1) for the treatment of
adult patients with relapsed or refractory CD30-positive Hodgkin
lymphoma following autologous stem cell transplant (ASCT), or following
at least two prior therapies when ASCT or multi-agent chemotherapy is
not a treatment option, and (2) the treatment of adult patients with
relapsed or refractory sALCL. The European Commission extended the
current conditional marketing authorization of ADCETRIS and approved
ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin
lymphoma at increased risk of relapse or progression following ASCT.

ADCETRIS has received marketing authorization by regulatory authorities
in 66 countries for relapsed or refractory Hodgkin lymphoma and sALCL.
See important safety information below.

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) Global Important Safety Information

CONTRAINDICATIONS

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

SPECIAL WARNINGS & PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): John Cunningham
virus (JCV) reactivation resulting in 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.

Patients should be closely monitored 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. ADCETRIS dosing should be held for
any suspected case of PML and should be permanently discontinued if a
diagnosis of PML is confirmed.

Pancreatitis: Acute pancreatitis has been observed in patients
treated with ADCETRIS. Fatal outcomes have been reported. Patients
should be closely monitored 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. ADCETRIS should be held 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, 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. New or worsening pulmonary
symptoms should be promptly evaluated and treated appropriately.

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.
Patients should be carefully monitored during treatment for emergence of
possible serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as
well as anaphylaxis, have occurred with ADCETRIS. Patients should be
carefully monitored during and after an infusion. If anaphylaxis occurs,
administration of ADCETRIS should be immediately and permanently
discontinued and appropriate medical therapy should be administered. If
an IRR occurs, the infusion should be interrupted and appropriate
medical management instituted. 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. These patients should be monitored closely and managed
according to best medical practice.

Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both
sensory and motor. ADCETRIS-induced PN is typically cumulative and
reversible in most cases. Patients should be monitored for symptoms of
PN, 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. Complete blood
counts should be monitored prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported.
Patients should be monitored closely for fever and managed according to
best medical practice if febrile neutropenia develops.

Stevens-Johnson syndrome (SJS): SJS and toxic epidermal
necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have
been reported. If SJS or TEN occurs, treatment with ADCETRIS should be
discontinued and appropriate medical therapy should be administered.

Gastrointestinal (GI) Complications: GI complications, some with
fatal outcomes, including intestinal obstruction, ileus, enterocolitis,
neutropenic colitis, erosion, ulcer, perforation and haemorragh, have
been reported. New or worsening GI symptoms should be promptly evaluated
and treated appropriately.

Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) have been reported. Serious cases of
hepatotoxicity, including fatal outcomes, have also occurred. Liver
function should be tested prior to treatment initiation and routinely
monitored in patients receiving ADCETRIS. 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. However, any patient who experiences an
event of hyperglycemia should have their serum glucose closely
monitored. Anti-diabetic treatment should be administered 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. The recommended
starting dose in patients with hepatic impairment or severe renal
impairment is 1.2 mg/kg administered as an intravenous infusion over 30
minutes every 3 weeks. Patients with renal or hepatic impairment should
be closely monitored for adverse events.

Sodium content in excipients: This medicinal product contains a
maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into
consideration for patients on a controlled sodium diet.

INTERACTIONS
Patients who are receiving a strong CYP3A4 and
P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk
of neutropenia and should be closely monitored. 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: Women of childbearing potential should be using 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. ADCETRIS should not be used during pregnancy
unless the benefit to the mother outweighs the potential risks to the
fetus. If a pregnant woman needs to be treated, she should be clearly
advised on the potential risk 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. Men being
treated with this medicine are advised not to father a child during
treatment and for up to 6 months following the last dose.

ADVERSE REACTIONS
Serious adverse drug reactions were:
pneumonia, acute respiratory distress syndrome, headache, neutropenia,
thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia,
peripheral motor neuropathy, peripheral sensory neuropathy,
hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and
Stevens-Johnson syndrome.

In the clinical studies of ADCETRIS, adverse reactions defined as very
common (≥1/10) were: infection, upper respiratory tract infection,
neutropenia, PN (sensory and motor), cough, dyspneoa, diarrhea, nausea,
vomiting, constipation, abdominal pain, alopecia, pruritus, myalgia,
arthralgia, fatigue, chills, pyrexia, infusion-related reactions and
weight decreased. Adverse reactions defined as common (≥1/100 to <1/10)
were: Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex,
anemia, thrombocytopenia, hyperglycemia, dizziness, demyelinating
polyneuropathy, ALT/AST increased, rash, and back pain.

About NINLAROTM (ixazomib) capsules

NINLAROTM (ixazomib) is an oral proteasome
inhibitor which is also being studied across the continuum of multiple
myeloma treatment settings as well as systemic light-chain (AL)
amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3
clinical trials and to receive approval. NINLARO was approved by the
U.S. Food and Drug Administration (FDA) in November 2015 following a
priority review. In the U.S., 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.

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 systemic light-chain (AL)
amyloidosis in 2014.

The comprehensive ixazomib clinical development program, TOURMALINE,
further reinforces Takeda's ongoing commitment to developing innovative
therapies for people living with multiple myeloma worldwide and the
healthcare professionals who treat them. TOURMALINE includes a total of
five ongoing pivotal trials – four, which together are investigating
every major multiple myeloma patient population, and one in light-chain
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

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

NINLAROTM (ixazomib): 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 ALUNBRIG™ (brigatinib)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD
Pharmaceuticals, Inc., which was acquired by Takeda in February 2017.
ALUNBRIG received Accelerated Approval on April 28th 2017,
from the U.S. Food and Drug Administration (FDA) for the treatment of
patients with anaplastic lymphoma kinase-positive (ALK+) metastatic
non-small cell lung cancer (NSCLC) 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 has also 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 ALTA 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. In addition to the ongoing Phase 1/2 and Phase 2 ALTA trial,
brigatinib is also being studied in the Phase 3 ALTA 1L trial to assess
its efficacy and safety in comparison to crizotinib in patients with
locally advanced or metastatic ALK+ NSCLC who have not received prior
treatment with an ALK inhibitor.

To learn more about ALUNBRIG, please visit www.ALUNBRIG.com or
call ALUNBRIG 1POINT at 1-844-A1POINT (1-844-217-6468).

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

IMPORTANT SAFETY INFORMATION (US)

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: Advise lactating women not to breastfeed during
treatment with ALUNBRIG and for 1 week following the final dose.

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.

For US Prescribing Information: https://www.alunbrig.com/assets/pi.pdf

About ICLUSIG® (ponatinib) tablets

Iclusig is a kinase inhibitor. The primary target for Iclusig is
BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic
myeloid leukemia (CML) and Philadelphia-chromosome positive acute
lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD's
computational and structure-based drug-design platform specifically to
inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL
but also its isoforms that carry mutations that confer resistance to
treatment, including the T315I mutation, which has been associated with
resistance to other approved TKIs. Iclusig is approved in the U.S., EU,
Australia, Switzerland, Israel, Canada and Japan.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

  • Treatment of adult patients with chronic phase, accelerated phase, or
    blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome
    positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other
    tyrosine kinase inhibitor (TKI) therapy is indicated.
  • Treatment of adult patients with T315I-positive chronic myeloid
    leukemia (chronic phase, accelerated phase, or blast phase) or
    T315I-positive Ph+ ALL.

Limitations of use:

Iclusig is not indicated and is not recommended for the treatment of
patients with newly diagnosed chronic phase CML.

IMPORTANT SAFETY INFORMATION

Based on the Phase 2 48-month follow-up analysis (N=449), except where
noted

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, fatigue, hypertension,
pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting,
myalgia and pain in extremity. Hematologic adverse reactions included
thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

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 Takeda

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.

View Comments and Join the Discussion!
 

Partner Center