Summary Basis of Decision for Verzenio

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 Verzenio is located below.

Recent Activity for Verzenio

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 Verzenio

Date SBD issued: 2019-09-26

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

Abemaciclib

Drug Identification Number (DIN):

  • DIN 02487098 - 50 mg tablet, oral administration
  • DIN 02487101 - 100 mg tablet, oral administration
  • DIN 02487128 - 150 mg tablet, oral administration
  • DIN 02487136 - 200 mg tablet, oral administration

Eli Lilly Canada Inc.

New Drug Submission Control Number: 215268

On April 5, 2019, Health Canada issued a Notice of Compliance to Eli Lilly Canada Inc. for the drug product Verzenio.

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 Verzenio is favourable for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer

  • in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy.
  • in combination with fulvestrant in women with disease progression following endocrine therapy. Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.
  • as a single agent in women with disease progression following an endocrine therapy and at least two prior chemotherapy regimens. At least one chemotherapy regimen should have been administered in the metastatic setting, and at least one should have contained a taxane.

1 What was approved?

Verzenio, a protein kinase inhibitor, was authorized for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer

  • in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy.
  • in combination with fulvestrant in women with disease progression following endocrine therapy. Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.
  • as a single agent in women with disease progression following an endocrine therapy and at least two prior chemotherapy regimens. At least one chemotherapy regimen should have been administered in the metastatic setting, and at least one should have contained a taxane.

Verzenio is not indicated for use in pediatric patients (<18 years of age), as its safety and efficacy have not been established in this population.

No overall differences were observed between geriatric patients (≥65 years of age) and younger patients with respect to safety and efficacy. However, subgroup analyses from the clinical studies showed that hematologic adverse events, hypokalemia (including Grade 3), hypocalcemia, Grade 3 or higher infections, decreased appetite, and increased blood creatinine were reported at higher frequencies in geriatric patients than in younger patients.

Verzenio 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.

Verzenio was approved for use under the conditions stated in its Product Monograph, taking into consideration the potential risks associated with the administration of this drug product.

Verzenio (50 mg, 100 mg, 150 mg and 200 mg abemaciclib) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains croscarmellose sodium, lactose monohydrate, microcrystalline cellulose 101, microcrystalline cellulose 102, polyethylene glycol, polyvinyl alcohol, silicon dioxide, sodium stearyl fumarate, talc, and titanium dioxide. The 150 mg tablet also contains iron oxide yellow. The 50 mg and 200 mg tablets also contain iron oxide red and iron oxide yellow.

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 Verzenio Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Verzenio approved?

Health Canada considers that the benefit-harm-uncertainty profile of Verzenio is favourable for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer

  • in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy.
  • in combination with fulvestrant in women with disease progression following endocrine therapy. Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.
  • as a single agent in women with disease progression following an endocrine therapy and at least two prior chemotherapy regimens. At least one chemotherapy regimen should have been administered in the metastatic setting, and at least one should have contained a taxane.

Breast cancer is the most commonly diagnosed malignancy among women worldwide, and it is the second leading cause of cancer-related deaths in Canadian women. Metastatic breast cancer continues to be a universally fatal disease, and the average overall survival is two or three years.

Breast cancer is a heterogenenous disease, with subtypes that can be characterized based on their hormonal receptor (HR) status and human epidermal growth factor receptor 2 (HER2) status. These influence the choice of treatment options for the disease. Aromatase inhibitors (AIs), tamoxifen and fulvestrant are all authorized in Canada for the initial treatment of metastatic breast cancer.

If a patient's disease progresses while receiving initial endocrine therapy, a different endocrine-based therapy is often the next option chosen for treatment. However, the efficacy of endocrine therapy decreases as resistance develops. When endocrine therapy is no longer an effective option, sequential single-agent cytotoxic chemotherapy becomes the standard of care.

Inhibitors of cyclin-dependent kinase (CDK) inhibitors CDK4 and CDK6 have recently been approved for use in combination with endocrine therapy for the initial treatment of HR-positive, HER2-negative metastatic disease. Abemaciclib, the medicinal ingredient in Verzenio, belongs to this class of drugs.

The safety and efficacy of Verzenio were demonstrated in three pivotal clinical studies: the Phase III studies MONARCH 3 and MONARCH 2, and the Phase II study MONARCH 1. Each one provided the primary support for one of the three approved indications.

MONARCH 3 evaluated the efficacy of Verzenio, in combination with an aromatase inhibitor, as initial endocrine-based therapy. In this study, Verzenio and a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole) or a placebo and an NSAI were administered as an initial treatment for HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women. The median follow-up time was 26.7 months for patients in both treatment arms. A statistically significant difference was observed between the two treatment arms with respect to the primary efficacy endpoint, progression-free survival (PFS). Progression-free survival was assessed according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). Patients who received Verzenio had a 46% reduction in the risk of disease progression or death compared to those who received the placebo plus NSAI.

MONARCH 2 evaluated the efficacy of Verzenio in combination with fulvestrant for the treatment of women with HR-positive, HER2-negative advanced breast cancerwho had disease progression on or after endocrine therapy and who had not received chemotherapy in the metastatic setting. Patients received either Verzenio and fulvestrant, or a placebo and fulvestrant. The median follow-up time was 20 months for both treatment arms. The results of the study demonstrated an improvement in the primary efficacy endpoint, investigator-assessed PFS, in which patients who received Verzenio had a statistically significant 44.7% reduction in the risk of disease progression or death compared to patients who received the placebo.

MONARCH 1 was a single-arm study evaluating the efficacy of Verzenio as a single agent (monotherapy) in women with refractory HR-positive, HER2-negative metastatic breast cancer. All patients experienced disease progression following endocrine therapy, and completed at least two prior chemotherapy regimens. At least one of these regimens should have been administered in the metastatic setting, and at least one should have included a taxane. The median duration of therapy was 138.5 days. The primary efficacy endpoint, confirmed objective response rate (ORR), was assessed by the investigator according to RECIST v1.1 and determined to be 19.7% (95% confidence interval [CI]: 13.3, 27.5), resulting from 26 partial responses and zero complete responses. An independent, blinded, radiographic review of scans was also performed for efficacy assessment, and gave similar results (ORR = 17.4%; 95% CI: 11.1, 25.0).

The clinical safety of Verzenio was established primarily through the data assessed from the three pivotal studies. In MONARCH 3 and MONARCH 2, adverse events, dose reductions, and discontinuations were more frequently reported among patients treated with Verzenio than in patients who received a placebo. Study drug discontinuations were reported in 17% of Verzenio-treated patients in MONARCH 3, and 16% in MONARCH 2, compared to 3% of placebo-treated patients in each of these studies. Dose reductions also occurred at similar frequencies among Verzenio-treated patients in both studies (47% in MONARCH 3 and 43% in MONARCH 2). Although MONARCH 1 was a single-arm study, the safety data reported from this study is consistent with the safety profile of Verzenio in the two randomized pivotal studies, MONARCH 3 and MONARCH 2.

The assessment of the safety profile demonstrated that the addition of Verzenio to an aromatase inhibitor or fulvestrant increased reports of diarrhea, neutropenia, fatigue, infections, nausea, vomiting, abdominal pain, decreased appetite, anemia, alopecia, leukopenia, headache, and thrombocytopenia. The most common adverse event in Verzenio-treated patients was diarrhea, with the highest incidences occurring during the first month of dosing in both randomized studies.

The most significant serious adverse events were venous thromboembolic events (VTEs), which were reported more frequently in patients treated with Verzenio than in patients treated with a placebo, and at similar frequencies in both MONARCH 3 and MONARCH 2 studies (in 5% and 6% of Verzenio-treated patients, respectively). Due to the potential for serious or fatal outcomes, VTEs have been listed in a Serious Warnings and Precautions box in the Verzenio Product Monograph.

A Risk Management Plan (RMP) for Verzenio was submitted by Eli Lilly Canada 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Verzenio Product Monograph meet the necessary regulatory labelling, plain language and design element requirements. A Look-alike Sound-alike brand name assessment was performed and the proposed name Verzenio was accepted.

Verzenio 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 Verzenio Product Monograph to address the identified safety concerns.

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 Verzenio?

The New Drug Submission (NDS) for Verzenio was reviewed as part of the New Chemical Entities Work Sharing Trial (NCEWST), a work-sharing initiative between Canada, Australia, Singapore, and Switzerland. This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.

For this submission, Health Canada completed the clinical review of Verzenio, while Australia's Therapeutic Goods Administration (TGA) completed the quality and non-clinical reviews. Health Canada also consulted quality review reports from Swissmedic, Switzerland's regulatory agency for medical products. Although the review of the submission was collaborative, each jurisdiction made their regulatory decision independently of the others.

Submission Milestones: Verzenio

Submission MilestoneDate
Pre-submission meeting:2017-08-23
Submission filed:2018-04-06
Screening
Screening Deficiency Notice issued:2018-06-01
Response filed:2018-06-05
Screening Acceptance Letter issued:2018-06-07
Review
Review of Risk Management Plan complete:2019-02-13
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2019-03-13
Quality Evaluation complete:2019-03-28
Clinical/Medical Evaluation complete:2019-04-05
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2019-04-05

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?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

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

The clinical review of Verzenio was completed by Health Canada as part of a work-sharing initiative with Australia, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Clinical Pharmacology

Abemaciclib, the medicinal ingredient in Verzenio, inhibits cyclin D-dependent kinases 4 and 6 (CDK4 and CDK6), which are involved in cell cycle regulation. It additionally prevents phosphorylation of the retinoblastoma (Rb) protein. This blocks the progression of the cell cycle from the G1 phase to the S phase, in which deoxyribonucleic acid (DNA) is replicated in preparation for cell division.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of abemaciclib have been characterized in patients and healthy subjects. In the therapeutic dose range of 50-200 mg, the increase in plasma exposure (as measured by the area under the concentration-time curve [AUC] and maximum plasma concentration [Cmax]) was dose proportional. Steady state was achieved within five days following repeated twice daily dosing, with a mean accumulation ratio of 5.8 and 3.7, based on the AUC and Cmax, respectively.

Pharmacokinetic data indicate that abemaciclib is absorbed slowly, and that abemaciclib and its metabolites are highly bound to plasma proteins (93-98%). Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib undergoes oxidative metabolism and is primarily excreted in the feces, with the majority of the eliminated dose as metabolites.

Based on population pharmacokinetic analysis, mild to moderate renal impairment did not appear to affect the pharmacokinetics of abemaciclib, whereas the effects of severe renal impairment are unknown.

Dose reduction is necessary in patients with severe hepatic impairment, as a significant fold increase in exposure to abemaciclib (as measured by the AUC) was observed in this patient population. Mild and moderate hepatic impairment did not produce clinically significant changes in exposure (1.2-fold and 1.1-fold, respectively) that would require dose adjustment.

Abemaciclib is primarily metabolized by cytochrome P450 (CYP) 3A4. Based on data both from a population-based pharmacokinetic model and a clinical pharmacology study, coadministration of Verzenio with moderate or strong CYP 3A4 inhibitors is expected to significantly increase the combined active species (abemaciclib and its metabolites). Therefore, dose reduction of abemaciclib is also required if concomitant use of Verzenio and moderate or strong CYP 3A4 inhibitors is unavoidable.

Abemaciclib should not be administered concurrently with strong CYP3A inducers, such as rifampin. Coadministration with rifampin caused a significant reduction of almost 80% of active moieties. Additionally, concomitant use of abemaciclib and metformin resulted in increased metformin exposure due to a general reduction in the systemic and renal clearance of metformin. Therefore, coadministration of abemaciclib with metformin or other clinically relevant substrates of the organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) 1 and MATE2K transporters should therefore be carried out cautiously.

In a single ascending dose study in healthy volunteers, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval. This outcome is consistent with preclinical and clinical data.

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

Clinical Efficacy

The clinical efficacy of Verzenio was demonstrated primarily in three studies, MONARCH 3, MONARCH 2, and MONARCH 1. Each study provided evidence supporting one of the approved indications. The safety of Verzenio was also evaluated in these three studies, and is addressed in further detail in the Clinical Safety section.

MONARCH 3

The MONARCH 3 study assessed the clinical efficacy of Verzenio for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy. MONARCH 3 was a double-blind, placebo-controlled Phase III study in which 493 patients were randomized in a 2:1 ratio to receive either Verzenio and a nonsteroidal aromatase inhibitor (NSAI) (number of patients [n] = 328), or a placebo and an NSAI (n = 165). Randomization was stratified based on metastatic disease site and prior (neo)adjuvant endocrine therapy.

Patients received 150 mg Verzenio or the placebo twice daily, as well as an NSAI (letrozole or anastrozole) once daily. The NSAI administered to each patient was chosen by the physician. Eighty percent (80%) of patients were given 2.5 mg letrozole and 20% of patients were given 1 mg anastrozole. Patients were monitored through successive 28-day cycles. Treatment continued until patients experienced disease progression or an unacceptable level of toxicity. The median follow-up time was 26.7 months for patients in both treatment arms.

The primary efficacy endpoint was progression-free survival (PFS), assessed by the investigator according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). Patients who were treated with Verzenio and an NSAI had a statistically significant 46% reduction in the risks of disease progression or death, compared to patients who received the placebo and NSAI. The hazard ratio (HR) was determined to be 0.540 (95% confidence interval [CI]: 0.418, 0.698). The results of an independent radiographic review was supportive of these findings.

The key secondary efficacy endpoints were the objective response rate (ORR) and overall survival. The ORRs for patients with measurable disease were 61.0% for patients who were treated with Verzenio and 45.5% for patients who received the placebo. The overall survival data were still immature at the latest data cut-off date, and a survival benefit has not been demonstrated.

MONARCH 2

The MONARCH 2 study evaluated the clinical efficacy of Verzenio for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with fulvestrant, in women with disease progression following endocrine therapy. MONARCH 2 was a Phase III placebo-controlled study conducted in 669 patients who had disease progression following prior endocrine therapy, and who had not received chemotherapy in the metastatic setting. Patients were randomized in a 2:1 ratio to receive either Verzenio and fulvestrant (n = 446) or a placebo and fulvestrant (n = 223). Randomization was stratified based on metastatic disease site and by sensitivity to prior endocrine therapy. Patient crossover between the treatment arms was not permitted.

Patients received 150 mg Verzenio or the placebo twice daily and were monitored through successive 28-day cycles. In both treatment arms, patients also received a 500 mg intramuscular injection of fulvestrant on Days 1 and 15 of the first cycle, and on Day 1 of every cycle thereafter. Pre- and perimenopausal women enrolled in the study additionally received a gonadotropin-releasing hormone agonist for at least four weeks prior to and for the duration of treatment. Treatment continued until patients experienced disease progression or an unacceptable level of toxicity. The median follow-up time was 20 months for both treatment arms.

The primary efficacy endpoint was PFS, assessed by the investigator according to RECIST v1.1. Patients who were treated with Verzenio and fulvestrant had a statistically significant 44.7% reduction in the risk of disease progression or death, compared to patients who received the placebo and fulvestrant (HR = 0.553; 95% CI: 0.449, 0.681). The hazard ratio was 0.553. Data from an independent radiographic review was consistent with these findings.

Secondary efficacy endpoints included ORR and overall survival. The ORR favoured the Verzenio plus fulvestrant treatment arm over the placebo plus fulvestrant comparator arm (48.1% and 21.3%, respectively). The overall survival data were still immature at the latest data cut-off date, and a survival benefit has not been demonstrated.

MONARCH 1

The MONARCH 1 study assessed the clinical efficacy of Verzenio for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer as a single agent in women with disease progression following endocrine therapy, and at least two prior chemotherapy regimens. At least one of these regimens should have been administered in the metastatic setting, and at least one should have included a taxane.

All 132 patients received 200 mg Verzenio twice daily. Patients were monitored through successive 28-day cycles and treatment continued until patients experienced disease progression or an unacceptable level of toxicity. The median duration of therapy was 138.5 days, corresponding to approximately five treatment cycles.

The primary efficacy endpoint was ORR, assessed by the investigator as 19.7% (95% CI: 13.3, 27.5) based on 26 partial responses and zero complete responses. A blinded independent review determined the ORR to be 17.4% (95% CI: 11.4, 25.0). The secondary efficacy endpoint, median duration of response, was determined to be 8.6 months (95% CI: 5.8, 10.2). The median time to response was 3.7 months.

Indication

Sponsor's proposed indicationHealth Canada-approved indication
Verzenio (abemaciclib) is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
  • in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy.
  • in combination with fulvestrant in women as initial endocrine-based therapy or with disease progression following endocrine therapy. Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.
  • as a single agent in adults with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
Verzenio (abemaciclib) is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
  • in combination with an aromatase inhibitor in postmenopausal women as initial endocrine-based therapy.
  • in combination with fulvestrant in women with disease progression following endocrine therapy. Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.
  • as a single agent in women with disease progression following endocrine therapy and at least two prior chemotherapy regimens. At least one chemotherapy regimen should have been administered in the metastatic setting, and at least one should have contained a taxane.

MONARCH 2 was designed to evaluate the safety and efficacy of Verzenio plus fulvestrant, compared to placebo plus fulvestrant, in both endocrine therapy-naïve patients and patients who had progression following endocrine therapy. However, the protocol was amended early during the conduct of this study, which stopped the enrollment of patients to the endocrine therapy-naïve cohort. As this was an exploratory cohort of patients with a small population size (only 28 patients enrolled in the Verzenio plus fulvestrant treatment arm, and 16 patients in the placebo plus fulvestrant arm), no valid statistical conclusions can be based on data from this group.

Additionally, although the target population in the proposed indication for single-agent Verzenio included male patients, they were excluded from the MONARCH 1 study enrollment criteria, and there are no efficacy data for abemaciclib monotherapy in men. An accurate benefit-harm-uncertainty assessment could not be performed, and it was concluded that there were insufficient data to include men in the Verzenio indication.

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

Clinical Safety

In total, 394 patients were exposed to Verzenio in combination with an aromatase inhibitor, 487 patients were exposed to Verzenio in combination with fulvestrant, 404 patients were exposed to Verzenio as a single agent, and 328 healthy subjects were exposed to Verzenio as a single agent in the completed studies. However, the three registration studies (MONARCH 3, MONARCH 2, and MONARCH 1) provided the primary safety data supporting the use of Verzenio in combination with endocrine therapies and as a single agent. Each of these three studies is described in detail in the Clinical Efficacy section.

In MONARCH 3, the median number of cycles was 16 in the Verzenio plus NSAI arm, and the median duration of treatment was 15.3 months. In the placebo plus NSAI arm, the median number of cycles was 15, and the median duration of treatment was 13.9 months. The median relative dose intensity was 86% and 98% for Verzenio and the placebo, respectively.

In MONARCH 2, the median number of cycles was 13 in the Verzenio plus fulvestrant arm, and the median duration of treatment was 52 weeks. In the placebo plus fulvestrant arm, the median number of cycles was nine, and the median duration of treatment was 34 weeks. The median dose intensity was 273 mg/day and 298 mg/day for Verzenio and placebo, respectively.

In MONARCH 1, the median number of cycles received per patient was five, with a median duration of therapy of 138.5 days.

In the Phase III studies, a higher incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and laboratory abnormalities were reported in the Verzenio plus endocrine therapy arm than in the placebo plus endocrine therapy arm. In both of the randomized studies, the most commonly reported TEAEs included diarrhea, neutropenia, fatigue, nausea, vomiting, abdominal pain, decreased appetite, and anemia. The most common adverse events leading to dose reductions, dose omissions, or discontinuation of Verzenio included diarrhea and neutropenia.

Discontinuations and dose reductions were also more frequent among patients treated with Verzenio in MONARCH 3 and MONARCH 2, relative to patients in the comparator arms. In MONARCH 3, 17% of patients treated with Verzenio discontinued treatment due to adverse events, compared with 3% of patients who received the placebo. The adverse reactions that most often led to discontinuation were increased alanine aminotransferase (ALT) (2%), lung infection (2%), diarrhea (1%), and venous thromboembolic events (VTEs) (1%). In MONARCH 2, 9% of patients treated with Verzenio and 3% of patients treated with the placebo discontinued treatment. Doses were reduced due to adverse events for 47% of Verzenio-treated patients in MONARCH 3 and 43% of Verzenio-treated patients in MONARCH 2.

The most common adverse event in Verzenio-treated patients was diarrhea, which was reported in 82% of patients in MONARCH 3 (Grade 3 in 10% of patients) and 86% of patients in MONARCH 2 (Grade 3 in 13% of patients). In both studies, the highest incidence occurred during the first month of dosing. These events were managed primarily through dose modifications and the coadministration of antidiarrheal agents. The most frequently reported Grade 3 or 4 adverse events (in at least 5% of patients) included neutropenia, leukopenia, and anemia in both MONARCH 3 and MONARCH 2; as well as increased ALT in MONARCH 3, and infections in MONARCH 2.

Venous thromboembolic events were also more common in patients who received Verzenio than in patients who received the placebo. In MONARCH 3, 16 patients (4.9%) treated with Verzenio experienced VTEs. Nine of these patients (2.8%) had serious adverse events of VTEs, including fatal outcomes for three patients. One patient (0.6%) receiving the placebo had a serious VTE. Pre-existing risk factors for VTEs were balanced in the two treatment arms. In MONARCH 2, VTEs were reported in 22 patients (5%) treated with Verzenio, and two patients (0.9%) treated with the placebo.

In MONARCH 3, 11 patients (3%) receiving Verzenio and three patients (2%) receiving the placebo experienced adverse events with fatal outcomes. In patients receiving Verzenio, these included lung infections in four patients (1.2%), VTE in two patients (0.6%), respiratory failure in two patients (0.6%), and cerebral ischemia, cerebrovascular accident, and pneumonitis in one patient each (0.3%). In MONARCH 2, nine patients (2.0%) receiving Verzenio and two patients (0.9%) receiving the placebo experienced adverse events with fatal outcomes. In patients receiving Verzenio, these included sepsis in three patients (0.7%), and hepatic failure, hepatotoxicity, cerebral infarction, lung infection, multiple organ dysfunction syndrome, and pneumonitis in one patient each (0.2%).

The safety profile observed in the single-arm MONARCH 1 study is consistent with observations from the randomized Phase III studies, MONARCH 3 and MONARCH 2. Treatment-emergent adverse events (TEAEs) of Grade 3 or higher were reported in 68% of patients, and SAEs were reported in 24.2% of patients. Ten patients (8%) discontinued treatment due to adverse events. To manage adverse events, doses were adjusted for 65 patients (49%) and omitted for 76 patients (58%). Diarrhea, neutropenia, and fatigue were among the most common reasons for both dose adjustments and dose omissions. Vomiting and nausea were also common reasons for dose omission. The most frequently reported adverse events were diarrhea (90%) and neutropenia (37%). The most frequently reported Grade 3 or 4 adverse events were neutropenia, diarrhea, fatigue, leukopenia, anemia, and nausea. Three deaths were reported during this study (2%), all of which were due to infections (pneumonitis, sepsis, and lung infection).

Appropriate warnings and precautions are in place in the approved Verzenio Product Monograph to address the identified safety concerns. The risk of VTEs, including deaths resulting from VTEs, is highlighted in a Serious Warnings and Precautions box in the Verzenio Product Monograph. Instructions are also included in this section to ensure that Verzenio is only prescribed and managed by qualified healthcare professionals who are experienced in the use of anticancer agents.

The safety outcomes of MONARCH 3, MONARCH 2, and MONARCH 1 indicate a favourable benefit-harm-uncertainty balance for the use of Verzenio for each of the approved indications.

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

7.2 Non-Clinical Basis for Decision

The non-clinical review of Verzenio was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Singapore, and Switzerland. The non-clinical package complied with International Council for Harmonisation (ICH) S9 guidelines for non-clinical evaluation for anticancer pharmaceuticals. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

In safety pharmacology studies performed in dogs, abemaciclib did not affect heart rate or electrocardiographic parameters. However, a slight decrease in blood pressure was detected in dogs at clinically relevant concentrations.

In repeat-dose toxicity studies, the primary abemaciclib-related toxicities were observed in the bone marrow, gastrointestinal tract, lymphoid tissues, and male reproductive tract, consistent with the pharmacological action of abemaciclib. Lung inflammation was also observed in rats and dogs, and signs of renal toxicity were observed in rats. The toxic effects on the male reproductive system were not reversible, while other toxic effects were partially or completely reversible.

In developmental toxicity studies in rats, abemaciclib was shown to be fetotoxic and teratogenic. In embryo-fetal toxicity studies, exposure to abemaciclib at clinically relevant concentrations resulted in reduced fetal weights and cardiovascular and skeletal malformations in rats.

The results of in vitro and in vivo genotoxicity studies indicate that abemaciclib and its active metabolites are not mutagenic or clastogenic. No long-term studies have been carried out to examine the carcinogenic potential of abemaciclib.

Appropriate warnings and precautionary measures are in place in the Verzenio Product Monograph to address the identified safety concerns. Considering the intended use of Verzenio, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

7.3 Quality Basis for Decision

The quality review of Verzenio was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

The Chemistry and Manufacturing information submitted for Verzenio 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 stored at room temperature (15ºC to 30ºC).

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.

Lactose monohydrate, an excipient in Verzenio tablets, is of animal origin. Lactose monohydrate used in the production of Verzenio is not considered a risk for bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE).