Summary Basis of Decision for Evenity
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 Evenity is located below.
Recent Activity for Evenity
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Evenity
Updated:
The following table describes post-authorization activity for Evenity, a product which contains the medicinal ingredient romosozumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02489597 - 105 mg/1.17 mL romosozumab, solution, subcutaneous
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02489597) market notification | Not applicable | Date of first sale:2019-08-12 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 197713 | 2016-08-18 | Issued NOC2019-06-17 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Evenity
Date SBD issued: 2019-11-21
The following information relates to the new drug submission for Evenity.
Romosozumab
Drug Identification Number (DIN):
- DIN 02489597 - 105 mg/1.17 mL, solution, subcutaneous administration
Amgen Canada Inc.orporated
New Drug Submission Control Number: 197713
On June 17, 2019, Health Canada issued a Notice of Compliance to Amgen Canada Incorporated for the drug product Evenity.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Evenity is favourable for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture.
1 What was approved?
Evenity, a sclerostin inhibitor, was authorized for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture.
No data are available to Health Canada regarding the use of Evenity in patients younger than 18 years of age. Therefore, an indication for pediatric use has not been authorized.
Of the 6,544 postmenopausal women with osteoporosis treated with Evenity in Phase II and Phase III clinical studies, 5,234 (80%) were 65 years of age or older, and 2,390 (36.5%) were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.
Evenity is contraindicated in:
- patients who are hypersensitive to romosozumab or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container;
- patients with hypocalcemia.
Pre-existing hypocalcemia must be corrected prior to initiating treatment with Evenity.
Evenity 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.
Evenity (105 mg/1.17 mL romosozumab) is presented as a solution. In addition to the medicinal ingredient, the solution contains acetate, calcium, polysorbate 20, sodium hydroxide, sucrose, and water for injection.
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 Evenity Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Evenity approved?
Health Canada considers that the benefit-risk profile of Evenity is favourable for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture.
Osteoporosis is a disease characterized by low bone mass, disruption of the bone structure, and skeletal fragility, resulting in decreased bone strength and an increased risk of fracture. Postmenopausal women with osteoporosis have bone loss related to estrogen deficiency and age. The most common clinical manifestations of osteoporosis are vertebral fractures, which are asymptomatic in two out of three patients. Hip fractures affect up to 15% of women with osteoporosis and their incidence increases with age. Osteoporotic fractures can result in significant morbidity and mortality.
Therapies available in Canada for the treatment of osteoporosis in postmenopausal women include bisphosphonates such as alendronate and etidronate, selective estrogen receptor modulators such as raloxifene, and biologics such as denosumab and teriparatide. Hormone replacement therapy, while effective for osteoporosis, is recommended only in women who also have menopausal symptoms. Supplementation of calcium and vitamin D is recommended in older adults to reduce the risk of fractures.
Evenity (romosozumab) is a humanized immunoglobulin G2 (IgG2) monoclonal antibody that inhibits the action of sclerostin, a regulatory factor in bone metabolism. Romosozumab increases bone formation and, to a lesser extent, decreases bone resorption.
Evenity has been shown to be efficacious in lowering the risk of fracture in postmenopausal women with osteoporosis who are at high risk for fracture. The market authorization of Evenity was based on efficacy and safety data derived from two large pivotal clinical trials. Study 20070337 (FRAME) compared Evenity (number of patients [n] = 3,589) to placebo (n = 3,591) for 12 months, followed by open-label denosumab in both groups to month 24. As an active comparator-controlled trial, Study 20110142 (ARCH) compared Evenity (n = 2,046) to oral alendronate (n = 2,047) for 12 months, followed by open-label alendronate in both groups until the end of the study. The study was designed as an event-driven study and the primary analysis was to occur after at least 330 subjects experienced a clinical fracture and all subjects had the opportunity to attend the month 24 visit. In the placebo-controlled study, Evenity reduced the incidence of new vertebral fractures through month 12. The reduction in risk of fracture persisted through month 24 in patients who received Evenity during the first 12 months. In the alendronate-controlled study, Evenity reduced the incidence of new vertebral fracture at month 24 and the risk of clinical fractures through the primary analysis period, after a median follow-up time of 33 months. In addition, Evenity increased bone mineral density at the lumbar spine, total hip, and femoral neck compared to the respective control group (placebo or alendronate) at month 12. In both studies, the results were clinically meaningful and statistically significant.
The safety of Evenity was evaluated in over 7,500 patients in Phase I, Phase II, and Phase III clinical studies who received at least one dose of Evenity, including over 5,700 patients who received Evenity for at least 12 months. Adverse events that were more frequently reported in Evenity-treated patients as compared to control patients in the first 12 months of treatment included cataracts, dyspepsia, asthenia, peripheral edema, nasopharyngitis, dyslipidemia, arthralgia, muscle spasms, neck pain, headache, paresthesia, insomnia, depression, and cough. Other adverse events included major adverse cardiovascular events (discussed below), hypocalcemia, hypersensitivity, osteonecrosis of the jaw, atypical femoral fractures, and injection-site reactions.
Importantly, an imbalance in major adverse cardiovascular events was observed during the 12-month double-blind treatment period of the alendronate-controlled Study 20110142. Positively-adjudicated major adverse cardiovascular events were reported in 41 (2.0%) Evenity-treated patients and 22 (1.1%) alendronate-treated patients. The imbalance was driven primarily by serious myocardial infarction and stroke events. A similar imbalance was not observed during the 12-month double-blind treatment period of Study 20070337.
Extensive subgroup analyses using individual and combined study data did not clearly identify a population at consistently increased relative risk for major adverse cardiovascular events with Evenity versus control. However, these analyses were limited based on the relatively small total number of patients who experienced events. The subgroups considered included patients with histories of previous myocardial infarction or stroke events, other cardiovascular diseases, and patients with major and minor risk factors for cardiovascular disease.
The imbalance in major adverse cardiovascular events reported in Study 20110142 and the remaining uncertainty regarding the baseline risk in the study population support risk minimization strategies implemented through product monograph labelling and pharmacovigilance activities. Accordingly, a Serious Warnings and Precautions box in the Evenity Product Monograph indicates that Evenity may increase the risk of myocardial infarction, stroke, and cardiovascular death, and highlights that its use is not recommended in patients with a history of myocardial infarction or stroke. The sponsor has a post-marketing requirement imposed by the United States Food and Drug Administration (FDA) to evaluate the feasibility of conducting an additional post-marketing study or trial assessing the cardiovascular safety of Evenity. Depending on the results of this feasibility evaluation, the FDA may require the sponsor to conduct an additional, comparative safety study or trial. The results of the feasibility evaluation, and any additional study or trial, if/when completed, will also be submitted to Health Canada (see What follow-up measures will the company take?).
A Risk Management Plan (RMP) for Evenity was submitted by Amgen Canada Incorporated 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 Evenity 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 Evenity was accepted.
Overall, the benefits of Evenity seen in the pivotal studies are considered to outweigh the potential risks in the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Evenity 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 Evenity?
The New Drug Submission (NDS) for Evenity was filed on August 18, 2016. A Notice of Deficiency (NOD) was issued on July 20, 2017 due to multiple deficiencies, which precluded establishing an overall benefit-risk ratio for Evenity. In particular, there were concerns related to cardiovascular safety signals detected in data from clinical trials that had not been submitted to Health Canada as part of the NDS (see Clinical Safety). The sponsor filed a response to NOD on August 8, 2018. Upon review of the new information provided in the sponsor's response to NOD, Health Canada issued a Notice of Compliance for Evenity on June 17, 2019.
Submission Milestones: Evenity
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2016-06-21 |
| Submission filed: | 2016-08-18 |
| Screening | |
| Screening Acceptance Letter issued: | 2016-10-07 |
| Review | |
| On-Site Evaluation: | 2017-03-08 - 2017-03-10 |
| Review of Risk Management Plan complete: | 2017-05-31 |
| Quality Evaluation complete: | 2017-07-06 |
| Clinical/Medical Evaluation complete: | 2017-07-07 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2017-07-04 |
| Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (safety issues): | 2017-07-20 |
| Response filed: | 2018-08-08 |
| Screening of Response to NOD | |
| Screening Acceptance Letter issued: | 2018-08-21 |
| Review of Response to NOD | |
| Review of Risk Management Plan complete: | 2019-01-22 |
| Quality Evaluation complete: | 2019-02-19 |
| Clinical/Medical Evaluation complete: | 2019-06-17 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2019-06-17 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2019-06-17 |
The Canadian regulatory decision on the review of Evenity was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Evenity, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) submitting:
- Periodic Benefit-Risk Evaluation Reports (PBRERs)/Periodic Safety Update Reports (PSURs) for Evenity every six months for the next three years, and thereafter, as requested by Health Canada. Each PBRER/PSUR is expected to contain analyses of the following types of adverse events:
- hypocalcemia, hypersensitivity, major adverse cardiovascular events (including the results of the comparative safety study of major adverse cardiovascular events as required by the United States Food and Drug Administration, if/when completed), osteonecrosis of the jaw, atypical femoral fractures, immunogenicity, malignancies, serious infections and infestation, pregnancy outcomes, hyperlipidemia/dyslipidemia, and cataracts.
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
The medicinal ingredient in Evenity, romosozumab, is a humanized monoclonal antibody (immunoglobulin G2 [IgG2]) that inhibits the action of sclerostin, a regulatory factor in bone metabolism. Romosozumab increases bone formation and, to a lesser extent, decreases bone resorption. Animal studies showed that romosozumab stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity, resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength.
Pharmacokinetic and/or pharmacodynamic data for romosozumab were available from 19 clinical trials. Two comparative bioavailability studies bridged the formulation tested in Phase III studies to the to-be-marketed formulation.
Romosozumab exhibited nonlinear pharmacokinetic properties, with the drug clearance decreasing as the dose increased.
Serum levels of the bone formation marker procollagen type 1 N-telopeptide (P1NP) increased and reached a peak at week 2 after initiating treatment with romosozumab. This increase was followed several months later by a decline to the P1NP levels observed with placebo.
Of the 5,914 postmenopausal women treated with romosozumab at the recommended dose, 18.1% developed anti-romosozumab binding antibodies. Of these, 4.7% were neutralizing antibodies. The presence of anti-romosozumab binding antibodies decreased romosozumab exposure by up to 22%, whereas neutralizing antibodies decreased its exposure by up to 63%.
Overall, the clinical pharmacology data provided support for the proposed regimen of a monthly subcutaneous dose of 210 mg Evenity. No dosage adjustments were recommended for patients with renal impairment or end-stage renal disease requiring hemodialysis.
For further details, please refer to the Evenity Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Evenity for the treatment of osteoporosis in postmenopausal women at high risk for fracture was evaluated in two pivotal Phase III clinical trials, Study 20070337 (FRAME) and Study 20110142 (ARCH).
Study 20070337 (FRAME) was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 7,180 postmenopausal women aged 55 to 90 years, who had a bone mineral density T-score less than or equal to -2.5 but greater than -3.5 at the total hip or femoral neck. Patients were randomized to receive Evenity 210 mg subcutaneously (number of patients [n] = 3,589) or placebo (n = 3,591) once monthly for 12 months, with daily supplementation of 500 to 1,000 mg calcium and 600 to 800 IU vitamin D. After the 12-month double-blind treatment period, patients transitioned to open-label treatment with denosumab 60 mg subcutaneously every 6 months for 12 months. The co-primary efficacy endpoints of the trial were the incidence of new vertebral fracture through month 12 and month 24.
The study demonstrated that Evenity reduced the incidence of new vertebral fractures through month 12 compared to placebo (relative risk reduction [RRR] = 72%; 95% confidence interval [CI]: 49%-85%; p<0.001). The result was clinically meaningful and statistically significant. The reduction in fracture risk persisted through month 24 (RRR = 76%; 95% CI: 60%-86%; p<0.001) in patients who received Evenity during the first year and transitioned to denosumab as compared to patients who transitioned from placebo to denosumab. Evenity also increased bone mineral density at the lumbar spine, total hip, and femoral neck compared with placebo at month 12.
Study 20110142 (ARCH) was a randomized, double-blind, alendronate-controlled clinical trial conducted in 4,093 postmenopausal women aged 55 to 90 years. Patients who were enrolled in the study had:
- a bone mineral density T-score less than or equal to -2.5 at the total hip or femoral neck and either at least one moderate or severe vertebral fracture or at least two mild vertebral fractures; or
- a bone mineral density T-score less than or equal to -2.0 at the total hip or femoral neck and either at least two moderate or severe vertebral fractures or a history of a recent proximal femur fracture.
Patients received monthly subcutaneous injections of Evenity (n = 2,046) or weekly oral dose of alendronate (70 mg) (n = 2,047) for 12 months, with daily supplementation of 500 to 1,000 mg calcium and 600 to 800 IU vitamin D. Following the 12-month double-blind treatment, the patients transitioned to open-label treatment with alendronate. The primary efficacy endpoints were the incidence of new vertebral fracture at month 24 and time to the first clinical fracture through the primary analysis period. Clinical fracture was a composite endpoint of nonvertebral fracture and symptomatic vertebral fracture. As this was an event-driven trial, the primary analysis was performed when all patients who remained in the study had completed the month 24 visit and clinical fracture events were confirmed for at least 330 patients.
The study demonstrated that treatment with Evenity reduced the incidence of new vertebral fracture at month 24 (RRR = 48%; 95% CI: 34%-60%; p<0.001) and the risk of clinical fractures through the primary analysis period (hazard ratio [HR] = 0.73; 95% CI: 0.61-0.88; p<0.001). The results were clinically meaningful and statistically significant. As subjects with nonvertebral fracture comprised 83% of the subjects with clinical fracture during the primary analysis period, the observed effect on clinical fractures was driven by results in this subgroup. The median duration of patient follow-up for the primary analysis period was 33 months (range: 0-56 months). Evenity also increased bone mineral density at the lumbar spine, total hip, and femoral neck as compared to alendronate at month 12.
Of note, neither study was prospectively powered to assess the effect of Evenity on hip fractures, which are associated with high morbidity and mortality in patients with osteoporosis.
Indication
The New Drug Submission for Evenity was filed by the sponsor with the following indication:
- Evenity is indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.
To reflect the patient population studied in the two pivotal trials, the indication was revised by removal of the wording " or patients who have failed or are intolerant to other available osteoporosis therapy". Accordingly, Health Canada approved the following indication:
- Evenity is indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture.
For more information, refer to the Evenity Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Evenity for the treatment of osteoporosis in postmenopausal women at high risk for fracture was evaluated primarily in two pivotal Phase III clinical trials, Study 20070337 (FRAME) and Study 20110142 (ARCH) (described in the Clinical Efficacy section). As the duration of treatment with Evenity is limited to one year, the 12-month controlled periods of the pivotal studies provided the most relevant clinical safety data.
In Study 20070337, there were 3,581 patients exposed to Evenity during the 12-month double-blind placebo-controlled period. Treatment-emergent adverse events were reported in 78.4% of patients who received Evenity and 79.7% of patients who received placebo. The most frequently reported adverse reactions in the Evenity group (with an incidence greater than or equal to 5% and with a higher incidence than placebo) were arthralgia (13.1%) and headache (6.6%). Serious adverse events were reported in 344 (9.6%) patients who received Evenity and 314 (8.8%) patients who received placebo. Deaths occurred in 29 (0.8%) patients in the Evenity group and 24 (0.7%) patients in the placebo group.
In Study 20110142, 2,040 patients were exposed to Evenity and 2,014 patients were exposed to alendronate during the 12-month double-blind period. Adverse events were reported in 75.6% of patients who received Evenity and 78.6% of patients who received alendronate. The most frequently reported adverse reactions in the Evenity group (with an incidence greater than or equal to 5%) were arthralgia (8.1%) and headache (5.2%). Serious adverse events were reported in 262 (12.8%) patients who received Evenity and 278 (13.8%) patients who received alendronate. Deaths occurred in 30 (1.5%) patients in the Evenity group and 22 (1.1%) patients in the alendronate group.
The following adverse events were more frequently reported in Evenity-treated patients compared to control (alendronate or placebo) in the first 12 months of treatment: cataracts, dyspepsia, asthenia, peripheral edema, nasopharyngitis, dyslipidemia, arthralgia, muscle spasms, neck pain, headache, paresthesia, insomnia, depression and cough. Other adverse events include major adverse cardiovascular events (discussed below), hypocalcemia (<0.1% Evenity versus <0.1% control), hypersensitivity (7% Evenity versus 7% control), osteonecrosis of the jaw (one patient in the Evenity group), atypical femoral fractures (one patient in the Evenity group) and injection-site reactions (5% Evenity versus 3% control).
Notably, during the 12-month double-blind treatment period of Study 20110142, an imbalance in major adverse cardiovascular events was observed for Evenity in comparison to alendronate. Positively-adjudicated major adverse cardiovascular events were reported in 41 (2.0%) Evenity-treated patients and 22 (1.1%) alendronate-treated patients (hazard ratio: 1.87 [95% CI: 1.11-3.14]). The reported imbalance was driven primarily by myocardial infarction and stroke events. A similar imbalance was not observed during the 12-month double-blind treatment period of Study 20070337.
The potential risk of myocardial infarction, stroke and cardiovascular death is highlighted in a Serious Warnings and Precautions box in the Evenity Product Monograph. Evenity is not recommended in patients with a history of myocardial infarction or stroke.
For more information, refer to the Evenity Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The medicinal ingredient in Evenity, romosozumab, was shown to selectively bind to human sclerostin (a regulatory factor in bone metabolism) in vitro.
In cynomolgus monkeys, treatment with romosozumab increased bone mineral density and bone mineral content of trabecular and/or cortical bone. The increases in bone mineral density correlated with increases in bone strength in most anatomical structures.
Pivotal toxicological studies in monkeys and rats did not identify any significant adverse effects on cardiovascular or respiratory endpoints. In rats, phosphorus, urea, and glucose levels were found to increase transiently. In addition, a transient decrease in the number of leukocytes was observed within the first months of treatment. The no-observed-adverse-effect level for toxicological endpoints was 38-fold and 93-fold higher in the rat and cynomolgus monkey, respectively, than the clinical exposure at the recommended dose of 210 mg romosozumab every month.
Carcinogenicity studies did not identify any changes in mortality or any significant increases in the incidence of neoplasms. Genotoxicity studies have not been conducted with romosozumab.
Reproductive and developmental effects of romosozumab were assessed in the rat in a preliminary and definitive embryo-fetal development study, a combined fertility and embryo-fetal development study, and a prenatal and postnatal development study. The combined developmental findings indicate that romosozumab may cause fetal harm.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Evenity Product Monograph. In view of the intended use of Evenity, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
Appropriate warnings and precautionary measures are in place in the Evenity Product Monograph to address the identified safety concerns.
For more information, refer to the Evenity Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
The medicinal ingredient in Evenity, romosozumab, is a humanized immunoglobulin G2 (IgG2) monoclonal antibody with high affinity and specificity for sclerostin. Sclerostin is a glycoprotein that binds to the low-density lipoprotein receptor-related proteins 4, 5, and 6 (LRP4, LRP5, and LRP6), thereby inhibiting Wingless-related integration (Wnt) signalling and reducing osteoblast-mediated bone formation. By inhibiting sclerostin, romosozumab increases bone formation and, to a lesser extent, decreases bone resorption. Romosozumab has an approximate molecular weight of 149 kDa.
Detailed characterization studies were performed to provide assurance that romosozumab consistently exhibits the desired characteristic structure and biological activity.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Romosozumab is expressed in a mammalian cell line (Chinese hamster ovary cells) by recombinant deoxyribonucleic acid (DNA) technology. The cell line is cryopreserved using a two-tier cell banking system. The cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses according to relevant International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated the stability of these cell banks.
The drug substance manufacturing process consists of cell culture, harvest, and purification operations, including a series of chromatographic, viral inactivation and viral filtration steps. The drug substance is formulated in a final ultrafiltration/diafiltration step, filtered, frozen at -30±10ºC, and shipped to the drug product filling site.
The sponsor has demonstrated that the proposed drug substance manufacturing facility is capable of consistently manufacturing formulated drug substance of the desired quality.
The formulated drug substance is thawed, pooled, diluted to 90 mg/mL, and filled into single-use syringes. Each prefilled single-use syringe contains 105 mg of romosozumab in 1.17 mL of solution (90 mg/mL).
The sponsor has demonstrated that the proposed drug product manufacturing site is capable of consistently manufacturing drug product of acceptable quality.
The integrated control strategy negotiated with the sponsor adequately monitors the quality of the drug substance and drug product through manufacturing and to the end of shelf life.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of romosozumab with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.
Through Health Canada's lot release testing and evaluation program, final product lots were tested using a subset of release methods. The results meet specifications and are comparable to the release results reported in the certificates of analysis. The methods are considered suitable for their intended use.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at 2ºC to 8ºC for Evenity is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.
An on-site evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was waived as the facility had been a subject to a recent OSE, completed with a satisfactory rating.
An OSE of the facility involved in the manufacture and testing of the drug product was conducted and resulted in a satisfactory rating.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.
The excipients used in the drug product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| EVENITY | 02489597 | AMGEN CANADA INC | ROMOSOZUMAB 105 MG / 1.17 ML |