On April 6, 2015 ARIAD Pharmaceuticals reported that Health Canada has approved the use of Iclusig (as ponatinib hydrochloride) in Canada for the treatment of adult patients with all phases of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive, or where there is prior TKI resistance or intolerance (Press release, Ariad, APR 6, 2015, View Source [SID:1234502927]).

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"Patients with CML or Ph+ ALL can become resistant to their therapies over time," said Professor Jeffrey Lipton, Ph.D., M.D., staff physician at The Princess Margaret Cancer Centre and one of the PACE trial investigators. "Iclusig will be a valuable new therapeutic option in Canada for patients with refractory CML and Ph+ ALL, where we have a proven unmet medical need."

Iclusig is approved under the Notice of Compliance with Conditions (NOC/c) policy based on promising evidence of clinical effectiveness following review by Health Canada. Products approved under this policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness, and have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, these products either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies.

"Throughout the development of Iclusig, we have worked closely with leading academic centers and clinical investigators in Canada. Iclusig is the only TKI that has been approved in Canada for indications that include CML and Ph+ ALL patients with the T315I mutation," stated Harvey J. Berger, M.D., chairman and chief executive officer of ARIAD. "We will strive to make Iclusig available as quickly as possible to appropriate patients with Ph+ leukemias throughout Canada."

Iclusig will be made available through a controlled distribution program. Under this program, prescribers who have completed the certification procedure are able to prescribe Iclusig. Trained pharmacies will verify the prescriber’s certified status prior to dispensing Iclusig to the patient.

"Iclusig provides a new treatment option for patients with difficult-to-treat CML or Ph+ ALL who previously had limited therapies available to them," said Cheryl-Anne Simoneau, president and chief executive officer at the Chronic Myelogenous Leukemia Society of Canada. "For appropriate patients, this can be an important new treatment option."

The Health Canada decision was based on two-year data from the pivotal Phase 2 PACE trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation of BCR-ABL. Iclusig demonstrated anti-leukemic activity, achieving a major cytogenetic response (MCyR) in 56 percent of chronic-phase CML patients and in 70 percent of patients with the T315I mutation. MCyR within the first 12 months of treatment was the primary endpoint of the PACE trial for chronic-phase patients.

In patients with advanced disease, 57 percent of accelerated-phase CML patients and 31 percent of blast-phase CML patients achieved a major hematologic response (MaHR) with Iclusig. MaHR within the first 6 months was the primary endpoint in the trial for patients with advanced disease. In patients with Ph+ ALL, 41 percent achieved MaHR.

ARIAD’s upcoming dose-ranging trial to evaluate three starting doses of Iclusig in patients with refractory, chronic-phase CML who are resistant to at least two approved TKIs — planned to begin in mid-2015 — will serve as the confirmatory trial for the Health Canada approval.

About CML and Ph+ ALL

CML is a cancer of the white blood cells that according to the Chronic Myelogenous Leukemia Society of Canada affects 1 in 100,000, with about 5,500 Canadians living with the disease. In 2010, more than 550 people in Canada were expected to be diagnosed with CML, and 480 people were expected to be diagnosed with ALL.

CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to the more aggressive phases referred to as accelerated phase and blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and TKIs. The BCR-ABL protein is expressed in both of these diseases.

About Iclusig (as ponatinib hydrochloride)

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.

Indications

ICLUSIG is 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 other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL that is T315I mutation positive or where there is prior TKI resistance or intolerance.

Marketing authorization with conditions is based on response rate. There are no trials demonstrating increased survival or improvement in symptoms with ICLUSIG. In the pivotal trial, the majority of the hematological responses occurred within 1 month. Consider discontinuing ICLUSIG if a hematological response has not been achieved by 3 months (90 days).

ICLUSIG for this indication has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the conditional nature of the authorization.

Contraindications

Do not use in patients who are hypersensitive to ponatinib or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
Do not use in patients who have unmanaged cardiovascular risk factors, including uncontrolled hypertension. Hypertension may contribute to the risk of arterial thrombotic events. Blood pressure should be monitored and managed to avoid hypertension.
Do not use in patients who are not adequately hydrated and with uncorrected high uric acid levels.

Serious Warnings and Precautions

Iclusig has serious warnings and precautions for: vascular occlusion, heart failure, hemorrhage, hepatotoxicity, myelosuppression, and pancreatitis.

ICLUSIG should only be prescribed and monitored by a physician who has completed the certification with the ICLUSIG Controlled Distribution Program and who is experienced in the use of antineoplastic therapy and in the treatment of CML or Ph+ ALL.

Vascular Occlusion (arterial and venous thrombosis and occlusions), occurred in 24% (129/530) of ICLUSIG-treated patients with and without cardiovascular risk factors (including patients less than 50 years old). In clinical trials, serious treatment-emergent arterial thrombosis (cardiovascular, cerebrovascular, and peripheral vascular) and occlusions were seen in 14% of the ICLUSIG-treated patients including fatal myocardial infarction, fatal cerebral infarction, stroke, disseminated intravascular coagulation, and arterial stenosis sometimes requiring urgent revascularization procedures. Some of these events occurred within 2 weeks of starting treatment with ICLUSIG. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or consider discontinuation in patients who develop arterial thrombotic events.
Heart Failure (in some cases, fatal), including left ventricular dysfunction and ejection fraction decreases, occurred in 8% of ICLUSIG-treated patients, 5% of which were serious.
Hemorrhage events (some fatal) including intracranial hemorrhage, hemorrhagic gastritis, (fatal), hemorrhagic cerebral infarction (fatal). Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia.
Hepatotoxicity (including fatal acute hepatic failure) has been reported. Monitor hepatic function prior to and during treatment. Consider ICLUSIG dose interruption followed by dose reduction or discontinuation in patients with hepatotoxicity.
Myelosuppression (thrombocytopenia, neutropenia, and anemia).
Pancreatitis (7%) and elevations in amylase (2% grade 3 or greater) or lipase (12% grade 3 or greater) have been reported.

ICLUSIG has not been studied in patients with renal impairment.

Most Common Adverse Reactions

Overall, the very common adverse reactions (≥ 10%) were platelet count decreased, rash, dry skin, abdominal pain, neutrophil count decreased, headache, lipase increased, fatigue, constipation, myalgia, arthralgia, nausea, anemia, ALT increased, hypertension, and AST increased.