Regulatory Decision Summary for ICLUSIG

Based on the efficacy and safety data provided in the submission and the additional risk mitigation measures to be put in place, the Iclusig benefit-risk profile is deemed favorable under the market authorized conditions of use as follows:

• Iclusig (as ponatinib hydrochloride) is indicated for the treatment of adult patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) 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 a response rate endpoint (CP-CML: major cytogenetic response [MCyR] rate; AP-CML, BP-CML, Ph+ ALL: major hematologic response [MaHR] 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 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.

Iclusig is a TKI which inhibits native Bcr Abl and many mutated forms of the Bcr Abl protein, including T315I that confers resistance to the currently market authorized Bcr-Abl TKIs. Iclusig acts by targeting several proteins on the surface of cancer cells, as well as targets within the cell. By blocking these target signals, Iclusig inhibits the viability of abnormal white blood cells.

Iclusig has been shown to be efficacious in CML and Ph+ALL patients for whom other TKI therapy is not appropriate. The market authorization with conditions was based primarily on a Phase II study (AP24534 10 201), also known as the PACE study. This study was a single arm, open label, international, multicentre study conducted in CML and Ph+ALL patients resistant or intolerant to treatment with either dasatinib or nilotinib, or with the T315I mutation. In this study, the primary efficacy endpoint for CP-CML patients was a major cytogenetic response (MCyR), which included complete cytogenetic responses (CCyR) and partial cytogenetic responses (PCyR). The primary efficacy endpoint for the AP-CML and BP-CML/Ph+ ALL patient cohorts was a major hematologic response (MaHR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). Results from the PACE study demonstrated that 55.8% of CP CML patients achieved MCyR by 12 months, 56.6% of AP CML patients achieved MaHR by 6 months, and 34.0% of BP CML/Ph+ALL patients achieved MaHR by 6 months.

A serious risk associated with Iclusig treatment is vascular occlusion (arterial and venous thrombosis and occlusions) in patients with and without cardiovascular risk factors. A post-hoc multivariate analysis of safety data suggests that reducing the average daily dose from 45 mg to 30 mg or 15 mg for CP CML patients who have achieved MCyR can reduce the risk of arterial thrombotic and occlusive events. This analysis is considered exploratory; confirmatory data are expected from a future Phase II study AP23534 14 203 in resistant CP CML patients with different starting doses of Iclusig.

The most common serious adverse drug reactions reported with Iclusig treatment were arterial ischemic events (cardiovascular, cerebrovascular and peripheral vascular), cardiac failure, effusion, atrial fibrillation, venous thromboembolism, dyspnea, pancreatitis, abdominal pain, platelet count decreased, lipase increased, anemia, diarrhea, neutrophil count decreased, febrile neutropenia, pancytopenia, and pyrexia.

As part of the conditions under the NOC/c Guidance, additional data will be assessed when the final clinical study report for the pivotal PACE study is provided. In addition, further data will also be evaluated when the final clinical study report for the confirmatory study AP24534 14 203 is received.

Overall, the therapeutic benefits seen in the pivotal study are promising and the benefit of Iclusig therapy is considered to outweigh the risks. Iclusig has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through stringent labelling and close monitoring. Appropriate warnings and precautions are in place in the Iclusig Product Monograph to address the identified safety concerns. Additionally, a Controlled Distribution Program will be instituted, consisting of mandatory prescriber certification to educate and update prescribers about the serious risks associated with Iclusig therapy and a patient informed consent process to ensure patients understand the risks. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Iclusig will be ongoing. Further evaluation will take place upon the submission of the requested studies once they become available.

For more information on Health Canadas decision, please view the Summary Basis of Decision.