The Phase 3 trial of ICLUSIG® (ponatinib) for the treatment of newly diagnosed Ph+ ALL met the primary endpoint, and no targeted agents have been approved in the US for these patients

Takeda (TSE: 4502/NYSE:TAK) today announced that the PhALLCON randomized Phase 3 trial met its primary endpoint and showed that adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who received ICLUSIG^® (ponatinib) combined with low-intensity chemotherapy had a higher rate of minimal residual disease (MRD)-negative complete response (CR) than
。 As reported in the literature, MRD negative is associated with
improved long-term outcomes in patients.
ICLUSIG is the only pan-mutant and third-generation tyrosine kinase inhibitor (TKI) that targets BCR::ABL1 and all known single drug-resistant mutations, including the most resistant T315I mutation
.

Awny Farajallah, MD, Global Medical Affairs Officer, Takeda Oncology, said: "Ph+ ALL is a rapidly progressive disease for which no targeted agents have been approved for first-line treatment in the United States, so there is an urgent need for an effective treatment that can inhibit the progression of refractory mutations associated with
poor long-term outcomes.
We are pleased to see that ICLUSIG has the potential to fill this gap in the treatment of these patients and look forward to sharing the findings
.
" ”

The PhALLCON study is an international multicenter randomized, open-label Phase 3 trial designed to evaluate the efficacy and safety
of ICLUSIG in combination with low-intensity chemotherapy versus imatinib for first-line therapy in adults with newly diagnosed Ph+ ALL.
No new safety signals
were observed in this trial.
The trial data will be discussed with regulators and shared
with the scientific community in the future.

About Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) Ph
+ ALL is a rare type of ALL that affects about 25% of adult ALL patients in the United States and is characterized by the presence of an abnormal gene
called the Philadelphia chromosome.
In Philadelphia chromosome-positive (Ph+) patients, fragments of chromosome 9 and chromosome 22 are swapped to form an abnormal chromosome
.
This interchange causes chromosome 9 to become longer and chromosome 22 to become shorter, resulting in the formation of BCR::ABL1, which is associated with
Ph+ ALL.

About ICLUSIG (ponatinib) tablets
ICLUSIG^® is a kinase inhibitor that targets BCR-ABL1, an abnormal tyrosine kinase
expressed in CML and Ph+ ALL.
ICLUSIG is a targeted anticancer drug designed using a computational and structure-based drug design platform to specifically inhibit the activity
of BCR ABL1 and its mutations.
ICLUSIG inhibits the bulk BCR ABL1 while inhibiting all BCR ABL1 therapeutic resistance mutations, including the most resistant T315I mutation
.
ICLUSIG received full FDA approval
in November 2016.
ICLUSIG is indicated for the treatment of adults with chronic phase (CP) CML, accelerated phase (AP) or blast phase (BP) CML or any other kinase inhibitor who are not suitable for at least 2 previous kinase inhibitors, and adults with T315I+ CML (CP, AP or BP) or T315I-positive Ph+ ALL
.
ICLUSIG is not suitable and is not recommended for the treatment of patients with
newly diagnosed CP-CML.

Important security information

Warnings and precautions

Arterial occlusive events (AOE): AOE occurs in both OPTIC and PACE patients, including fatal cases
, in patients treated with ICLUSIG.
These events include cardiovascular, cerebrovascular, and peripheral vascular events
.
In 94 patients with OPTIC (45 mg to > 15 mg), the incidence of AOE was 14%; 6% is 3 or 4 degrees
.
Among the 449 patients with PACE, the incidence of AOE was 26%; Grade 3 or 4 in 14% of patients
.
The incidence of fatal AOE was 2.
1% in OPTIC and 2%
in PACE.
Some patients with PACE develop recurrent or multisite vaso-occlusion
.
These events
occur in patients with or without cardiovascular risk factors, including those aged 50 years or younger.
In PACE, the most common risk factors observed in these events were hypertension, hypercholesterolemia, and a history
of non-ischaemic heart disease.
In OPT and PACE, AOE is more common in older people
.

OPTIC excludes patients with hypertension or uncontrolled diabetes and those with clinically significant, uncontrolled, or active cardiovascular disease
.
PACE excludes patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within 3 months prior to the first administration of ICLUSIG
.
ICLUSIG's expected benefits should be weighed against whether the risks outweigh the risks
.

Patients should be monitored for AOE
.
ICLUSIG should be suspended, followed by reuse or discontinuation
in equal or reduced amounts, depending on recurrence/severity.
When deciding whether to restart ICLUSIG, the return-risk ratio
should be weighed.

Venous thromboembolic event (VTE): patients receiving ICLUSIG have severe or severe VTE
.
Among the 449 patients with PACE, the incidence of VTE was 6%, and severe or severe (grade 3 or 4) VTE was 5.
8%.

VTE includes deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with blindness
.
Patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients) had higher
incidences.
Of the 94 patients with OPTIC, 1 developed VTE (1st degree retinal vein occlusion).

Patients should be monitored for VTE
.
ICLUSIG should be suspended, followed by reuse or discontinuation
in equal or reduced amounts, depending on recurrence/severity.

Heart failure: patients receiving ICLUSIG have had a severe or severe heart failure event
.
Of the 449 patients with PACE, the incidence of heart failure was 9%; 7%
for severe or severe (3 degrees or more).
In 94 patients with OPTIC, the incidence of heart failure was 13%; Severe or severe (3rd or 4th degree) was 1.
1%.

The most common (≥2%) heart failure events in PACE were congestive heart failure (3.
1%), decreased ejection fraction (2.
9%), and heart failure (2%)
.
The most commonly reported heart failure events in OPTIC (1 patient > each group) were left ventricular hypertrophy (3.
2%) and elevated BNP (3.
2%)
.
Patients should be monitored for signs or symptoms consistent with heart failure and treated clinically indicated
.
ICLUSIG should be suspended first, followed by tapering or discontinuation
depending on whether there is a new or worsening of heart failure.

Hepatotoxicity: ICLUSIG can cause liver toxicity, including liver failure and death
.
Three patients developed explosive liver failure, resulting in death, and one of them developed liver failure
within 1 week of ICLUSIG activation.
These fatal cases occur in patients
with BP-CML or Ph+ ALL.
The incidence of hepatotoxicity was 28% in 94 patients with OPTIC and 32%
in 449 patients with PACE.
Both OPTIC (6% of 94 patients) and PACE (13% of 449 patients) had grade 3 or 4 hepatotoxicity
.
The most common hepatotoxic events are elevated ALT, AST, GGT, bilirubin, and alkaline phosphatase
.
Baseline liver function should be monitored, followed by at least monthly or clinical
indications.
ICLUSIG should be suspended and then reduced or discontinued
depending on relapse/severity.

Hypertension: patients receiving ICLUSIG have developed severe or severe hypertension, including hypertensive crisis
.
Hypertension with confusion, headache, chest pain, or shortness of breath may require urgent clinical intervention
.
Baseline hypertension should be monitored, followed by clinical indications and treatment of hypertension
.
If hypertension cannot be controlled with medication, ICLUSIG
should be suspended, reduced, or discontinued.
If hypertension is significantly worsening, unstable, or refractory, ICLUSIG should be withheld and evaluation for renal artery stenosis
considered.

Pancreatitis: patients receiving ICLUSIG have developed severe or severe pancreatitis
.
Lipase and amylase elevations
may also occur.
In most cases, drug reduction or discontinuation occurs, and pancreatitis resolves within
2 weeks.
Serum lipase should be checked every 2 weeks for the first 2 months, followed monthly or clinically indicated
.
Patients with a history of pancreatitis or alcohol abuse should consider additional serum lipase monitoring
.
ICLUSIG should be suspended and then reused or discontinued
in equal or reduced amounts, depending on severity.
If lipase is elevated with abdominal symptoms, the patient should be evaluated for pancreatitis
.

Increased toxicity in newly diagnosed chronic-phase CML: Prospective randomized clinical trials of first-line therapy in patients with newly diagnosed CP-CML showed that the risk of serious adverse effects was twice as high as that of imatinib 400 mg once daily alone
.
The median treatment exposure period was less than 6 months
.
The trial was discontinued
due to safety concerns.
The incidence of arteriovenous thrombosis and obstruction was at least 2 times higher in
the ICLUSIG group than in the imatinib group.
The following rates were higher in patients treated with ICLUSIG than in the imatinib-treated group: bone marrow suppression, pancreatitis, hepatotoxicity, heart failure, hypertension, and skin and subcutaneous tissue disorders
.
ICLUSIG is not suitable and is not recommended for the treatment of patients with
newly diagnosed CP-CML.

Neuropathy: patients with both OPTIC and PACE have peripheral and cranial neuropathy
.
In PACE, some of these events are 3 or 4 degrees
.
Patients should be monitored for neuropathy symptoms such as dysesthesia, hyperesthesia, paresthesia, malaise, burning, neuropathy pain, or weakness
.
ICLUSIG should be suspended, followed by reuse or discontinuation
in equal or reduced amounts, depending on recurrence/severity.

Ocular toxicity: patients treated with ICLUSIG develop severe or severe ocular toxicity
that results in blindness or blurred vision.
The most common ocular toxicities in OPTIC and PACE are dry eyes, blurred vision, and eye pain
.
Retinal toxicity includes age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floating
.
Comprehensive ophthalmologic examinations
should be performed at baseline and at regular intervals during treatment.

Bleeding: fatal and severe bleeding
occurred in patients receiving ICLUSIG.
Fatal bleeding occurred in PACE and severe bleeding
occurred in OPTIC and PACE.
In PACE, patients with AP-CML, BP-CML, and Ph+ ALL had a higher
rate of major bleeding events.
Gastrointestinal bleeding and subdural haematomas are the most commonly reported serious bleeding events
.
Events are common in patients
with grade 4 thrombocytopenia.
Patients should be monitored for bleeding and treated as clinically indicated
.
ICLUSIG should be suspended, followed by reuse or discontinuation
in equal or reduced amounts, depending on recurrence/severity.

Fluid retention: patients receiving ICLUSIG have had fatal and severe fluid retention
.
One case of cerebral edema in PACE was fatal, and serious events included pleural effusion, pericardial effusion, and angioedema
.
Patients should be monitored for fluid retention and treated as clinically indicated
.
ICLUSIG should be suspended, followed by reuse or discontinuation
in equal or reduced amounts, depending on recurrence/severity.

Arrhythmias: Arrhythmias occur in both OPTIC and PACE patients, including ventricular and atrial arrhythmias
.
Some patients had severe or severe events (grade 3 or 4), resulting in hospitalisation
.
Patients should be monitored for signs and symptoms suggestive of bradycardia (fainting, dizziness) or rapid heart rate (chest pain, palpitations, or dizziness) and treated as clinically indicated
.
ICLUSIG should be suspended, followed by reuse or discontinuation
in equal or reduced amounts, depending on recurrence/severity.

Myelosuppression: patients with both OPTIC and PACE develop grade 3 or 4 neutropenia, thrombocytopenia, and anemia
.
Patients with AP-CML, BP-CML, Ph+ ALL have a higher incidence of myelosuppression than patients
with CP-CML.
Complete blood counts should be checked every 2 weeks for the first 3 months, followed by monthly or clinically indicated
.
If ANC is less than 1 x 10 9/L or platelets are less than 50 x 10 9/L, ICLUSIG should be suspended until ANC is at least 1.
5 x 10 9/L and platelets are at least 75 x 10 ⁹/L, followed by equal or reduced reuse
.

Tumor lysis syndrome (TLS): severe TLS has been reported
in both OPTIC and PACE patients.
Before initiating ICLUSIG therapy, adequate hydration should be ensured and high uric acid levels
should be managed.

Posterior reversible leukoencephalopathy syndrome (RPLS): RPLS (aka posterior reversible encephalopathy syndrome) has been reported
in patients receiving ICLUSIG.
Patients may present with neurologic signs and symptoms, visual disturbances, and hypertension
.
Diagnosis
is based on supportive findings from magnetic resonance imaging (MRI) of the brain.
ICLUSIG should be suspended until remission
.
The safety of multiplexing ICLUSIG after RPLS mitigation is unknown
.

Impaired wound healing and gastrointestinal perforation: patients receiving ICLUSIG developed impaired
wound healing.
ICLUSIG
should be withheld at least 1 week before elective surgery.
It should not be administered
for at least 2 weeks after major surgery and until the wound has healed adequately.
The safety of restarting ICLUSIG after resolution of wound healing complications is unclear
.
Patients receiving ICLUSIG have developed gastrointestinal perforation or fistula
.
Patients with gastrointestinal perforation should be permanently discontinued
.

Embryo-fetal toxicity: According to its mechanism of action and animal studies, ICLUSIG in pregnant women can harm the fetus
.
Pregnant women should be informed of the potential risk
to the fetus of the drug.
Women of childbearing age should use effective contraception
during ICLUSIG treatment and for 3 weeks after the last dose.

The most common (>20%) adverse reactions
were rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, fever, nausea, pancreatitis/lipase elevation, bleeding, anemia, liver dysfunction, and AOE
.
The most common (>20%) grade 3 or 4 laboratory abnormalities are low platelet count, low neutrophil count, and leukopenia
.

To report suspected adverse reactions, call Takeda Pharmaceutical Corporation at 1-844-817-6468 or FDA at 1-800-FDA-1088 or visit www.
fda.
gov/medwatch
.

Strong inhibitors of drug interactions
CYP3A: concomitant medications should be avoided, and ICLUSIG should be reduced if concomitant medications cannot be avoided
.

CYP3A strong inducer: avoid concomitant use
.

Breastfeeding in special populations: women are advised to avoid lactation
during ICLUSIG treatment and for 6 days after the last dose.

Men and women of childbearing age: women of childbearing age should verify pregnancy status
before initiating ICLUSIG.

Ponatinib may impair female fertility, and whether such effects are reversible is unknown
.

Underlying hepatic impairment: the starting dose of ICLUSIG should be reduced to 30 mg orally once daily in patients with impaired basal function, as patients with impaired underlying liver function are more likely to experience adverse effects
than patients with normal liver function.

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