Summary Basis of Decision for Brukinsa
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Brukinsa is located below.
Recent Activity for Brukinsa
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 Brukinsa
Date SBD issued: 2021-07-15
The following information relates to the new drug submission for Brukinsa.
Zanubrutinib
Drug Identification Number (DIN):
- DIN 02512963 - 80 mg zanubrutinib, capsule, oral administration
BeiGene Switzerland GmbH
New Drug Submission Control Number: 242748
On March 1st, 2021, Health Canada issued a Notice of Compliance to BeiGene Switzerland GmbH for the drug product Brukinsa.
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 Brukinsa is favourable for the treatment of adult patients with Waldenström’s macroglobulinemia.
1 What was approved?
Brukinsa, a Bruton’s tyrosine kinase (BTK) inhibitor, was authorized for the treatment of adult patients with Waldenström’s macroglobulinemia.
Brukinsa is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.
No clinically relevant differences in efficacy or safety were observed in geriatric patients (≥65 years of age) compared to younger patients in clinical trials.
Brukinsa is contraindicated in patients who are hypersensitive to zanubrutinib or to any ingredient in the formulation, including any non-medicinal ingredient or component of the container.
Brukinsa 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.
Brukinsa (80 mg zanubrutinib) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains ammonium hydroxide (trace), colloidal silicon dioxide, croscarmellose sodium, dehydrated ethanol (trace), gelatin, iron oxide black (trace), isopropyl alcohol (trace), magnesium stearate, microcrystalline cellulose, n‑butyl alcohol (trace), propylene glycol (trace), purified water (trace), shellac glaze in ethanol (trace), sodium lauryl sulphate, 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 Brukinsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Brukinsa approved?
Health Canada considers that the benefit-harm-uncertainty profile of Brukinsa is favourable for the treatment of adult patients with Waldenström’s macroglobulinemia (WM).
Waldenström’s macroglobulinemia (WM) is a rare form of cancer that begins in the white blood cells. An estimated 90% to 95% of patients with WM carry a somatic mutation in the myeloid differentiation primary response 88 (MYD88MUT) gene, which can activate cellular processes that can lead to malignant cell growth. Conversely, an estimated 10% of WM patients carry the wild type MYD88 (MYD88WT), which has been associated with a higher rate of symptomatic disease progression and disease transformation. Therefore, MYD88WT WM is considered to represent an unmet therapeutic need in WM. Waldenström’s macroglobulinemia can be indolent (slow-growing) for many years before becoming serious or life-threatening, posing major clinical challenges for oncologists and significant morbidity in the elderly. It primarily affects the elderly (median age >63 years), with males affected twice as often as females, and has an estimated incidence of 1 in 200,000 individuals in Canada. Waldenström’s macroglobulinemia is characterized by the overproduction of immunoglobulin M (IgM), which can cause fever, night sweats, weight loss, fatigue, hyperviscosity syndrome, peripheral neuropathy, significant hepatomegaly or splenomegaly, other symptomatic bulky organomegaly, cytopenias, hemolytic anemia or immune complex vasculitis. Any of the aforementioned symptoms demonstrate overt disease progression, and are clinically indicated for treatment as per the Seventh International Workshop on Waldenström’s Macroglobulinemia (IWWM).
In Canada, therapeutic approaches for WM in individuals with no symptoms are based on watchful waiting. In individuals with symptoms, treatment strategies include plasmapheresis (removal of IgM from the blood), alkylating agents, anti-CD20 therapies, purine analogues, and proteasome inhibitors, used either as single agents or in combination. Additionally, Bruton’s tyrosine kinase (BTK) inhibitors have emerged as a promising option for the treatment of WM. Bruton’s tyrosine kinase is a signalling molecule of the B cell antigen receptor and cytokine receptor pathways. In B cells, BTK signalling results in the activation of pathways necessary for B cell proliferation, trafficking, chemotaxis, and adhesion. At the time of authorization of Brukinsa, only one BTK inhibitor, ibrutinib, was authorized for first-line use in patients with WM. However, most fit patients requiring first-line therapy for WM are treated with a chemoimmunotherapy regimen, with ibrutinib reserved mainly for use as a second-line therapy, or for patients who are frail or who have comorbidities. Zanubrutinib, the medicinal ingredient in Brukinsa, is a second-generation BTK inhibitor.
The clinical efficacy of Brukinsa was evaluated in study BGB-3111-302 (ASPEN), a pivotal Phase III study in adult patients with WM. Patients either had relapsed or refractory WM, or were treatment-naïve and considered unsuitable for standard chemoimmunotherapy regimens. Patients with a MYD88 mutation (MYD88MUT) confirmed by gene sequencing were assigned to Cohort 1 (number of patients [n] = 201). Patients with wild type MYD88 (MYD88WT; n = 26) or a missing/inconclusive mutational status (n = 2) were assigned to Cohort 2.
Patients in Cohort 1 were randomized in a 1:1 ratio to receive either Brukinsa 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. Ibrutinib was determined to be an appropriate active control, as it is an acceptable standard of care for the proposed indication in the Canadian setting.
The primary efficacy endpoint was the rate of complete response or very good partial response (VGPR) in patients with relapsed or refractory WM MYD88MUT, as assessed by an independent review committee (IRC). At the time of the primary efficacy analysis, the median follow-up time was 18.8 months. The results showed a clinically meaningful and durable VGPR rate of 29% (95% confidence interval [CI]: 20, 40) in patients treated with Brukinsa, and 20% (95% CI: 12, 30) in patients treated with ibrutinib. Treatment-naïve (TN) patients with MYD88MUT WM derived a similar durable VGPR rate. No complete response was observed in either arm. The risk difference of VGPR rate between the Brukinsa and ibrutinib treatment groups was estimated at 10.7% (95% CI: -3, 24; p = 0.12). The primary endpoint was not statistically significant (2-sided p-value of 0.12).
Additionally, in a non-randomized exploratory subset of relapsed or refractory MYD88WT WM patients treated with Brukinsa (n = 21), the VGPR rate as assessed by the IRC was 29% (95% CI: 11, 52), which was similar to and consistent with the VGPR rate observed in patients treated with Brukinsa with MYD88MUT WM in Cohort 1. Treatment-naïve patients with MYD88WT WM derived a similar benefit. In light of the unmet therapeutic needs in the MYD88WT WM population, these results are considered clinically meaningful.
Overall, the efficacy results demonstrated durable responses in TN and relapsed or refractory WM patients, irrespective of MYD88 status, as compared to ibrutinib. Although the primary endpoint results did not reach statistical significance, the study results were considered clinically meaningful and therefore sufficient as a basis for approval.
Safety data from 101 patients treated with Brukinsa and 98 patients treated with ibrutinib in the ASPEN study were analyzed. In patients treated with Brukinsa, the most frequently reported treatment-emergent adverse reactions (TEAEs; in ≥20% of patients) of all grades were musculoskeletal pain (30%), neutropenia (25%), upper respiratory tract infection (24%), diarrhea (21%), and hemorrhage (21%). The most frequently reported TEAEs of Grade 3 or higher were neutropenia (16%), hypertension (6%), thrombocytopenia (6%), hemorrhage (5%), anemia (5%), diarrhea (3%), pneumonia (3%), and pyrexia (2%).
Treatment discontinuations due to adverse events were reported for 4% of patients treated with Brukinsa and 9% of patients treated with ibrutinib. Dose reduction or modification due to adverse events were reported for 14% of patients treated with Brukinsa and 24% of patients treated with ibrutinib. The frequency at which dose modifications and discontinuations were observed in the ibrutinib arm are in line with those of other pivotal trials for ibrutinib, which suggests that Brukinsa is likely a tolerable treatment.
Interstitial lung disease (ILD) is an important but rare risk, and was identified as a TEAE in the pivotal trial. Interstitial lung disease is included in the Warnings and Precautions section of the Brukinsa Product Monograph.
Clinically meaningful differences were identified regarding the safety of Brukinsa compared to ibrutinib. These include a decreased risk in developing atrial fibrillation, hypertension and diarrhea. Collectively, these explain the better tolerability of Brukinsa relative to that of ibrutinib.
A Risk Management Plan (RMP) for Brukinsa was submitted by BeiGene Switzerland GmbH 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. A Serious Warnings and Precautions box has been added to the Brukinsa Product Monograph. It includes the instruction that treatment with Brukinsa should be initiated and supervised by a qualified physician experienced in the use of anticancer therapies, and highlights the risk of serious hemorrhage.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Brukinsa Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Brukinsa was accepted.
Brukinsa 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 Brukinsa 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 Brukinsa?
Two separate requests were submitted for an expedited review process under the Priority Review Policy regarding the indication for Brukinsa: one for the treatment of mantle cell lymphoma (MCL), and one for the treatment of Waldenström’s macroglobulinemia (WM).
The request for priority status for the treatment of MCL was rejected, as the benefit‑risk profile of Brukinsa for the treatment of MCL is not considered to be significantly improved over that of existing treatments for this condition.
The request for priority status for the treatment of WM was accepted. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Brukinsa provides a significant increase in efficacy and/or significant decrease in risk, such that the overall benefit‑risk profile is improved over existing therapies for a life‑threatening disease that is not adequately managed by a drug marketed in Canada.
Submission Milestones: Brukinsa
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-06-04 |
| Request for priority status | |
| Filed (for Waldenström's macroglobulinemia [WM]) | 2020-06-16 |
| Filed (for mantle cell lymphoma [MCL]) | 2020-06-19 |
| Approval (for WM) issued by Director, Bureau of Medical Sciences | 2020-07-17 |
| Rejection (for MCL) issued by Director, Bureau of Medical Sciences | 2020-07-24 |
| Submission filed | 2020-08-13 |
| Screening | |
| Screening Acceptance Letter issued | 2020-09-03 |
| Review | |
| Labelling Review complete | 2021-01-06 |
| Review of Risk Management Plan complete | 2021-01-08 |
| Quality Evaluation complete | 2021-02-23 |
| Clinical/Medical Evaluation complete | 2021-02-26 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-03-01 |
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications 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:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Zanubrutinib, the medicinal ingredient in Brukinsa, is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), a signalling molecule of the B cell antigen receptor and cytokine receptor pathways. In B cells, BTK signalling results in the activation of pathways necessary for B cell proliferation, trafficking, chemotaxis, and adhesion. Uncontrolled proliferation can lead to conditions such as Waldenström’s macroglobulinemia (WM). Zanubrutinib inhibits BTK activity by forming a covalent bond with a cysteine residue in the active site of BTK.
Pharmacodynamic studies indicated that the median steady state BTK occupancy of zanubrutinib in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a total daily dose of 320 mg in patients with B cell malignancies. The median steady state BTK occupancy in lymph nodes was 94% and 100% following the recommended dosage of 320 mg once daily or 160 mg twice daily, respectively.
The pharmacokinetics of zanubrutinib were evaluated in healthy subjects and in patients with B cell malignancies. Exposure to zanubrutinib, as measured by the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC), increased proportionally over a dosage range of 40 mg (0.13 times the recommended total daily dose) to 320 mg (the recommended total daily dose). The systemic accumulation of zanubrutinib was limited following repeated administration.
The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Brukinsa have been characterized. In a food effect study, the systemic exposure of zanubrutinib was not affected by a high-fat meal. In vitro, zanubrutinib is primarily metabolized by cytochrome P450 (CYP) 3A. The mean half-life of zanubrutinib was approximately 2 to 4 hours following a single oral dose of 160 mg or 320 mg.
The results of a population pharmacokinetic analysis indicated that age, sex, race, and body weight did not have any clinically meaningful effects on the pharmacokinetics of Brukinsa.
Compared to subjects with normal liver function, the unbound AUC of zanubrutinib increased by 23%, 43%, and 194% in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively.
Renal elimination of zanubrutinib is minimal. Based on a population pharmacokinetic analysis, mild and moderate renal impairment (creatinine clearance [CrCl] ≥30 mL/min) had no influence on the exposure of zanubrutinib. Limited pharmacokinetic data are available in patients with severe renal impairment (CrCl <30 mL/min) or in patients requiring dialysis.
At the approved recommended doses (320 mg once daily or 160 mg twice daily), there were no clinically relevant effects on the QTc interval. In a thorough QT study in healthy subjects, a single dose of 160 mg or 480 mg zanubrutinib did not prolong the QT interval to any clinically relevant extent. The maximum plasma exposure of zanubrutinib in this study was close to the maximum plasma exposure observed in patients following the recommended dose of 320 mg once daily. The effect of Brukinsa on the QTc interval above the therapeutic exposure has not been evaluated.
For further details, please refer to the Brukinsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Brukinsa was evaluated primarily in the ASPEN study (BGB-3111-302), a pivotal Phase III study in adult patients (≥18 years of age) with WM. Patients either had a clinical and definite histological diagnosis of relapsed or refractory WM, or were treatment-naïve and considered unsuitable for standard chemoimmunotherapy regimens. Additionally, patients met at least one criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström’s Macroglobulinemia (IWWM-7) and had measurable disease, defined as a serum immunoglobulin M (IgM) level greater than 0.5 g/dl. Patients with a MYD88 mutation (MYD88MUT) confirmed by gene sequencing were assigned to Cohort 1 (number of patients [n] = 201). Patients with wild type MYD88 (MYD88WT; n = 26) or a missing/inconclusive mutational status (n = 2) were assigned to Cohort 2.
Patients in Cohort 1 were randomized in a 1:1 ratio to receive either Brukinsa 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. Ibrutinib was determined to be an appropriate active control, as it is an acceptable standard of care for the proposed indication in the Canadian setting. The primary efficacy endpoint was the rate of complete response (CR) or very good partial response (VGPR) in patients with relapsed or refractory WM (MYD88MUT; Cohort 1), as assessed by an independent review committee (IRC). At the time of the primary efficacy analysis, the median follow-up time for patients in Cohort 1 was 18.8 months. The results of the primary analysis showed a VGPR rate of 29% (95% confidence interval [CI]: 20, 40) in patients treated with Brukinsa, and 20% (95% CI: 12, 30) in patients treated with ibrutinib. No CR was observed in either arm.
The risk difference of VGPR rate between the Brukinsa and ibrutinib treatment groups was estimated at 10.7% (95% CI: -3, 24; p = 0.12). The primary endpoint was not met as the results were not statistically significant (2-sided p-value of 0.12), but the VGPR rate observed in Brukinsa-treated patients demonstrates activity that is considered clinically meaningful. The results of the primary analysis (in patients with relapsed or refractory WM) were supported by a VGPR rate of 26% (95% CI: 9, 51) in the IRC-assessed treatment-naïve patients and an investigator assessment of CR and VGPR in both treatment-naïve patients and patients with relapsed or refractory WM.
Additionally, in a non-randomized exploratory subset of relapsed or refractory WM patients treated with Brukinsa (n = 21), the VGPR as assessed by the IRC was 29% (95% CI: 11, 52), which was similar to and consistent with the VGPR rate observed in patients treated with Brukinsa in Cohort 1. Treatment-naïve patients with MYD88WT WM also derived a similar benefit. Due to the unmet therapeutic need in this subpopulation of patients, this finding is considered clinically meaningful.
Overall, the efficacy results demonstrated durable responses in WM patients, irrespective of MYD88 status, as compared to ibrutinib. Notably, the primary endpoint results did not reach statistical significance, however the totality of the results were considered clinically meaningful and therefore sufficient as a basis for approval.
Indication
Health Canada approved the following indication:
Brukinsa (zanubrutinib) is indicated for the treatment of adult patients with Waldenström’s macroglobulinemia.
The proposed indication was for the treatment of patients with WM, and was revised to specify adult patients in order to accurately reflect the patient population in the clinical studies.
For more information, refer to the Brukinsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Evidence of the clinical safety of Brukinsa was obtained primarily from the pivotal ASPEN study (described in the Clinical Efficacy section), based on data from 101 patients treated with Brukinsa and 98 patients treated with ibrutinib. At the time of the safety analysis, the median duration of study treatment was 19 months in patients treated with Brukinsa and 19 months in patients treated with ibrutinib.
In patients treated with Brukinsa, the most frequently reported treatment‑emergent adverse reactions (TEAEs; in ≥20% of patients) of all grades were musculoskeletal pain (30%), neutropenia (25%), upper respiratory tract infection (24%), diarrhea (21%), and hemorrhage (21%). Grade 3 or higher TEAEs were reported in 58% of patients treated with Brukinsa, with neutropenia (16%), hypertension (6%), thrombocytopenia (6%), hemorrhage (5%), anemia (5%), diarrhea (3%), pneumonia (3%), and pyrexia (2%) as the most frequently reported events (in ≥2% of patients).
Treatment discontinuations due to adverse events were reported for 4% of patients treated with Brukinsa and for 9% of patients treated with ibrutinib. The most frequently reported adverse events resulting in discontinuation were neutropenia (1%), cardiomegaly (1%), subdural hemorrhage (1%), and plasma cell myeloma (1%). Dose reduction or modification due to adverse events were reported for 14% of patients treated with Brukinsa and 24% of patients treated with ibrutinib. The most frequently reported adverse events resulting in dose reduction were hemorrhage, diarrhea, and infections. The frequency at which dose modifications and discontinuations were observed in the ibrutinib arm are in line with those of other pivotal trials for ibrutinib, which suggests that Brukinsa is likely a tolerable treatment.
Interstitial lung disease (ILD) is an important but rare risk, and was identified as a TEAE in the pivotal trial in WM patients in both cohorts (n = 2) and in the sponsor’s global database (n = 13). Cases of ILD have been reported with other BTK inhibitors (ibrutinib and acalabrutinib). Although ILD has not been identified as frequently in patients treated with Brukinsa, relative to patients treated with ibrutinib, ILD/pneumonitis was identified in patients treated with Brukinsa in both cohorts in the pivotal study. Interstitial lung disease is included in the Warnings and Precautions section of the Brukinsa Product Monograph.
A Serious Warnings and Precautions box has been added to the Brukinsa Product Monograph. It includes the instruction that treatment with Brukinsa should be initiated and supervised by a qualified physician experienced in the use of anticancer therapies, and highlights the risk of serious hemorrhage.
Notably, some important clinically meaningful differences were identified regarding the safety of Brukinsa relative to ibrutinib. Treatment with Brukinsa was associated with an increased risk of developing neutropenia over time when compared to treatment with ibrutinib. However, this did not translate into an overall increase in the risk of infections. In contrast, specific events associated with ibrutinib occurred less frequently following treatment with Brukinsa, such as atrial fibrillation (14% vs 2%), hypertension (16% vs 11%), major bleeding (9% vs 6%), and diarrhea (32% vs 21%). Additionally, reductions in the risk of developing atrial fibrillation, bleeding, hypertension, diarrhea, and pneumonia over time were observed following treatment with Brukinsa, compared to treatment with ibrutinib. Collectively, these are considered clinically meaningful safety benefits that likely explain the higher tolerability of Brukinsa relative to that of ibrutinib.
Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified, and to promote the safe and effective use of Brukinsa. Overall, the benefit‑harm‑uncertainty profile of Brukinsa is favourable for the approved indication.
For more information, refer to the Brukinsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Zanubrutinib, the medicinal ingredient in Brukinsa, demonstrated irreversible and selective inhibition of Bruton’s tyrosine kinase (BTK) in vitro, antiproliferative activity in hematological tumour cells, and effective tumour regression in mouse xenograft models.
Zanubrutinib was well-tolerated based on results from a 6-month study in rats and a 9-month study in dogs, in which the orally administered doses were similar to or exceeded anticipated clinical exposures. In the 6-month study in rats, the main toxicology finding was gastrointestinal tract toxicity associated with histopathological changes. Fully or partially reversible histopathological changes were observed in the pancreas, lungs, and skeletal muscle, which were considered related to zanubrutinib. The no-observed-adverse-effect level (NOAEL) was determined to be 300 mg/kg/day. At this dose, the systemic exposure (as measured by the area under the concentration-time curve; AUC) was approximately 25 times higher in males and 42 times higher in females than the human exposure at the recommended dose.
In the 9-month study in dogs, the toxicological findings or changes were minimal or mild, including abnormal stool, conjunctiva hyperemia, lymphoid depletion, or erythrophagocytosis in the gut-associated lymphoid tissues. The NOAEL was determined to be 100 mg/kg/day. At this dose, the systemic exposure was approximately 20 times higher in males and 18 times higher in females than the human exposure at the recommended dose.
A fertility and early embryonic development study was conducted in which male and female rats were administered oral doses of zanubrutinib ranging from 30 to 300 mg/kg/day. Doses were administered to male rats starting 4 weeks prior to mating and through the mating period, and to female rats starting 2 weeks prior to mating until gestation day 7. No effects were observed on male or female fertility. However, morphological abnormalities in sperm and an increase in post-implantation loss were observed at the dose of 300 mg/kg/day, which corresponds to approximately 9 times the recommended human dose based on body surface area.
Embryo-fetal developmental toxicity studies were conducted in rats and rabbits. Zanubrutinib was administered orally during the period of organogenesis at doses of 30, 75, or 150 mg/kg/day to pregnant rats and doses of 30, 70, or 150 mg/kg/day to pregnant rabbits. In rats, malformations in the heart (2- or 3-chambered hearts) were observed at all dose levels at incidences ranging from 0.3% to 1.5%, in the absence of maternal toxicity. The lowest dose (30 mg/kg/day) corresponds to approximately 5 times the exposure (based on the AUC) in patients receiving the recommended human dose. In rabbits, post-implantation loss was observed at the highest dose (150 mg/kg/day) and was associated with maternal toxicity. This dose corresponds to approximately 33 times the exposure in patients receiving the recommended human dose.
A pre- and postnatal developmental toxicity study was conducted in rats, in which zanubrutinib was administered orally at doses of 30, 75, or 150 mg/kg/day from implantation through weaning. From the groups receiving doses of 75 and 150 mg/kg/day, offspring had decreased body weights prior to weaning. Adverse ocular findings including cataract or protruding eye were observed at all dose levels. The lowest dose (30 mg/kg/day) corresponds to approximately 4 times the exposure in patients receiving the recommended human dose.
Zanubrutinib was not found to be mutagenic in a bacterial mutagenicity (Ames) assay. Results from a chromosome aberration assay in mammalian (Chinese hamster ovary) cells and an in vivo bone marrow micronucleus assay in rats indicate that zanubrutinib is not clastogenic. Carcinogenicity studies have not been conducted with zanubrutinib.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Brukinsa Product Monograph. Considering the intended use of Brukinsa, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Brukinsa 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 Brukinsa 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 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).
Proposed limits of drug‑related impurities are considered adequately qualified (i.e. within International Council for 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 biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| BRUKINSA | 02512963 | BEIGENE SWITZERLAND GMBH | ZANUBRUTINIB 80 MG |