Summary Basis of Decision for Kirsty
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 Kirsty is located below.
Recent Activity for Kirsty
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.
The following table describes post-authorization activity for Kirsty, a product which contains the medicinal ingredient insulin aspart. 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 and Applications Guidance.
Updated: 2023-08-17
Drug Identification Number (DIN):
- DIN 02520974 - 100 units/mL insulin aspart, solution supplied in a prefilled pen, subcutaneous administration
- DIN 02520982 - 100 units/mL insulin aspart, solution supplied in a multidose vial, subcutaneous administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NDS # 273553 | 2023-03-22 | Issued NOC 2023-05-11 | Submission filed to transfer ownership of the drug product from BGP Pharma ULC to Biocon Sdn. Bhd. An NOC was issued. |
| Drug product (DIN 02520974) market notification | Not applicable | Date of first sale: 2022-10-20 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 258856 | 2021-11-19 | Issued NOL 2021-12-21 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the primary container closure system and the specifications used to release a primary container closure system component. |
| NDS # 243229 | 2020-10-30 | Issued NOC 2021-10-12 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Kirsty
Date SBD issued: 2022-01-19
The following information relates to the New Drug Submission for Kirsty.
Insulin Aspart
Drug Identification Number (DIN):
- DIN 02520974 - 100 units/mL insulin aspart, solution supplied in a prefilled pen, subcutaneous administration
- DIN 02520982 - 100 units/mL insulin aspart, solution supplied in a multidose vial, subcutaneous administration
BGP Pharma ULC
New Drug Submission Control Number: 243229
On October 12, 2021, Health Canada issued a Notice of Compliance (NOC) to BGP Pharma ULC for Kirsty, a biosimilar to NovoRapid (the reference biologic drug). The terms "biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Kirsty contains the medicinal ingredient insulin aspart, which has been demonstrated to be highly similar to insulin aspart contained in the reference product, NovoRapid.
Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. The weight of evidence for a biosimilar is provided by the structural and functional studies; the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought. For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.
In this drug submission, NovoRapid is the reference biologic drug. Similarity between Kirsty and NovoRapid was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within the submission, the sponsor requested the authorization of Kirsty for the same indication currently authorized for NovoRapid.
The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada's review, the benefit-risk profile of Kirsty is considered to be similar to the benefit-risk profile of the reference product, and is therefore considered favourable for the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia. Kirsty should normally be used in regimens together with an intermediate- or long-acting insulin. Kirsty (10 mL vials) may also be used for continuous subcutaneous insulin infusion in pump systems which are licensed in Canada for insulin infusion.
1 What was approved?
Kirsty, an antidiabetic agent, was authorized for the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia. Kirsty should normally be used in regimens together with an intermediate- or long-acting insulin. The product supplied in 10 mL vials may also be used for continuous subcutaneous insulin infusion in pump systems which are licensed in Canada for insulin infusion.
Evidence from clinical studies and experience suggests that use in the pediatric population is not associated with any differences in safety or effectiveness in comparison to the adult population.
There were no clinically relevant differences in the pharmacokinetics and pharmacodynamics of insulin aspart between elderly and younger subjects.
Kirsty is a biosimilar to NovoRapid. Both drugs contain the medicinal ingredient, insulin aspart and have the same formulation, strength, dosage form, presentations and route of administration. Insulin aspart is produced by recombinant deoxyribonucleic acid (rDNA) technology.
Similarity between Kirsty and the reference biologic drug, NovoRapid, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, comparative bioavailability studies, and comparative clinical trials in patients with diabetes mellitus who require insulin for the control of hyperglycemia, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Kirsty (100 units/mL insulin aspart) is presented as a solution available in a prefilled pen (3 mL cartridge) or a 10 mL vial. In addition to the medicinal ingredient, the solution contains disodium hydrogen phosphate dihydrate, glycerol, metacresol, phenol, sodium chloride, water for injection, and zinc chloride. Hydrochloric acid and sodium hydroxide are used for pH adjustment.
The use of Kirsty is contraindicated during episodes of hypoglycemia. Kirsty is also contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Kirsty Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.
2 Why was Kirsty approved?
Based on Health Canada's review, the benefit-risk profile of Kirsty is considered to be similar to that of the reference product, NovoRapid, and is therefore considered favourable for the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia. Kirsty should normally be used in regimens together with an intermediate-acting or long-acting insulin. Kirsty (10 mL vials) may also be used for continuous subcutaneous insulin infusion in pump systems which are licensed in Canada for insulin infusion. Similarity between Kirsty and NovoRapid was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Diabetes mellitus is a metabolic disorder of carbohydrate metabolism characterized by elevated blood glucose levels (hyperglycemia) over a prolonged period of time. Type 1 diabetes mellitus (T1DM) usually begins at a young age and is mainly due to autoimmune destruction of the pancreatic ß-cells that produce insulin. As a result, patients with T1DM require lifelong insulin supplementation for survival. In type 2 diabetes mellitus (T2DM), the most common form of diabetes accounting for over 90% of all diabetes cases, the combined impact of impaired insulin secretion and insulin resistance results in hyperglycemia. Due to the latter, hyperglycemia may prevail despite plasma insulin levels exceeding those in non-diabetic individuals. Long-term complications from hyperglycemia include heart disease, stroke, retinopathy, and nephropathy. The therapeutic management of diabetes mellitus includes oral antidiabetic drugs such as metformin and biologics such as insulin and glucagon-like peptide-1 receptor agonists.
Kirsty and NovoRapid contain the medicinal ingredient insulin aspart, a unique human insulin analogue of recombinant deoxyribonucleic acid (rDNA) origin that rapidly lowers blood glucose. Kirsty is considered to be biosimilar to NovoRapid. NovoRapid is authorized in Canada for the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia. NovoRapid should normally be used in regimens together with an intermediate or long-acting insulin. NovoRapid (10 mL vials) may also be used for continuous subcutaneous insulin infusion (CSII) in pump systems which are licensed in Canada for insulin infusion.
The New Drug Submission (NDS) filed for Kirsty requested authorization for the same indication that is currently granted to NovoRapid. This request was supported by data from an extensive analytical and biological similarity assessment, in combination with data from comparative non-clinical and clinical studies of Kirsty and the reference product.
Based on the submitted comparative structural and functional studies, Kirsty and NovoRapid were judged highly similar in terms of quality attributes. In addition, the results of a pivotal, Phase I, comparative bioavailability study (MYL-1601D-1001) conducted in healthy subjects established comparable pharmacokinetics and pharmacodynamics between Kirsty and NovoRapid. Furthermore, the comparative Phase III clinical study (MYL-1601D-3001) demonstrated no clinically meaningful differences in efficacy, safety, and immunogenicity between Kirsty and US-sourced NovoLog (used as a suitable proxy for the Canadian reference product) in patients with type 1 diabetes mellitus. The study met its primary endpoint demonstrating that immunogenicity, as assessed by the treatment-emergent antibody response (TEAR) rate, was comparable between the two groups with 24.9% of Kirsty patients and 27.8% of NovoRapid subjects being TEAR positive, after 24 weeks of treatment. The results for secondary endpoints were similar between both groups, with no notable differences at 24 weeks. The types, frequency, and severity of adverse events were similar between patients treated with Kirsty and those treated with NovoLog. The demonstration of similarity enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug for the indication authorized.
Kirsty has demonstrated a comparable safety profile with its reference product, NovoRapid. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. A Serious Warnings and Precautions box highlighting hypoglycemia as the most common adverse effect of insulin product and describing other serious warnings and precautions has been included in the Product Monograph for Kirsty, as is found in the Product Monograph for NovoRapid.
A Risk Management Plan (RMP) for Kirsty was submitted 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 Kirsty Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name Kirsty was accepted.
Overall, Kirsty is considered to have a benefit-risk profile comparable to that which has been established for the claimed indication of its reference biologic drug, NovoRapid. The benefits of Kirsty are considered to outweigh the potential risks.
The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Kirsty 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 Quality (Chemistry and Manufacturing), Non-clinical, and Clinical and Basis for Decision sections.
3 What steps led to the approval of Kirsty?
The Canadian regulatory decision on the review of the quality component of the New Drug Submission for Kirsty 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) as well as questions posed by the European Medicines Agency (EMA) and subsequent responses were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Kirsty
| Submission Milestone | Date |
|---|---|
| New Drug Submission filed | 2020-10-30 |
| Screening | |
| Screening Acceptance Letter issued | 2020-12-17 |
| Review | |
| Review of Risk Management Plan completed | 2021-08-16 |
| Quality evaluation completed | 2021-09-22 |
| Non-clinical evaluation completed | 2021-10-01 |
| Clinical/medical evaluation completed | 2021-10-08 |
| Labelling review completed | 2021-10-06 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2021-10-12 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
The onus is on the Kirsty sponsor to monitor the post-market safety profile of this biosimilar as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Kirsty Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.
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 Quality Basis for Decision
Kirsty was developed as a biosimilar to the reference biologic drug, NovoRapid. For biosimilars, the weight of evidence is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.
The biological activity of Kirsty is considered to be representative of the mechanism of action and pharmacological effect of NovoRapid.
Comparative Structural and Functional Studies
Comparative assessment to demonstrate biosimilarity between the proposed biosimilar drug product, Kirsty, and the reference product, European Union (EU)-sourced NovoRapid, included structural and functional characterization studies, as well as forced degradation studies. These studies also included batches of United States (US)-sourced NovoLog, in which insulin aspart is also the medicinal ingredient.
The studies conducted have established a high degree of similarity in the primary, secondary, and tertiary structure, as well as the purity, biological activity, and forced degradation profiles of the medicinal ingredients in the biosimilar and its reference biologic drug. Taken together, these studies suggest a high degree of comparability between Kirsty and EU-sourced NovoRapid.
Characterization of the Drug Substance
The Kirsty drug substance (insulin aspart) is an analogue to human insulin. Structurally, it is a two-chain peptide consisting of 51 amino acids, with the A and B chains composed of 21 and 30 amino acids, respectively. Insulin aspart differs from human insulin by a single amino acid, where the proline residue at position B28 has been replaced by aspartic acid.
Detailed characterization studies were performed to provide assurance that insulin aspart consistently exhibits the desired characteristic structure and biological activity.
Impurities and degradation products arising from manufacturing or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The Kirsty drug substance (insulin aspart) is produced by recombinant deoxyribonucleic acid (rDNA) technology in a Pichia pastoris expression system.
The manufacturing process of the drug substance consists of a series of stages which include fermentation, recovery, and purification. The materials used in the manufacture of the drug substance are considered suitable and meet standards appropriate for their intended use.
The Kirsty drug product is a sterile, clear, and colourless solution for subcutaneous injection containing 3.50 mg/mL insulin aspart (equivalent to 100 units [U] of insulin aspart per mL).
The manufacturing process for the drug product, Kirsty, involves the preparation of an excipient solution and an insulin aspart solution, that are subsequently combined. The resulting formulated bulk solution then undergoes prefiltration, sterile filtration at the point-of-fill, and aseptic filling into 3 mL cartridges or 10 mL vials. Following filling and inspection of the filled containers, the 3 mL cartridges are assembled into prefilled pens. Both vials and prefilled pens are stored at 2-8 oC. Upon quality control testing, the prefilled pens and vials are released, labelled, and packaged.
The 10 mL vial product presentation was used in the Phase I studies. The manufacturing process was then scaled up to its commercial scale for both presentations. Prefilled pens of Kirsty produced using the commercial-scale process were used in the Phase III study.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of insulin aspart 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 were validated and in accordance with International Council for Harmonisation (ICH) guidelines.
The results of process validation studies showed that predefined acceptance criteria for parameters related to quality, efficacy, and safety are consistently met.
Kirsty is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. Through this program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.
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 30-month shelf life at 5 ± 3 °C for Kirsty is considered acceptable for both vials and prefilled pens.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are 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 and drug product was recommended based on risk assessment scores determined by Health Canada. However, due to the coronavirus disease 2019 (COVID-19) pandemic, an OSE was not feasible. In lieu of an OSE, several risk mitigation strategies were used to resolve issues identified in the submission. Kirsty will be placed in Lot Release Evaluation Group 3 to allow lot-by-lot assessment of lots intended for use in Canada.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The Kirsty drug substance (insulin aspart) is produced by recombinant deoxyribonucleic acid (rDNA) technology in a Pichia pastoris expression system, which is not susceptible to mammalian viruses. The raw materials used in the drug product formulation are not of animal or human origin.
Raw materials/excipients are sourced from qualified suppliers, except for two raw materials used in the drug substance manufacturing process, which are manufactured in-house. Excipients and a small subset of raw materials are reported to be of compendial grade. The remaining raw materials, although they may be supplied as compendial-grade materials, are tested to meet in-house specifications. Furthermore, attestations have been provided for each raw material and excipient confirming that they are free of the risk of transmitting transmissible spongiform encephalopathy (TSE) and bovine spongiform encephalopathy (BSE) agents.
A two-tiered cell banking system has been established for the manufacture of insulin aspart. Both the master and working cell banks have been thoroughly characterized and tested for microbial contamination in accordance with International Council for Harmonisation (ICH) guidelines. Stability of the cell banks has been demonstrated to date and continues to be verified.
7.2 Non-Clinical Basis for Decision
For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.
The non-clinical database submitted for Kirsty was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The non-clinical studies compared Kirsty to reference insulin aspart from EU-sourced NovoRapid and insulin aspart from US-sourced Novolog, and included in vitro pharmacodynamic and in vivo toxicity comparability studies.
The in vitro pharmacodynamic studies demonstrated comparable physiochemical properties and biological activity between Kirsty and reference insulin aspart (EU-NovoRapid and US-NovoLog). Comparable binding affinities and binding kinetics were observed with insulin receptors A and B (IR-A and IR-B) and the insulin-like growth factor-1 receptor (IGF-1R). The biological activity (e.g., receptor activation of IR-A, IR-B, and IGF-1R), metabolic activity (e.g., inhibition of lipolysis, stimulation of adipogenesis, and glucose uptake), and mitogenic potency of Kirsty and reference insulin aspart were also comparable. No comparative in vivo pharmacodynamic studies were conducted.
The pivotal comparative repeat-dose toxicity study did not show toxicity or tolerability concerns for Kirsty that differed from those of the reference insulin aspart (US-NovoLog). In the study, rats were administered subcutaneous injections of Kirsty or reference insulin aspart at doses of 0.105, 0.315, or 1.05 mg/kg body weight twice per day (equal to 0.21, 0.63, or 2.1 mg/kg body weight per day) for 28 days. An additional group of rats was administered vehicle. Rats that were given Kirsty did not develop any unique adverse effects. Female rats administered Kirsty or reference insulin aspart showed reduced motor activity due to hypoglycemia, which is consistent with the pharmacological activity of insulin aspart. Insulin aspart pharmacokinetics (as measured by the area under the concentration-time curve [AUC] and maximum concentration [Cmax]) was dissimilar between Kirsty and reference insulin aspart in males. Anti-drug antibody development was not assessed. Overall, no toxicity or tolerability concerns were reported for Kirsty that differed from those of reference insulin aspart.
The results of the comparative non-clinical studies as well as the potential risks to humans have been included in the Kirsty Product Monograph. In view of the intended use of Kirsty, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Kirsty Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.
Analytical similarity studies (described above) were conducted as a three-way assessment to demonstrate similarity between Kirsty and EU-sourced NovoRapid (used as a proxy for Canadian-sourced NovoRapid), as well as to evaluate additional pairwise comparisons such as Kirsty versus US-sourced NovoLog, and US-sourced NovoLog versus EU-sourced NovoRapid. This approach was intended to bridge EU-sourced NovoRapid to US-sourced NovoLog as the latter was used as a comparator in non-clinical, pharmacokinetic/pharmacodynamic, and Phase III clinical studies. Overall, similarity was shown between Kirsty and EU-approved NovoRapid. The data provided within the studies also support the similarity between US-licensed NovoLog and EU-approved NovoRapid.
Comparative Pharmacokinetic and Pharmacodynamic Studies
The primary activity of Kirsty (insulin aspart) is the regulation of glucose metabolism. Insulins, including Kirsty, bind to insulin receptors on muscle and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and the simultaneous inhibition of glucose output from the liver. Insulin aspart has a more rapid onset of action than human insulin. This is due to a substitution at position B28 that increases charge repulsion between the insulin molecules, preventing their self-association and the formation of hexamers, thereby resulting in a rapid absorption of the insulin molecules at the subcutaneous sites.
Comparable pharmacokinetics and pharmacodynamics between Kirsty and NovoRapid were established in a comparative pharmacokinetic and pharmacodynamic study conducted in healthy subjects. The pivotal Phase I Study MYL-1601D-1001 was conducted to evaluate the similarity of pharmacokinetic properties and pharmacodynamic activity of Kirsty, EU-sourced NovoRapid, and US-sourced NovoLog in healthy participants using the euglycemic clamp technique. Study MYL-1601D-1001 was a randomized, multicentre, double-blind, single-dose, three-treatment, three-period, six-sequence crossover study. Each subject received single dose subcutaneous injections of 0.2 U/kg of three versions of insulin aspart: Kirsty, EU-sourced NovoRapid, and US-sourced NovoLog, under fasted conditions. As this is the pivotal pharmacokinetic and pharmacodynamic comparability study in the Kirsty development program, the results focus on the comparison between Kirsty and the EU-sourced NovoRapid, which is considered a suitable proxy for NovoRapid authorized in Canada as it meets all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Blood samples were collected up to 12 hours after dosing. Plasma insulin aspart concentration profiles and smoothed glucose infusion rate (GIR) profiles were used to calculate pharmacokinetic and pharmacodynamic parameters, respectively. The results of the study demonstrated pharmacokinetic comparability between Kirsty and NovoRapid. The point estimate of the geometric mean ratio for the maximum concentration (Cmax) and the 90% confidence interval (CI) of the geometric mean ratio for the area under the concentration versus time curve from 0 to the time of the last quantifiable concentration (AUCT) were within the comparability margins of 80.0% to 125.0%. Moreover, the study demonstrated pharmacodynamic comparability between Kirsty and NovoRapid as the 95% CI of the geometric mean ratio for the area under the body weight-standardized glucose infusion rate versus time curve from 0 to 12 hours (AUCGIR,0-12h) and the maximum smoothed body weight-standardized glucose infusion rate (GIRmax) were within the comparability margins of 80.0% to 125.0%.
Overall, the pivotal comparative bioavailability study conducted in healthy subjects established comparable pharmacokinetics and pharmacodynamics between Kirsty and NovoRapid, indicating no clinically meaningful differences between the biosimilar and the reference biologic drug. Predefined comparability margins of 80.0% to 125.0% for 90% and 95% confidence intervals for pharmacokinetic and pharmacodynamic parameters, respectively, were met.
For further details, please refer to the Kirsty Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy and Safety
The comparative clinical efficacy of Kirsty and US-sourced NovoLog (used as a suitable proxy for the Canadian reference product) was evaluated in Study MYL-1601D-3001, a Phase III, randomized, open-label, parallel-group, 24-week clinical study in type 1 diabetes mellitus patients.
The primary objective of this study was to demonstrate that immunogenicity, as assessed by the treatment-emergent antibody response (TEAR) rate, was similar between Kirsty and NovoLog. An immunogenicity primary endpoint was selected in order to address residual uncertainty regarding how anti-insulin aspart antibodies affect efficacy and safety. This endpoint was considered suitable and was supported by traditional secondary efficacy endpoints, which included hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), prandial, basal, and total daily insulin, and seven-point self-monitoring of blood glucose.
Male and female patients enrolled in the study were 18 to 65 years of age with a clinical diagnosis of type 1 diabetes mellitus for at least 6 months prior to screening and a stable weight with a body mass index of 18.5 to 35.0 kg/m2 at screening. Patients had to be on a stable dose of once-daily basal Lantus or Toujeo injection and multiple daily bolus of NovoLog or Humalog injections for at least 3 months at screening. They also had to have an HbA1c value of 6.5 to 10.0% and hemoglobin ≥10.0 g/dL at screening.
In the Kirsty group, the mean age was 44.5 years, 54.2% of subjects were male, and 45.8% were female. The majority of patients (210 [88.2%] patients) were White and 23.9% of subjects were of Hispanic or Latino ethnicity. In the NovoLog group, the mean age was 44.2 years, 55.0% of subjects were male, and 45.0% were female. The majority of subjects (210 [87.5%] subjects) were White and 18.8% of subjects were of Hispanic or Latino ethnicity. The mean duration of diabetes at baseline was 22.3 years in the Kirsty group and 21.3 years in the NovoLog group.
The intention-to-treat analysis set was comprised of 478 patients (238 treated with Kirsty and 240 treated with NovoLog). Overall, the baseline disease characteristics of the two treatment groups were similar, except for differences in levothyroxine use in the patients assigned to Kirsty treatment (38 [16%] Kirsty versus 0 [0%] NovoLog). Though this medication can interfere with glycemic control by attenuating the effects of insulin, it was expected that subjects included in the study had stably managed hypothyroidism and there were no observed clinically meaningful differences impacting glycemic control during the run-in or treatment periods.
The study met its primary endpoint demonstrating that immunogenicity, as assessed by the TEAR rate, was comparable between the two groups with 24.9% of Kirsty patients and 27.8% of NovoLog subjects being TEAR positive, after 24 weeks of treatment. The results for secondary endpoints were similar between both groups, with no notable differences at 24 weeks. Numerical differences existed for TEAR positive patients’ change in HbA1c within the Kirsty group from baseline to 24 weeks, and between the Kirsty and NovoLog group at 24 weeks, but these differences were not clinically meaningful. Overall, the efficacy profile of Kirsty was similar to NovoLog up to 24 weeks of treatment.
The types, frequency, and severity of adverse events were similar between patients treated with Kirsty and patients treated with NovoLog. For the Kirsty group, 108 (45.4%) patients reported treatment-emergent adverse events (TEAEs) compared to 103 (42.9%) patients in the NovoLog group. The most frequent TEAEs for both groups were nasopharyngitis, hypoglycemia, and upper respiratory tract infection. Severe (grade 3 or higher) TEAEs were reported in 22 (9.2%) patients in the Kirsty group and 14 (5.8%) patients in the NovoLog group. The most frequently reported severe TEAE was hypoglycemia. A serious adverse event (SAE) of hypoglycemia was reported in 15 (6.3%) patients in the Kirsty group and 10 (4.2%) patients in the NovoLog group. Overall, hypoglycemic events and nocturnal hypoglycemia were reported at a similar frequency and severity in both treatment groups. The rate difference in the SAE of hypoglycemia was not associated with more frequent use of rescue medicine and there did not appear to be a clinically meaningful difference between treatment groups.
The results from this study also demonstrated similar immunogenicity in terms of the development of anti-drug antibodies (ADAs), neutralizing antibodies (NAb), and cross-reactive antibodies. Overall, the safety profile of Kirsty is similar to the reference insulin aspart.
The clinical efficacy study indicated there are no clinically meaningful differences between the biosimilar and the reference biologic drug. Overall, the safety profile of Kirsty is considered to be comparable to that which has been established for the reference biologic drug NovoRapid. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the Kirsty Product Monograph, as they are in the Product Monograph for NovoRapid.
For more information, refer to the Kirsty Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Immunogenicity
Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). One of the secondary objectives of Study MYL-1601D-3001 (described in the Comparative Clinical Efficacy and Safety section) was to compare the change from baseline to Week 24 in the immunogenicity of Kirsty relative to NovoLog when administered in combination with Lantus.
In Study MYL-1601D-3001, at any visit from baseline (inclusive) to Week 24, cumulative ADA positive samples were identified in 210 (88.2%) patients in the Kirsty group and 202 (84.2%) patients in the NovoLog group. Out of those ADA positive samples, NAb positive samples were seen in 33 (13.9%) patients in Kirsty and 30 (12.5%) patients in NovoLog group. At baseline visit, prior to Kirsty treatment, there were 189 (79.4%) and 170 (70.8%) subjects that were ADA positive in the Kirsty and Novolog groups, respectively. Out of these patients, 15 (6.3%) and 17 (7.1%) were NAb positive at baseline in Kirsty and Novolog groups, respectively.
Overall, the comparative immunogenicity results ruled out clinically meaningful differences in immunogenicity between the biosimilar and the reference biologic drug in patients with diabetes mellitus.
Indications
Kirsty is considered to be biosimilar to NovoRapid, the reference biologic drug. Similarity between Kirsty and NovoRapid was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication.
Within this drug submission, the sponsor requested the authorization of Kirsty for the indication that is currently granted to NovoRapid.
Upon review of the submitted information, Kirsty has been authorized for the same indication currently held by NovoRapid, as follows:
Kirsty (insulin aspart) is indicated for treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia.
Kirsty should normally be used in regimens together with an intermediate or long-acting insulin.
Kirsty (10 mL vials) may also be used for continuous subcutaneous insulin infusion in pump systems which are licensed in Canada for insulin infusion.
The indication has been granted on the basis of demonstrated similarity between Kirsty and the reference biologic drug, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanism of the disease involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| KIRSTY | 02520974 | BIOCON SDN.BHD | INSULIN ASPART 100 UNIT / ML |
| KIRSTY | 02520982 | BIOCON SDN.BHD | INSULIN ASPART 100 UNIT / ML |