Summary Basis of Decision for Scemblix

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

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

Recent Activity for Scemblix

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.

Summary Basis of Decision (SBD) for Scemblix

Date SBD issued: 2022-10-06

The following information relates to the new drug submission for Scemblix.

Asciminib (supplied as asciminib hydrochloride)

Drug Identification Number (DIN):

  • DIN 02528320 - 20 mg asciminib, tablet, oral administration
  • DIN 02528339 - 40 mg asciminib, tablet, oral administration

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 255700

On June 22, 2022, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product Scemblix.

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‑harm-uncertainty profile of Scemblix is favourable for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) previously treated with two or more tyrosine kinase inhibitors.

1 What was approved?

Scemblix, an antineoplastic agent, was authorized for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase previously treated with two or more tyrosine kinase inhibitors.

Scemblix is not authorized for use in pediatric patients (younger than 18 years of age), as no clinical safety or efficacy data are available for this population.

In clinical studies, no overall differences in the safety or efficacy of Scemblix were observed in geriatric patients (65 years of age or older) compared to those younger than 65 years of age.

Scemblix (20 mg and 40 mg asciminib, supplied as asciminib hydrochloride) is presented as a tablet. In addition to the medicinal ingredient, each tablet contains colloidal silicon dioxide, croscarmellose sodium, hydroxypropylcellulose, iron oxide (yellow and red for 20 mg film-coated tablets; black and red for 40 mg film-coated tablets), lactose monohydrate, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.

The use of Scemblix is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Scemblix Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Scemblix approved?

Health Canada considers that the benefit-harm-uncertainty profile of Scemblix is favourable for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) previously treated with two or more tyrosine kinase inhibitors.

In Canada, there are approximately 460 new cases of chronic myeloid leukemia (CML) annually, representing one case for every 100,000 people. It is estimated that there are approximately 5,500 Canadians currently living with this form of leukemia, which usually occurs during or after middle age.

Philadelphia chromosome-positive chronic myeloid leukemia is a form of CML that occurs when pieces of chromosomes 9 and 22 break off and switch places (i.e., translocate) forming the BCR::ABL1 fusion gene. The changed chromosome 22 with the fusion gene on it is called the Philadelphia chromosome. The fusion gene encodes a BCR::ABL abnormal protein with strong tyrosine kinase activity, which drives the pathogenesis of CML.

Typically, CML has three clinical phases: an initial chronic phase, during which the disease process is easily controlled; then a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal.

Canadian clinical guidelines recommend first-line treatment with a BCR::ABL tyrosine kinase inhibitor (TKI) for all newly diagnosed patients with CML-CP. The first-generation TKI, imatinib, and the second-generation TKIs, dasatinib, nilotinib and bosutinib, are recommended for first-line treatment. For patients with a refractory disease or patients who are intolerant of first-line TKI therapy, the second-generation TKIs and a third-generation TKI, ponatinib, are used as second-line treatment options.

The currently available first-, second-, and third-generation BCR::ABL TKIs have similar mechanisms of action, as they all target the adenosine triphosphate (ATP)-binding pocket of ABL to inhibit the kinase activity of the BCR::ABL protein. Some patients develop resistance to the ATP-competitive TKIs, which has led to treatment failures and minimized treatment options, resulting in a high unmet medical need for therapies with novel mechanisms of action that target alternative sites of the BCR::ABL protein.

Asciminib, the medicinal ingredient in Scemblix, is an orally available BCR::ABL tyrosine kinase inhibitor with a novel mechanism of action. It acts by specifically targeting the ABL myristoyl pocket, thereby inhibiting cell proliferation and resulting in tumour regression in in vitro and in vivo models of CML.

Scemblix has been shown to be efficacious in patients with Ph+ CML-CP previously treated with at least two TKIs. The market authorization was based on the efficacy and safety results of the pivotal Phase III, randomized (2:1), active-controlled, open-label, multicentre study (CABL001A2301 [ASCEMBL], herein referred to as A2301), in which Scemblix was compared to bosutinib in a total of 233 patients. A Phase I, open-label, dose-finding study (CABL001X2101, herein referred to as X2101) provided supportive data from 200 patients for the clinical efficacy and safety of Scemblix. Both studies were ongoing at the time of the review of the submitted clinical data.

The primary efficacy endpoint of the pivotal study was the major molecular response (MMR) rate at 24 weeks. Molecular responses are quantified by measuring the reduction in BCR::ABL1 messenger ribonucleic acid (mRNA) (i.e., BCR::ABL1 transcripts) relative to a standardized baseline. Major molecular response is defined as BCR::ABL1 transcript levels on the International Scale (BCR::ABL1IS) ≤0.1%. A key secondary endpoint was MMR rate at 96 weeks. Major molecular response is a validated endpoint that is associated with and predictive of long‑term survival.

The primary efficacy analysis of patients with Ph+ CML-CP demonstrated that Scemblix, administered at a dose of 40 mg twice daily, led to a durable, consistent, clinically meaningful, and statistically significantly higher MMR rate compared to bosutinib at 24 weeks (MMR was achieved by 26% of patients treated with Scemblix and by 13% of patients treated with bosutinib). Subgroup analyses also showed results favouring treatment with Scemblix across all categories of patients. By the data cut-off date for this submission, the timepoint for the assessment of the key secondary endpoint of MMR rate at 96 weeks had not yet been reached.

In the supportive Phase I study X2101, 23% and 39% of Ph+ CML-CP patients treated with Scemblix achieved MMR at 24 weeks and 96 weeks, respectively. These results were similar and consistent with the MMR rates observed in the primary analysis. The treatment effect in Ph+ CML-CP patients from the Phase I study was observed irrespective of the line of therapy (third, fourth, fifth, or higher line).

The safety profile of Scemblix was evaluated in 356 patients from the pivotal study A2301 and the supportive study X2101. This patient population included 341 patients with Ph+ CML in chronic phase and 15 patients in accelerated phase, all of whom received Scemblix as monotherapy. The clinically significant risks identified from the pooled safety population were cardiovascular toxicity (e.g., arrhythmias, including QTc prolongation), hypertension, myelosuppression, pancreatic toxicity (including asymptomatic elevation of serum lipase and amylase), hepatitis B virus infection reactivation, and hypersensitivity. While there was an increased incidence of thrombocytopenia in the Scemblix arm, gastrointestinal toxicity, rash, and increased transaminases were less frequent compared to the bosutinib arm. The increased frequency of thrombocytopenia reported with Scemblix was not accompanied by a higher frequency of hemorrhage. There were fewer dose reductions, dose interruptions, and permanent discontinuations in the Scemblix arm compared to the bosutinib arm.

Non-clinical studies demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, fetotoxicity and teratogenicity.

To ensure that long-term data are provided for Scemblix, the sponsor agreed to post-market commitments including the submission of the efficacy analysis at Week 96 and the final efficacy analysis (with data on overall survival and progression-free survival) from the pivotal study A2301.

A Risk Management Plan (RMP) for Scemblix was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Scemblix Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Scemblix was accepted.

Overall, the benefits of Scemblix therapy seen in the clinical studies are positive and are considered to outweigh the potential risks for the target patient population. Scemblix has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Scemblix Product Monograph to address the identified safety concerns. Further evaluation will take place upon the submission of the requested long-term efficacy analyses.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued 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 Scemblix?

The New Drug Submission (NDS) for Scemblix was reviewed as part of the New Active Substance Work-Sharing Initiative (NASWSI), a work-sharing initiative of the national health regulatory agencies of Canada, Australia, Singapore, Switzerland, and the United Kingdom (the Access Consortium). This partnership aims to promote collaboration, optimize the use of resources, reduce duplication, and enhance the ability of each agency to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.

Health Canada reviewed the clinical efficacy and pharmacology components of the NDS for Scemblix. The reviews of the other components were completed as follows:

  • Clinical safety data were reviewed by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA).
  • Non-clinical data were reviewed by the Swiss Agency for Therapeutic Products (Swissmedic).
  • Quality data were reviewed by Singapore’s Health Sciences Authority (drug substance) and Australia’s Therapeutic Goods Administration (drug product).

The review of the submission was collaborative, with each regulatory agency sharing the outcome of its review with the others.

As per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the reviews of the clinical safety component of the NDS, as well as the non-clinical and quality components, were based on a critical assessment of the foreign reviews conducted by the regulatory agencies listed above. The data package submitted to Health Canada was referred to as necessary. The Canadian regulatory decision on the Scemblix NDS was made independently based on the Canadian review.

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

Submission Milestones: Scemblix

Submission MilestoneDate
Pre-submission meeting2020-12-01
New Drug Submission filed2021-08-13
Screening
Screening Acceptance Letter issued2021-08-27
Review
Review of Risk Management Plan completed2022-04-13
Biopharmaceutics evaluation completed2022-05-06
Biostatistics evaluation completed2022-05-30
Quality evaluation completed2022-06-01
Labelling review completed2022-06-09
Non-clinical evaluation completed2022-06-21
Clinical/medical evaluation completed2022-06-21
Notice of Compliance issued by Director General, Pharmaceutical Products Directorate2022-06-22

4 What follow-up measures will the company take?

In addition to requirements outlined in the Food and Drugs Act and Regulations, Health Canada requested and the sponsor agreed to commitments to be addressed post-authorization to ensure that longer-term data are provided for Scemblix. These commitments include submitting to Health Canada:

  • An efficacy analysis at Week 96 for the pivotal Phase III, multicentre, active-controlled, open-label, randomized study (A2301) comparing the efficacy and safety of Scemblix to bosutinib in the treatment of 233 patients with chronic myeloid leukemia in chronic phase who received at least two prior tyrosine kinase inhibitors.
  • The final efficacy analysis of long-term efficacy data (overall survival and progression-free survival) from the pivotal study A2301.

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

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 decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Scemblix. When available, the PAAT will be incorporated into this SBD.

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

As described above, the New Drug Submission (NDS) for Scemblix was reviewed as part of the New Active Substance Work-Sharing Initiative. Health Canada reviewed the clinical efficacy and pharmacology components of the NDS for Scemblix. The review of the clinical safety component was conducted by the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA). Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

As described above, the review of the clinical safety component of the NDS for Scemblix was based on the critical assessment of the foreign review report by the MHRA, referring to the data filed in Canada, as necessary, in accordance with Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Asciminib, the medicinal ingredient in Scemblix, is an oral ABL/BCR::ABL1 tyrosine kinase inhibitor (TKI). It inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket.

Asciminib is rapidly absorbed, with a median time to reach maximum plasma concentration (Tmax) of 2 to 3 hours after oral administration. A food-effect study demonstrated that oral administration of the Scemblix tablet (asciminib 40 mg) under fed conditions resulted in a reduction in asciminib bioavailability when compared to dosing under fasted conditions. The effect was greater under high-fat, high-calorie conditions (greater than 60% reduction in the area under the concentration-time curve [AUC]) than under low-fat, low-calorie conditions (approximately 30% reduction in the AUC). The Scemblix Product Monograph reflects the results of this food-effect study and recommends that Scemblix should be taken without food.

Asciminib is primarily metabolized via oxidation mediated by cytochrome P450 (CYP) 3A4 (CYP3A4) and glucuronidation mediated by uridine diphosphate (UDP)-glucuronosyltransferase 2B7 (UGT2B7) and UGT2B17.

Drug-drug interaction studies showed that concomitant administration of Scemblix with strong CYP3A4 inducers reduced asciminib plasma concentrations. Concomitant administration of Scemblix with CYP3A4 substrates or CYP2C9 substrates increased plasma concentrations of these substrates. Concomitant administration of Scemblix with P-glycoprotein substrates may increase plasma concentrations of these substrates. A list of established or potential drug-drug interactions, along with appropriate precautionary measures, has been included in the approved Scemblix Product Monograph.

The concentration-effect analysis demonstrated that asciminib treatment is associated with an exposure-related prolongation of the QT interval corrected for heart rate by Fridericia formula (QTcF interval). Asciminib is not predicted to cause large mean increases in QTcF interval (i.e., over 20 ms) following a total daily dose of 80 mg.

Key clinical pharmacology findings, relevant risks and uncertainties are appropriately addressed in the Scemblix Product Monograph. The clinical pharmacology data support the use of Scemblix for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Scemblix was primarily assessed in the pivotal study CABL001A2301 (ASCEMBL), herein referred to as A2301. This was a Phase III, multicentre, active-controlled, open-label, randomized study designed to compare the efficacy and safety of Scemblix versus bosutinib in the treatment of patients with Philadelphia chromosome‑positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) who had received at least two prior tyrosine kinase inhibitors (TKIs). Bosutinib is an accepted standard of care for CML-CP. A Phase I, open-label, dose-finding study (CABL001X2101, herein referred to as X2101) provided supportive data for the clinical efficacy of Scemblix. Both studies were ongoing at the time of the review of the submitted clinical data.

Pivotal Study

In the pivotal study, 233 patients with Ph+ CML-CP were randomized in a 2:1 ratio to receive Scemblix (40 mg twice daily) or bosutinib (500 mg once daily). Patients were stratified according to major cytogenetic response status at baseline. In both treatment arms, patients were to continue treatment until treatment failure (i.e., lack of efficacy), unacceptable toxicity or withdrawal.

Enrolled patients were at least 18 years of age, had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, had adequate organ function, had evidence of BCR::ABL1 transcripts at screening, had received prior treatment with two or more adenosine triphosphate (ATP)-competitive TKIs (imatinib, nilotinib, dasatinib, radotinib or ponatinib), and had experienced a treatment failure or intolerance of the most recent TKI. As bosutinib has no activity against the T315I and V299L mutant forms of the BCR::ABL1 protein, patients who had known T315I or V299L mutations were not included for this study. Overall, patient demographics and baseline disease characteristics were balanced between the two arms. Of the 233 patients, 19% were 65 years or older, while 3% were 75 years or older. The majority (75%) of patients were Caucasian, 14% were Asian, and 4% were Black. Of the 233 patients, 81% and 18% had ECOG performance status scores of 0 and 1, respectively. Enrolled patients had received two (48%), three (31%), four (15%), or five or more (6%) prior lines of TKIs.

The primary efficacy endpoint of the pivotal study was the major molecular response (MMR) rate at 24 weeks. Molecular responses are quantified by measuring the reduction in BCR::ABL1 messenger ribonucleic acid (mRNA) (i.e., BCR::ABL1 transcripts) relative to a standardized baseline. Major molecular response is defined as BCR::ABL1 transcript levels on the International Scale (BCR::ABL1IS) ≤0.1%. A key secondary endpoint was MMR rate at 96 weeks. Major molecular response is a validated endpoint that is associated with and predictive of long‑term survival.

In the primary efficacy analysis conducted at 24 weeks, patients who were administered Scemblix 40 mg twice daily demonstrated a durable, consistent, clinically meaningful and statistically significant (p <0.03), superior MMR rate (25.5%; 95% confidence interval [CI]: 18.9, 33.0) compared to bosutinib (13.2%; 95% CI: 6.5, 22.9). Subgroup analyses demonstrated a consistent treatment effect across all subgroups.

The results of the primary efficacy analysis were supported by the results obtained for the secondary endpoints that included the depth of the response, time to response, complete cytogenic response, and time to treatment failure, all of which favoured Scemblix over bosutinib. Notably, the key secondary endpoint of MMR rate at 96 weeks could not be evaluated as the study had not reached the 96-week threshold for all randomized patients. Therefore, due to the hierarchical testing approach, the additional secondary endpoints are considered exploratory. The final analysis of the clinical efficacy data at 96 weeks will be submitted to Health Canada.

Other endpoints of interest included progression-free survival and overall survival. The data for these two endpoints were immature at the data cut-off date. The final efficacy analysis of long-term survival data from the pivotal study will be submitted to Health Canada by November 2025.

Supportive Study

Study X2101 provided supportive efficacy data from a subset of 115 CML-CP patients not harbouring a T315I mutation who were enrolled across cohorts treated with Scemblix as a single‑agent at doses ranging from 10 mg twice daily to 200 mg twice daily. The patients had received prior treatment with at least two different TKIs and had experienced a treatment failure or intolerance of the most recent TKI. Eighty-six out of the 115 CML-CP patients not harbouring the T315I mutation across the treatment cohorts were evaluable for the analysis of molecular response. Of these, 23% (20 patients) achieved MMR by Week 24. These results are consistent with the results from the primary efficacy analysis in the pivotal study A2301.

Overall Analysis of Efficacy

Overall, based on the information provided in the NDS, Scemblix is considered a beneficial and clinically meaningful treatment option for patients with CML-CP who were previously treated with two or more TKIs.

Indication

The New Drug Submission for Scemblix was filed by the sponsor with the following indication, which Health Canada subsequently approved:

  • Scemblix is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) previously treated with two or more tyrosine kinase inhibitors.

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

Clinical Safety

All Patient Safety Pool

The overall safety profile of Scemblix was evaluated in 356 patients with Ph+ CML in chronic phase (CP) and accelerated phase (AP) who received at least one dose of Scemblix. This All Patient Safety pool was derived from the pivotal study A2301 (156 Ph+ CML-CP patients) and the supportive study X2101 (115 Ph+ CML-CP patients, 70 Ph+ CML-CP patients with T315I mutation, and 15 Ph+ CML-AP patients) (see Clinical Efficacy section). The median duration of treatment from the All Patient Safety pool was 89 weeks. The safety risks identified from this broad patient population, including incidence of adverse events of any grade, adverse events Grade 3 or higher, adverse events leading to permanent discontinuation, and fatal adverse events, were included in the Warnings and Precautions section of the Scemblix Product Monograph.

Cardiovascular toxicity (including ischemic cardiac and central nervous system conditions, arterial thrombotic, and embolic conditions) and cardiac failure occurred in 28 (8%) and 10 (2.8%), respectively, of 356 patients treated with Scemblix, in the safety pool. Arrythmia, including QTc prolongation, occurred in 24 of 356 (7%) of patients receiving Scemblix. Hypertension was also observed in 18% of patients in the safety pool. Although these patients had pre-existing cardiovascular conditions or risk factors and prior treatment with two or more TKIs, the observed cardiovascular events were deemed clinically significant due to their serious and potentially life-threatening nature. A causal association with Scemblix could not be excluded.

Myelosuppression, including thrombocytopenia (28%), neutropenia (19%) and anemia (13%), was observed in the All Patient safety pool. In general, myelosuppression was reversible and managed by temporarily withdrawing Scemblix. Scemblix was permanently discontinued in less than 2% of patients with myelosuppression.

Asymptomatic increases in amylase and lipase levels were observed with an incidence of 21% in blood samples from the All Patient Safety pool; clinical events of pancreatitis were reported in 2.5% of patients.

Hepatitis B virus reactivation was also identified as an adverse event of special interest, based on the safety profile of other BCR::ABL TKI inhibitors. Accordingly, a standard statement was included in the Warnings and Precautions section of the Scemblix Product Monograph.

Pivotal Study

In the pivotal study, the safety population, i.e., patients who received at least one dose of Scemblix, included 156 patients with Ph+ CML-CP previously treated with two or more TKIs. The median duration of treatment was 67 weeks for the Scemblix arm and 30 weeks for the bosutinib arm (which included 76 patients).

The most common adverse reactions (≥10%) associated with the use of Scemblix, were gastrointestinal disorders (diarrhea, nausea, abdominal pain), fatigue, upper respiratory tract infection, musculoskeletal pain, headache, rash, and hypertension. Scemblix-treated patients had a higher incidence (>10% difference) of thrombocytopenia compared to the bosutinib arm, whereas gastrointestinal toxicity, rash, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were more frequently observed in the bosutinib arm, consistent with its known safety profile. The increased incidence of thrombocytopenia in patients treated with Scemblix did not lead to an increased incidence of hemorrhage compared to patients treated with bosutinib.

Serious adverse events occurred in 15% of patients who received Scemblix; the most common were pyrexia, urinary tract infection and thrombocytopenia, which were all observed in 1.3% of patients.

Overall, the incidence of patients experiencing an adverse reaction, patients who discontinued treatment due to an adverse reaction, and patients who required treatment interruption or dose adjustment for management of adverse reactions were lower in patients receiving Scemblix compared to those receiving bosutinib. The most common reactions leading to dose discontinuation, interruption, or adjustment were thrombocytopenia and neutropenia.

Overall, the safety profile of Scemblix was considered acceptable for the target patient population. Appropriate warnings and precautions (including recommendations for monitoring and dosage modifications) are in place in the approved Scemblix Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

As described above, the New Drug Submission (NDS) for Scemblix was reviewed as part of the New Active Substance Work-Sharing Initiative. The Swiss Agency for Therapeutic Products (Swissmedic) completed the review of the non-clinical component of the NDS for Scemblix. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

As described above, the review of the non-clinical component of the NDS for Scemblix was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Asciminib is an oral inhibitor of ABL/BCR::ABL1 tyrosine kinase. It inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket (hence, asciminib is also referred to as a first-in-class STAMP inhibitor).

Asciminib was evaluated in safety pharmacology, repeat-dose toxicity, genotoxicity, reproductive toxicity, and phototoxicity studies.

Repeat-dose toxicity studies identified the pancreas, liver, hematopoietic system, adrenal glands, and gastrointestinal tract as targets of toxicity for asciminib.

Asciminib did not exhibit mutagenic, clastogenic or aneugenic potential in in vitro and in vivo genotoxicity studies. Carcinogenicity studies have not been conducted with asciminib.

Reproductive and developmental studies in rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, fetotoxicity and teratogenicity.

In vitro and in vivo phototoxicity studies indicate that asciminib has phototoxic potential.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Scemblix Product Monograph. In view of the intended use of Scemblix, there were no pharmacological or toxicological issues within this submission which precluded the authorization of Scemblix. Appropriate warnings and precautionary measures are in place in the Scemblix Product Monograph to address the identified safety concerns.

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

7.3 Quality Basis for Decision

As described above, the New Drug Submission (NDS) for Scemblix was reviewed as part of the New Active Substance Work-Sharing Initiative. The quality components of the NDS were reviewed by Singapore’s Health Sciences Authority (the information concerning the drug substance) and Australia’s Therapeutic Goods Administration (the information concerning the drug product). While the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

As described above, the Canadian review of the quality components of the NDS for Scemblix was based on a critical assessment of the foreign reviews, referring to the data filed in Canada, as necessary, in accordance with Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Scemblix 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 is acceptable when the drug product is protected from moisture and stored at a temperature up to 25 ºC.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The excipient lactose monohydrate is derived from bovine milk obtained from healthy animals under the same conditions as milk collected for human consumption. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.

Report a problem or mistake on this page
Please select all that apply:
Date modified: