Summary Basis of Decision for Iclusig

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug
Contact: Bureau of Metabolism, Oncology, and Reproductive Science

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Iclusig is located below.

Recent Activity for Iclusig

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Iclusig

Updated: 2024-05-07

The following table describes post-authorization activity for Iclusig, a product which contains the medicinal ingredient ponatinib (supplied as ponatinib hydrochloride). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Drug Identification Numbers (DINs):

 

DIN 02437333 - 15 mg ponatinib (supplied as ponatinib hydrochloride), tablet, oral administration

DIN 02437341 - 45 mg ponatinib (supplied as ponatinib hydrochloride), tablet, oral administration

 

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 277221

2023-07-14

Issued NOC 2023-10-04

Submission filed as a Level I – Supplement for labelling updates to remove references to the Iclusig Controlled Distribution Program. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box; Indications; and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert and inner and outer labels. An NOC was issued.

Drug product (DIN 02437333) market notification

Not applicable

Date of first sale: 2023-06-29

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

SNDS-C # 258641

2021-11-15

Issued NOC 2022-10-03

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c) for NDS # 165121, issued 2015-04-02, and to migrate the PM to the 2020 format. The submission also requested the removal of the conditions from the NOC based on the included safety and efficacy data from two confirmatory studies (Study 201 PACE and Study 203 OPTIC). The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC.

DIN 02437341 reported as dormant

Not applicable

2022-08-08

The manufacturer reported the DIN as dormant as per section C.01.014.71 and subsection C.01.014.5(1)(a)(ii) of the Food and Drug Regulations.

NDS # 265711

2022-06-29

Issued NOC 2022-08-08

Submission filed to change the name of the drug sponsor from ARIAD Pharmaceuticals, Inc. to Takeda Pharmaceuticals U.S.A., Inc. An NOC was issued.

PBRER-C # 261667

2022-02-18

Filed 2022-07-27

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C #12 for the period 2020-12-14 to 2021-12-13. The information was reviewed and found acceptable.

DIN 02437341 reported as dormant

Not applicable

2022-01-20

The manufacturer reported the DIN as dormant as per section C.01.014.71 and subsection C.01.014.5(1)(a)(ii) of the Food and Drug Regulations.

PSUR-C # 249733

2021-02-19

Filed 2021-10-08

Submission filed in response to commitments made as per the provisions of the of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C #11 for the period 2019-12-14 to 2020-12-13. The information was reviewed and found acceptable.

PSUR-C # 236366

2020-02-21

Filed 2020-09-03

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C #10 for the period 2018-12-14 to 2019-12-13. The information was reviewed and found acceptable.

PSUR-C # 218658

2019-02-19

Filed 2020-01-30

Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PSUR-C #9 for the period 2017-12-14 to 2018-12-13. The information was reviewed and found acceptable.

SNDS # 226913

2019-06-14

Issued NOC under NOC/c Guidance

2019-08-16

Submission filed as a Level I – Supplement to update the PM. The changes were in response to an Advisement Letter issued by Health Canada dated 2019-04-08 requesting new safety information about the risk of artery dissection and artery aneurysm vascular with endothelial growth factor receptor tyrosine kinase inhibitors. Revisions were made to the Serious Warnings and Precautions Box, Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III Patient Medication Information. The submission was reviewed and considered acceptable, and an NOC under NOC/c Guidance was issued.

SNDS # 225728

2019-05-06

Issued NOC under NOC/c Guidance

2019-06-21

Submission filed as a Level I – Supplement to revise the package insert to meet the Plain Language Labelling requirements. The package insert was reviewed and considered acceptable, and an NOC was issued

SNDS # 212521

2018-01-09

Issued NOC under NOC/c Guidance

2018-12-12

Submission filed as a Level I – Supplement to provide a safety and efficacy update to the PM based on longer term follow up of patients in the pivotal trial. As a result of the submission, the following sections of the PM were updated: Serious Warnings and Precautions Box, Warnings and Precautions, Adverse Reactions, and Dosage and Administration, sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The benefit/risk profile for Iclusig remains positive when used for its approved indication. The submission was reviewed and considered acceptable, and an NOC under NOC/c Guidance was issued.

Summary Safety Review posted

Not applicable

Posted

2018-12-03

 

Summary Safety Review posted for vascular endothelial growth factor receptor tyrosine kinase inhibitors.

PSUR-C # 213869

2018-02-20

Filed

2018-07-17

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C #8 for the period 2016-12-14 to 2017-12-13. No further action was required.

New safety review started by Health Canada

Not applicable

Started between 2017-11-01 and 2017-11-30

Health Canada started a safety review for vascular endothelial growth factor (VEGF) receptor inhibitors between 2017-11-01 and 2017-11-30.

SNDS # 212407

2018-01-05

Issued NOC 2018-03-08

Submission filed as a Level I – Supplement to introduce a carton label and update the manufacturer contact information. The submission was reviewed and considered acceptable, and an NOC was issued.

PSUR-C # 202990

2017-02-17

Filed 2018-01-09

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C #7 for the period 2016-06-14 to 2016-12-13. No further action was required.

PSUR-C # 198086

2016-08-31

Filed 2018-01-08

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PSUR-C #5 for the period 2015-06-14 to 2015-12-13, and #6 for the period 2015-12-14 to 2016-06-13. No further action was required.

NC # 199527

2016/10/21

Issued No Objection Letter 2017/02/23

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information.

As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.

PBRER-C # 192489

2016/02/22

Filed

2016/08/12

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #5 for the period 2015/06/14 to 2015/12/13. The information was reviewed and found acceptable.

PSUR-C # 188123

2015/09/29

Filed

2016/08/12

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance: PSUR-C #3 for the period 2014/06/14 to 2014/12/13 and PSUR-C #4 for the period 2014/12/14 to 2015/06/13. The information was reviewed and found acceptable.

NC # 191981

2016/02/04

Issued No Objection Letter 2016/05/18

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information.

As a result of the NC, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.

Advisory posted

Not applicable

Posted: 2016/05/04

Advisory posted on the Healthy Canadians website, containing important safety information for the general public and healthcare professionals.

Drug product (DIN 02437341) market notification

Not applicable

Date of first sale: 2016/01/07

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02437333) market notification

Not applicable

Date of first sale: 2015/08/21

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 165121

2013/05/23

Issued NOC under the NOC/c Guidance 2015/04/02

Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance. issued for New Drug Submission.
Summary Basis of Decision (SBD) for Iclusig

Date SBD issued: 2015-07-02

The following information relates to the New Drug Submission for Iclusig.

Ponatinib (supplied as ponatinib hydrochloride)
15 mg and 45 mg, tablets, oral

Drug Identification Number (DIN):

  • DIN 02437333 - 15 mg, tablet
  • DIN 02437341 - 45 mg, tablet

ARIAD Pharmaceuticals, Inc.

New Drug Submission Control Number: 165121

 

On April 2, 2015, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to ARIAD Pharmaceuticals, Inc. for the drug product Iclusig. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Iclusig is favourable 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 (T)hreonine-315-(I)soleucine (T315I) mutation positive or where there is prior TKI resistance or intolerance.

Marketing authorization with conditions is based on a response rate endpoint. For chronic phase CML (CP-CML) patients, the response rate endpoint was that of a major cytogenetic response (MCyR). For AP-CML, BP-CML, and Ph+ALL patients, the response rate endpoint was that of a major hematologic response (MaHR). Note, there are no current studies which demonstrate increased survival or improvement in symptoms with use of Iclusig.

The market authorization with conditions is also based on the pending results of ongoing studies to verify its clinical benefit. Patients should be advised of the nature of the authorization.

 

1 What was approved?

 

Iclusig, a protein-tyrosine kinase inhibitor, was authorized 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 (T)hreonine-315-(I)soleucine (T315I) mutation positive or where there is prior TKI resistance or intolerance.

Market authorization with conditions is based on a response rate endpoint. There are no studies demonstrating increased survival or improvement in symptoms with Iclusig. In the pivotal study, the majority of the hematological responses occurred within one month. Consider discontinuing Iclusig if a hematological response has not been achieved by three 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.

Iclusig is only available through a controlled program referred to as the Iclusig Controlled Distribution Program. Under this program, only prescribers who have completed the certification and are registered with the program are able to prescribe Iclusig. In addition, trained pharmacists will verify the prescriber’s certified status prior to dispensing Iclusig to the patient.

Elderly patients (≥65 years of age) with chronic phase CML (CP-CML) are more likely to experience adverse reactions when compared to patients less than 65 years of age. Evidence from clinical assessments suggests that use in the geriatric population (with CP-CML) is associated with reduced safety and effectiveness. For further information, refer to the Warnings and Precautions section of the Iclusig Product Monograph.

The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

Iclusig is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Iclusig is also contraindicated for patients who have unmanaged cardiovascular risk factors, including uncontrolled hypertension. In addition, Iclusig is contraindicated in patients who are not adequately hydrated and with uncorrected high uric acid levels. Iclusig was approved for use under the conditions stated in the Iclusig Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Iclusig (15 mg and 45 mg ponatinib, as ponatinib hydrochloride) is presented as a tablet. In addition to the medicinal ingredient, the tablet also contains the following non-medicinal ingredients: colloidal anhydrous silica, lactose monohydrate, polyethylene glycol, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, sodium starch glycolate, talc, and titanium dioxide.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Iclusig Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Iclusig approved?

 

Health Canada considers that the benefit/risk profile of Iclusig is favourable 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 (T)hreonine-315-(I)soleucine (T315I) mutation positive or where there is prior TKI resistance or intolerance.

Market authorization with conditions is based on a response rate endpoint. There are no studies demonstrating increased survival or improvement in symptoms with Iclusig. In the pivotal Phase II study (Study AP24534-10-201), the majority of the hematological responses occurred within one month. One should consider discontinuing Iclusig if a hematological response has not been achieved by three months (90 days).

Iclusig was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Chronic myeloid leukemia is a life-threatening hematopoietic stem cell disease characterized by a proliferation of granulocytes and their immature myeloid precursors including blast cells. The disease is causally linked to a characteristic cytogenetic abnormality resulting from a reciprocal switching of the long arms of chromosomes 9 and 22, referred to as a ‘translocation’. As a result, part of the breakpoint cluster region (‘Bcr’) gene from chromosome 22 becomes linked to the Abelson (‘Abl’) gene from chromosome 9. The result of this translocation is the abnormal fusion gene referred to as ‘Bcr-Abl’ which is located on a shorter version of chromosome 22. The shortened chromosome 22 is usually known as the ‘Philadelphia chromosome’ (Ph). Generally, most people with CML have the Philadelphia chromosome.

Untreated CML commonly progresses through three phases: chronic phase (CP), accelerated phase (AP), and blast phase (BP). The majority of patients are diagnosed in the chronic phase, which can last approximately three to five years if left untreated. The disease then progresses, often through the AP, followed by terminal BP. In BP, the average survival is two to four months, given that this stage of disease is often refractory to treatment.

Acute lymphoblastic leukemia (ALL) is also a life-threatening disease characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. Most cases of ALL show chromosomal and genetic abnormalities such as the ‘Bcr-Abl’ translocation [for example (e.g.) Philadelphia chromosome]. These cases are commonly referred to as Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). The average overall survival of Ph+ALL is four and a half to six months, and the five year overall survival rate is 3-10% among ALL patients who relapse.

In Canada, currently marketed authorized Bcr-Abl tyrosine kinase inhibitors include imatinib, dasatinib, nilotinib, and bosutinib.

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.

The following warnings have been included in a Serious Warnings and Precautions Box in the Product Monograph for Iclusig: vascular occlusion, heart failure, hemorrhage events, hepatotoxicity, myelosuppression, and pancreatitis. In addition, Iclusig has not been studied in patients with renal impairment.

A Risk Management Plan (RMP) for Iclusig was submitted by ARIAD Pharmaceuticals Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

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. 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.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Iclusig?

 

The New Drug Submission (NDS) for Iclusig was filed with Health Canada on May, 23, 2013. During the clinical review of the NDS, two major efficacy and safety issues were identified as follows: inability to identify a safe starting dose or exposure duration; and durability of response was not demonstrated based on data with a median duration of follow-up of only 9.9 months. As a result, the data provided at the time did not allow Health Canada to undertake an accurate benefit/risk assessment. On January 9, 2014 a Notice of Deficiency (NOD) was issued to the sponsor requesting the provision of more data. In response to the NOD, the sponsor provided additional data, including an updated clinical study report for the Phase II PACE study with a median duration of follow-up of 27.9 months. In addition, the sponsor was also able to demonstrate the benefit of a 45 mg starting dose in all cohorts. The sponsor's response to the NOD adequately addressed major concerns identified by Health Canada. Accordingly, Health Canada granted the sponsor market authorization under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor agreed to provide additional information to confirm the clinical benefit.

 

Submission Milestones: Iclusig

Submission Milestone Date
Submission filed: 2013-05-23
Screening 1  
Screening Acceptance Letter issued: 2013-06-24
Review 1  
Biopharmaceutics complete: 2013-08-28
Quality Evaluation complete: 2013-12-09
Clinical Evaluation complete: 2014-01-07
Labelling Review complete: 2013-12-09
Biostatistics Evaluation complete: 2013-10-25
Notice of Deficiency (NOD) issued by Director General (safety and efficacy issues): 2014-01-09
Response filed: 2014-07-02
Screening 2  
Screening Acceptance Letter issued: 2014-07-31
Review 2  
Biopharmaceutics complete: 2014-12-03
Quality Evaluation complete: 2015-02-12
Clinical Evaluation complete: 2015-04-02
Labelling Review complete: 2015-02-11
Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued: 2015-02-13
Response filed (Letter of Undertaking): 2015-02-27
Notice of Compliance (NOC) issued by Director General under the Notice of Compliance with Conditions (NOC/c) Guidance: 2015-04-02

 

The Canadian regulatory decision on the non-clinical and clinical review of Iclusig was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, Health Canada has requested the sponsor agree to provide the following reports:

  • Final clinical study report for the pivotal study AP24534-10-201 (PACE): A Pivotal Phase II Study of Iclusig in Patients with Refractory Chronic Myeloid Leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) which is expected to be provided in March 2017.
  • Final clinical study report for confirmatory Study AP24534-14-203: A Randomized, Open-label, Phase II Study of Iclusig in Patients with Resistant CP-CML to characterize the efficacy and safety of a range of doses. Starting doses of 15 mg, 30 mg, and 45 mg were administered to CP-CML patients with and without the (T)hreonine-315-(I)soleucine (T315I) mutation. Also to be included is pharmacokinetic sampling to provide exposure-toxicity and exposure-response data in order to identify appropriate dose ranges for patients with the T315I mutation and for patients who progressed after two or more tyrosine kinase inhibitors, with no other options. This report is expected to be provided in June 2019.

As part of the requirements outlined in the Food and Drugs Act and Regulations, the sponsor shall provide the following:

  • Report(s) of all serious adverse drug reactions (ADRs) that occurred in Canada and all serious unexpected ADRs that occurred outside of Canada. These reports should be forwarded within 15 days to the Marketed Health Products Directorate.
  • Annual safety summary reports should be provided to the Therapeutic Products Directorate in a manner deemed consistent with the current Guidance Document: Notice of Compliance with Conditions (NOC/c).

Health Canada also requested that the sponsor submit results of the following ongoing studies in the event that they change the benefit/risk profile of Iclusig. These studies are not considered commitments under the NOC/c guidance.

  • Final clinical study report for enhanced pharmacovigilance study regarding vascular occlusive events (Expected 12/2017).
  • Final clinical study report for prospective observational study regarding vascular occlusive events when ponatinib is given with / without anticoagulant or antiplatelet agents (Expected 06/2019).
  • Long-term follow-up of patients in 07-101 and 10-201 studies, including long-term risk of vascular occlusive events and narratives for these events (Expected 03/2017).

 

5 What post-authorization activity has taken place for Iclusig?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Iclusig is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

The clinical pharmacological data support the use of Iclusig for the specified indication. Appropriate warning and precautions are in place in the approved Iclusig Product Monograph to address the identified safety concerns.

Pharmacodynamics
QT Interval Prolongation

The potential for Iclusig to cause QT interval prolongation was assessed in 39 leukemia patients. No clinically significant QT interval prolongation was observed; however, a thorough QT study has not been performed. A clinically significant effect on QT interval prolongation therefore cannot be excluded. For further information, refer to the Action and Clinical Pharmacology section of the Iclusig Product Monograph.

Pharmacokinetics
Drug-Drug Interactions

Ponatinib is metabolized by esterases and/or amidases, and also by cytochrome P450 (CYP) 3A4. Caution should be exercised with concurrent use of Iclusig and moderate or strong CYP3A4 inhibitors and strong CYP3A4 inducers.

For further details, please refer to the Iclusig Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Iclusig was primarily evaluated in one Phase II study AP24534-10-201, also known as the PACE study. This study is an ongoing multicentre, international, open-label study which enrolled patients with chronic myeloid leukemia (CML) in chronic (CP), accelerated(AP), or blast phase (BP) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation. A total of 449 patients were enrolled, of which 444 patients were eligible for the efficacy analysis. The remaining five patients who were not eligible for the efficacy analysis also received Iclusig and were included in the safety analysis.

Chronic myeloid leukemia patients enrolled in the PACE study were assigned to one of six cohorts based on their disease phase (i.e. CP; AP; BP/Ph+ALL) and resistance or intolerance to dasatinib or nilotinib or, presence of the T315I mutation. The six cohorts were as follows:

  • Cohort A (CP-CML and Resistant/Intolerant to dasatinib or nilotinib)
  • Cohort B (CP-CML with T315I mutation)
  • Cohort C (AP-CML and Resistant/Intolerant to dasatinib or nilotinib)
  • Cohort D (AP-CML with T315I mutation)
  • Cohort E (BP-CML/Ph+ALL and Resistant/Intolerant to dasatinib or nilotinib)
  • Cohort F (BP-CML/Ph+ALL with T315I mutation)

Resistance in CP-CML patients was defined as failure to achieve either a complete hematologic response (CHR) by 3 months, a minor cytogenetic response by 6 months, or a major cytogenetic response (MCyR) by 12 months while on dasatinib or nilotinib. Patients with CP-CML who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response (CCyR) or progression to AP-CML or BP-CML at any time on dasatinib or nilotinib were also considered resistant.

Resistance in AP-CML and BP-CML/Ph+ALL was defined as failure to achieve either a major hematological response (MaHR) (AP-CML by 3 months, BP-CML/Ph+ALL by 1 month), loss of MaHR (at any time), or development of kinase domain mutation in the absence of a MaHR while on dasatinib or nilotinib.

Intolerance was defined as the discontinuation of dasatinib or nilotinib due to toxicities despite optimal management in the absence of CCyR for CP-CML patients or MaHR for AP-CML, BP-CML, or Ph+ALL patients.

The primary efficacy endpoint for CP-CML patients (Cohorts A and B) was the proportion of patients achieving a major cytogenetic response (MCyR) by 12 months.

The primary efficacy endpoint in AP-CML and BP-CML/Ph+ALL patients (Cohorts C through F) was the proportion of patients achieving a major hematological response (MaHR) by 6 months.

For all patients, other secondary efficacy endpoints evaluated included confirmed MCyR, time to response, duration of response, progression-free survival, and overall survival.

All patients enrolled in the PACE study commenced the study with a 45 mg starting dose of Iclusig taken orally once daily, with or without food. Patients were instructed to take the prescribed dose at the same time each day. Each 28-day dosing period was considered as one cycle. Efficacy was then assessed every two cycles up to 27 cycles for AP-CML and BP-CML/Ph+ALL patients, or every three cycles up to 27 cycles for CP-CML patients. Assessments of cytogenetic response by bone marrow aspirate after cycle 27 were conducted at intervals that were determined by the depth of the individual patient’s molecular response.

During the course of the study, dose reductions to 30 mg once daily or 15 mg once daily were permitted for the management of adverse events due to treatment toxicity. Doses could also be held for up to 28 days.

In the original filing of the Iclusig submission, the efficacy data submitted by the sponsor were based on a median duration of follow-up of 9.9 months, which Health Canada considered insufficient to demonstrate long-term durability of response. As a result, Health Canada issued a Notice of Deficiency (NOD) to the sponsor requesting that it provide further follow-up efficacy data. In response to the NOD, the sponsor submitted an updated clinical study report for the PACE study which provided data with a longer duration of follow-up (median 27.9 months; range: 0.07 months to 39.5 months). At the time of this analysis, the median duration of treatment with Iclusig was 866 days in CP-CML patients, 590 days in AP-CML patients, and 86 days in BP-CML/Ph+ALL patients.

The analysis of efficacy results, based on the longer follow-up data provided (27.9 months follow-up), demonstrated that Iclusig exhibited clinically meaningful responses in all disease groups. Results from the PACE study showed that 149 of the 267 CP-CML patients (55.8%) achieved MCyR rate by 12 months, thereby demonstrating efficacy in this patient population. Note however, the primary efficacy endpoint for CP-CML was based on an unconfirmed MCyR, which was the detection of a CCyR or partial cytogenetic response (PCyR) on a single bone marrow aspirate.

As for AP-CML patients, 47 of 83 (56.6%) achieved MaHR by 6 months which also demonstrated the efficacy in this population who are resistant to dasatinib or nilotinib or have the T315I mutation. However, given the small sample size [Number of patients (n) = 18] in the T315I cohort, while it may be concluded that Iclusig has shown efficacy in this patient population, the magnitude of the efficacy cannot be accurately estimated.

Efficacy results presented for the BP-CML/PH+ALL disease groups were initially combined in the original filing of the Iclusig submission whereby 32 of 94 (34.0%) of BP-CML/Ph+ALL patients achieved MaHR by 6 months. However, given the difference in the underlying disease process between these groups, Health Canada requested that the sponsor analyze the overall response rate for these two groups separately. In response to Health Canada’s request, the sponsor provided a separate analysis for these two groups, based on the data with a median duration of follow-up of 27.9 months. Results from this analysis showed 30.6% of BP-CML patients and 40.6% of Ph+ALL patients achieved MaHR.

For CP-CML patients who achieved MCyR, the average time to MCyR was 84 days (range: 49 to 334 days) and for patients who achieved MMR, the average time to MMR was 168 days (range: 55 to 965 days). The median time to MaHR in patients with AP-CML and BP-CML/Ph+ALL among responders was 21 days (range: 12 to 176 days) and 26 days (range: 11 to 168 days), respectively.

The ‘time to response’ observed in all cohorts was consistent with earlier data analyzed in the original efficacy data submitted [that is (i.e.) median Iclusig exposure of 9.9 months]. The observed short ‘time to response’ is of clinical importance, given that patients who fail to achieve a hematologic response within this timeframe are considered not likely to benefit from further treatment with Iclusig. As a result, recommendations have been made in the Iclusig Product Monograph to consider discontinuation of Iclusig in patients who fail to achieve a hematologic response by 90 days (3 months). In addition, recommendations have been made to consider implementing a dose reduction in CP-CML patients upon achieving MCyR with a 45 mg starting dose. These suggested dosing regimens are designed to maximize the patient’s chance of rapidly achieving a response, while mitigating the risk of experiencing serious adverse events.

During the study, patients received a reduced dose or a temporary dose interruption to manage adverse events. Based on the original efficacy data submitted (i.e. median 9.9 month follow-up data), within a disease group, fewer patients in the T315I cohorts had dose reductions or interruptions than patients in the resistant/intolerant cohorts. Across disease groups, patients with dose adjustments decreased with increasing disease severity; this trend was especially notable in the BP-CML/Ph+ALL disease group. In the total patient population (n = 449), 52.1% of patients from all disease cohorts combined required a dose reduction, and 65.5% of patients required a dose interruption, mainly due to ponatinib toxicity. For all disease cohorts, the average dose intensity was 36.5 mg/day, representing 81% of the recommended 45 mg dose (range: 30.8 mg/day for CP-CML to 44 mg/day for BP-CML/Ph+ALL). This observation underscores Health Canada’s concern that the 45 mg daily dose may not be the optimal dose for the indication sought (i.e. all disease cohorts, intolerant and resistant). This concern was also included in the NOD issued to the sponsor, along with the request to provide longer efficacy data. In response to the NOD, the sponsor demonstrated the benefit of a 45 mg starting dose in all cohorts and provided efficacy data based on the longer median follow-up of 27.9 months. The PACE study continued to show efficacy for the 45 mg starting dose in all subgroups, including those with the T315 mutation.

While the sponsor demonstrated the benefit of a 45 mg starting dose along with continued efficacy in all cohorts, a post hoc multivariate dose-response analysis based on the longer median follow-up data of 27.9 months demonstrated maintenance of response with a dose reduction from 45 mg to 30 mg or 15 mg in patients with CP-CML. The same data analysis did not support dose reductions for patients with more advanced disease (AP-CML, BP-CML/Ph+ALL) and therefore dose reduction for maintenance of response is not recommended for these patients. The sponsor plans to further to investigate optimal dose strength in a new Iclusig clinical confirmatory study AP24534-14-203 conducted in a patient population similar to the authorized indication (See Answer #4 - What follow-up measures will the company take?)

For more information, refer to the Iclusig Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Iclusig was based primarily on the Phase II study AP24534-10-201, also known as the PACE study previously described in the Clinical Efficacy section. The PACE study enrolled 449 CML and Ph+ALL patients who were resistant or intolerant to prior dasatinib or nilotinib or those with a T315I mutation. At the time of this analysis, patients had a median duration of follow-up of 27.9 months; the PACE study remains ongoing at this time.

Based on the interim safety data provided, 69% (310/449) patients experienced a dose interruption of at least three days and 65% (291/449) experienced a dose reduction, mainly due to ponatinib (medicinal ingredient of Iclusig) toxicity. The average dose intensity was 36 mg/day, or 80% of the expected 45 mg daily dose. The average dose intensity for CP-CML patients was 31 mg/day. The rates of treatment-emergent adverse events resulting in discontinuation were 17% (46/270) in CP-CML, 11% (9/85) in AP-CML and 14% (13/94) in BP-CML/Ph+ALL.

The most common non-hematologic adverse reactions (≥20%) were rash (35%), dry skin (32%), and abdominal pain (23%). The most common adverse events (≥1%) that led to treatment discontinuation were platelet count decreased (5%) and neoplasm progression (3%). The most common adverse reactions (≥5%) that led to dose modification were platelet count decreased (29%), neutrophil count decreased (13%), lipase increased (11%), abdominal pain (9%), rash (8%), and pancreatitis (6%).

Adverse drug reactions which were very common (≥10%) in frequency were decreased platelet count, rash, dry skin, and abdominal pain, decreased neutrophil count, headache, lipase increased, fatigue, constipation, myalgia, arthralgia, nausea, anemia, increased alanine aminotransferase (ALT), hypertension, and increased aspartate aminotransferase (AST).

Adverse events uniquely associated with Iclusig administration included serious treatment-emergent arterial and venous thrombosis and occlusions, including cardiovascular, cerebrovascular, and peripheral vasculature. These serious events occurred in 24% (129/530) of Iclusig-treated patients, with and without cardiovascular risk factors (including patients less than 50 years old). The median time to onset of arterial occlusion events was 244 days (range 3 to 952 days). Vascular occlusion events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia.

Arterial occlusion and thrombosis have occurred in 19% of Iclusig-treated patients with some patients experiencing events of more than one type. Patients have required revascularization procedures (cerebrovascular, coronary, and peripheral arterial) due to vascular occlusion from Iclusig.

Cardiovascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 10% of Iclusig-treated patients. Patients have developed heart failure concurrent or subsequent to the myocardial ischemic event.

Cerebrovascular occlusion, including fatal stroke, has occurred in 7% of Iclusig-treated patients. Iclusig has been associated with stenosis over multiple segments in major arterial vessels which supply the brain.

Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, have occurred in 7% of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations.

Venous thrombosis and occlusions occurred in 5% of Iclusig-treated patients, including deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis and retinal venous occlusions with vision loss.

A multivariate analysis conducted on the safety data indicated that reducing the daily dose from 45 mg to 30 mg or 15 mg for CP-CML patients who have achieved MCyR may reduce the risk of arterial thrombotic events. Based on this observation, the labelling for Iclusig includes a proposed dose reduction strategy in CP-CML patients who achieve a response. The multivariate analysis however did not support such a dose reduction strategy for patients with more advanced disease (AP-CML, BP-CML/Ph+ALL) and is therefore not recommended in these patients. However, the multivariate analysis conducted was considered exploratory in nature; further evaluation regarding the optimal starting dose is anticipated from a future confirmatory Phase II study AP24534-14-203 in CP-CML patients (See What follow-up measures will the company take?). Furthermore, for any patients who do not achieve a therapeutic response by 90 days, it is recommended that Iclusig be discontinued to manage the risk of unnecessary exposure in these patients.

To further manage the risk of unnecessary exposure, Iclusig will only be available through a controlled access program known as the Iclusig Controlled Distribution Program. Under this program, only prescribers who complete the certification program will be able to prescribe Iclusig, and only pharmacies that have been appropriately trained with regards to the serious risks associated with Iclusig will be able to dispense the drug. Prior to receiving Iclusig treatment, patients will also be required to sign an Informed Consent confirming that they understand the serious risks associated with Iclusig treatment.

The following safety events are also known to be associated with Iclusig treatment.

Cardiac events such as congestive heart failure and reduced left ventricular ejection fraction are associated with the use of Iclusig. In the PACE study, 8.0% of patients experienced cardiac failure or left ventricular dysfunction, of which 5.1% were categorized as serious and 0.9% resulted in a fatal outcome. The time from initiation of treatment to reporting of these adverse events averaged 196 days (range 1 - 981 days). For further information, please refer to the Iclusig Product Monograph.

Cardiac arrhythmias and conduction abnormalities (QT prolongation) have also been observed with use of Iclusig. Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. The cardiac rhythms identified (1 case each) were: complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses.

Supraventricular tachyarrhythmia adverse events occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization.

Blood pressure elevation at one or more time points during Iclusig treatment occurred in 67% of Iclusig-treated patients and resulted in the adverse event of hypertension or worsening of hypertension in 26%.

Myelosuppression was commonly reported in all patient populations. Severe (Grade 3 or 4) myelosuppression occurred in 48% of patients treated with Iclusig. The frequency of Grade 3 or 4 thrombocytopenia (40%), neutropenia (34%), and anemia (20%) was reported with a higher frequency in patients with AP-CML and BP-CML/Ph+ALL than in patients with CP-CML.

Hepatotoxicity, including acute fatal hepatic failure, has been observed in Iclusig-treated patients within one week of starting treatment. The incidence of adverse events of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 18%. Iclusig treatment may result in elevation in ALT, AST, or both. The adverse events of ALT or AST elevation were not reversed by the date of the last follow-up in 26% of patients. The median time from the initial onset for the adverse events of ALT elevation was 114 days (range 1- 926 days) and the median time to initial onset for the adverse events of AST elevation was 95 days (range 1-993 days).

Bleeding events were commonly reported, with 26% (115/449) of Iclusig-treated patients experiencing at least one event. Serious bleeding events and hemorrhage, including fatalities, occurred in 6% (28/449) of Iclusig-treated patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, or Ph+ALL than CP-CML patients. Cerebral hemorrhage and gastrointestinal hemorrhage/hemorrhagic gastritis (fatal) were the most commonly reported serious bleeding events. Some hemorrhagic events occurred in patients with grade 4 thrombocytopenia.

Iclusig is associated with pancreatitis (7%; 5% grade 3) and elevations in serum lipase (41 %; 12% grade 3 or greater). The frequency of pancreatitis is greater in the first two months of Iclusig use.

Fluid retention adverse events (1% Grade 3 or greater) occurred in 28% of patients treated with Iclusig. These events included peripheral edema, pericardial effusion, pleural effusion, and ascites.

For more information, refer to the Iclusig Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical studies assessing ponatinib (medicinal ingredient in Iclusig) included a number of in vitro and in vivo studies conducted to characterize the primary and secondary pharmacodynamic activities. Pharmacodynamic studies included the assessment of the ponatinib mechanism of action, potency, and specificity of target kinase inhibition. Ponatinib absorption, distribution, metabolism and excretion were investigated using in vitro studies and in vivo mouse, rat, and monkey studies. Toxicological evaluation of ponatinib was conducted in laboratory animals (mice, rats, and monkeys), and in in vitro systems. These studies included single-dose toxicity studies, repeat-dose toxicity studies, in vivo genotoxicity studies, reproductive and development studies, phototoxicity studies and in vitro genotoxicity studies using Salmonella, E. coli, and human peripheral blood lymphocytes.

Review of the non-clinical studies indicated that ponatinib, when taken at the recommended human dose, is expected to be associated with some toxicity. Organs likely to be affected include the gastrointestinal system, cardiovascular system, thyroid gland, liver, pancreas, skin, and bone marrow.

Ponatinib may also impair male and female fertility. While fertility studies using ponatinib were not conducted, ponatinib effects on male and female reproductive organs were observed during conduct of general toxicology studies. Observations included degeneration of epithelium in rats and monkeys and follicular atresia in the monkey ovary with associated endometrial atrophy. Effects seen in rats were at exposures close to the recommended human dose (45 mg/day), and in monkeys, at exposures approximately four times the recommended dose in humans.

Embryo-fetal toxicity has been reported in animal studies of ponatinib at exposures lower than human exposures at the recommended human. In studies in pregnant rats, embryo-fetal toxicity in the form of post-implantation loss, reduced fetal body weight, and multiple soft tissue and skeletal alterations were observed at maternal toxic dosages. Multiple fetal soft tissue and skeletal alterations were also observed at maternal nontoxic dosages.

Appropriate warnings and precautionary measures are in place in the Iclusig Product Monograph to address the identified safety concerns.

For more information, refer to the Iclusig Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Iclusig has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life of 24 months for the drug product is acceptable, when stored between 15 to 30°C.

Proposed limits of drug-related impurities are considered adequately qualified [that is, within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies].

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

The Iclusig 45 mg tablet contains 121 mg of lactose monohydrate which is of animal origin. Letters of attestation confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this product indicating that it is considered to be safe for human use. No other raw materials are of human or animal origin.

 

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