Summary Basis of Decision for Trurapi

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

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

Recent Activity for Trurapi

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 Trurapi, 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 AnchorAnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-08-02

Drug Identification Number (DIN):

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 268368 2022-10-03 Issued NOC 2023-05-24 Submission filed as a Level I – Supplement for changes to the drug product manufacturing process. The information was reviewed and considered acceptable. An NOC was issued.
Drug product (DIN 02529254) market notification Not applicable Date of first sale: 2022-11-03 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 254352 2021-07-05 Issued NOC 2022-07-20 Submission filed as a Level I – Supplement for a new presentation with two new routes of administration. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02529254) was issued for the new presentation. A Regulatory Decision Summary was published.
SNDS # 253575 2021-06-09 Issued NOC 2021-11-26 Submission filed as a Level I – Supplement to update the PM and Package Insert to correct a discrepancy in the instructions for use. The submission was reviewed and considered acceptable. As a result of the SNDS, changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 247795 2020-12-21 Issued NOC 2021-05-20 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, and Storage, Stability and Disposal sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
Drug product (DINs 02506564, 02506572) market notification Not applicable Date of first sale: 2021-03-30 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 226573 2019-10-30 Issued NOC 2020-10-15 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Trurapi

Date SBD issued: 2021-01-27

The following information relates to the New Drug Submission for Trurapi.

Insulin aspart

Drug Identification Number (DIN):

  • DIN 02506572 - 100 units/mL insulin aspart, solution, subcutaneous injection
  • DIN 02506564 - 100 units/mL insulin aspart, solution, subcutaneous injection

sanofi‑aventis Canada Inc.

New Drug Submission Control Number: 226573

 

On October 15, 2020, Health Canada issued a Notice of Compliance (NOC) to sanofi‑aventis Canada Inc. for Trurapi, 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. Trurapi 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, immunogenicity, and safety between the two products. To be considered a biosimilar, the weight of evidence 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 Trurapi and NovoRapid was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within this drug submission, the sponsor requested the authorization of Trurapi for one of the indications that is 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 Trurapi 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. Trurapi should normally be used in regimens together with an intermediate or long-acting insulin.

 

1 What was approved?

 

Trurapi, an anti-diabetic agent, was authorized for the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia. Trurapi should normally be used in regimens together with an intermediate or long-acting insulin.

Trurapi is a biosimilar to NovoRapid. Both drugs contain the medicinal ingredient insulin aspart. Insulin aspart is produced by recombinant deoxyribonucleic acid (rDNA) technology.

Similarity between Trurapi and the reference biologic drug, NovoRapid, has been established on the basis of comparative structural and functional studies, comparative non-clinical 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.

Trurapi is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. Trurapi is also contraindicated during episodes of hypoglycemia.

Trurapi 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.

Trurapi (100 units/mL insulin aspart) is presented as a solution for injection in 3 mL cartridges and in a pre-filled disposable pen injector (Trurapi SoloSTAR). In addition to the medicinal ingredient, the solution contains hydrochloric acid, metacresol, phenol, polysorbate 20, sodium chloride, sodium hydroxide, water for injection, and zinc chloride.

For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.

Additional information may be found in the Trurapi Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Trurapi approved?

 

Health Canada considers that the benefit-risk profile of Trurapi is highly similar to that of the biologic drug, NovoRapid for use in the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia. Trurapi should normally be used in regimens together with an intermediate or long-acting insulin. Similarity between Trurapi 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 anti-diabetic drugs such as metformin and biologics such as insulin and glucagon-like peptide-1 receptor agonists.

Trurapi and NovoRapid contain the medicinal ingredient insulin aspart, a unique human insulin analogue of recombinant deoxyribonucleic acid (rDNA) origin that rapidly lowers blood glucose. The New Drug Submission (NDS) filed for Trurapi requested authorization for one of the indications and clinical uses that are currently authorized for the Canadian Reference Product, NovoRapid. This request was based on an extensive analytical and biological similarity assessment between Trurapi and NovoRapid, in combination with comparative non-clinical and clinical data.

The biosimilar and the reference biologic drug were judged highly similar in terms of quality attributes (based on comparative structural and functional studies).

The results of a pivotal, Phase I, comparative bioavailability study (Study PDY12695) conducted in patients with type I diabetes mellitus (T1DM) established comparable pharmacokinetics and pharmacodynamics between Trurapi and NovoRapid.

The comparative Phase III clinical study (Study EFC15081) ruled out clinically meaningful differences in efficacy, safety, and immunogenicity between Trurapi and NovoRapid in patients with diabetes mellitus also using insulin glargine. The demonstration of similarity enables the biosimilar to rely on the safety and efficacy information of the reference biologic drug for the indication authorized.

The results of this 26-week study and the subsequent 6-month extension study provided data from 597 patients with T1DM or type II diabetes mellitus (T2DM). The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) from baseline to Week 26 using a non-inferiority margin of 0.3%. The safety assessment included an analysis of the immunogenicity of Trurapi and NovoRapid.

At Week 26, treatment with Trurapi provided a mean reduction in HbA1c that was non-inferior to that achieved with the reference product. Fasting plasma glucose decreased from baseline to week 26 in both treatment groups and no relevant differences were observed in the percentage of patients achieving a target HbA1c <7%.

Trurapi has demonstrated a comparable safety profile with its reference product, NovoRapid. The types, frequency, and severity of adverse events were comparable between Trurapi and the reference biologic drug. The incidence of documented symptomatic hypoglycemia was similar in the two treatment groups as was the incidence of severe hypoglycemia. There were no episodes of diabetic ketoacidosis reported as serious adverse events (SAEs) in the reference product and two episodes reported in the Trurapi group. The results also demonstrated similarity in terms of development of insulin aspart antibodies between the treatment groups. 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 has been included in the Product Monograph for Trurapi, as is found in the Product Monograph for NovoRapid.

A Risk Management Plan (RMP) for Trurapi was submitted by sanofi‑aventis Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Truvelog was not accepted. A concern was identified with the risk of name confusion with other currently marketed drug products and the sponsor was requested to submit a new brand name. Upon review, the new brand name Trurapi was accepted.

Based on Health Canada's review, the benefit-risk of Trurapi 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. Trurapi should normally be used in regimens together with an intermediate or long-acting insulin. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Trurapi 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. 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. For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.

 

3 What steps led to the approval of Trurapi?

 

Submission Milestones: Trurapi

Submission Milestone Date
Submission filed 2019-10-30
Screening  
Screening Acceptance Letter issued 2019-12-20
Review  
Review of Risk Management Plan complete 2020-07-03
Quality Evaluation complete 2020-10-07
Clinical/Medical Evaluation complete 2020-10-13
Labelling Review complete 2020-10-13
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate 2020-10-15

 

The Canadian regulatory decision on the review of Trurapi was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the European Medicines Agency (EMA) was used as an added reference.

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?

 

The onus is on the Trurapi sponsor to monitor the post-market safety profile of this biosimilar product 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 Trurapi 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.

As part of the marketing authorization for Trurapi, 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):

  • Since hypoglycaemia, systemic allergic reactions, medication errors and consequences of anti-insulin antibody formation/lack of efficacy are recognized risks for insulin products, the sponsor is requested to closely monitor these events in Periodic Benefit Risk Evaluation Report (PBRERs). In the PBRERs, the sponsor should include an overview and analysis of medication error cases, with a focus on cases reported with an adverse event. Based on the review of this data, the sponsor should also discuss whether further risk minimisation measures should be proposed.

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Trurapi is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision

 

Trurapi 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 Trurapi is considered to be representative of the mechanism of action and pharmacological effect of NovoRapid.

Comparative Structural and Functional Studies

Comparative testing to demonstrate biosimilarity between the proposed biosimilar drug product, Trurapi, and the reference product, European Union (EU)‑sourced NovoRapid, included side-by-side structural and functional characterization studies, statistical evaluation of critical quality attributes between batches, comparative stability (long-term, accelerated, forced degradation), as well as in-use stability studies. These studies also included batches of United States (US)‑sourced NovoLog, in which insulin aspart is also the medicinal ingredient.

Furthermore, long-term, accelerated, stressed, in-use stability, and forced degradation studies showed similar stability profiles, degradation pathways, and degradation rates between Trurapi, EU‑sourced NovoRapid (the reference product), and US‑sourced NovoLog.

The studies conducted have established a high degree of similarity in the primary, secondary and tertiary structure, as well as the purity, biological activity, stability, 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 Trurapi and EU-sourced NovoRapid.

Characterization of the Drug Substance

The Trurapi drug substance (insulin aspart) is an analogue to human insulin. Structurally, it is a two-chain peptide consisting of 51 amino acids, with 21 amino acids in the A-chain and 30 amino acids in the B-chain with a single substitution of the amino acid proline by aspartic acid at position B28.

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 and/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 Trurapi drug substance (insulin aspart) is produced by recombinant deoxyribonucleic acid (rDNA) technology in a non-pathogenic strain of Escherichia coli.

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 Trurapi 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). It is available as 3 mL glass cartridges intended for use with suitable reusable pen devices, or as the Trurapi SoloSTAR disposable pen injector in which the cartridge is irreversibly integrated.

The manufacturing process for the drug product, Trurapi, involves the preparation of an excipient solutions and an insulin aspart solution that are then combined. The resulting formulated bulk solution then undergoes pre-filtration, sterile filtration at the point-of-fill, and aseptic filling into 3 mL cartridges. Following filling and inspection of the filled containers, the 3 mL cartridges are assembled into the disposable pen injectors or packaged as 3 mL cartridges into cartons for use with a marketed, re-useable pen.

The final commercial formulation was used in both Phase I and Phase III clinical trials, including the pivotal trial PDY12695.

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.

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 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 pre-defined acceptance criteria for parameters related to quality, efficacy, and safety are consistently met.

Trurapi 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. Due to the COVID-19 pandemic, it was not possible to complete the planned in-house laboratory testing. Instead, a paper‑based assessment was conducted which involved examination of selected standard operating procedures (SOPs) and the accompanying raw data for multiple lots of Trurapi. The assessment supported the methods as being 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 24 month shelf life at 2°C ‑ 8°C is considered acceptable for Trurapi. Additionally, drug product in-use stability data support the proposed in-use shelf life of 28 days at room temperature up to 30°C, protected from light.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance and drug product was not warranted since the facilities were recently evaluated and obtained a satisfactory rating.

All sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The insulin aspart drug substance was manufactured in a recombinant, non-pathogenic strain of Escherichia coli, which is not susceptible to mammalian viruses. The excipients used in the drug product formulation are not of animal or human origin.

The manufacturing process involves master and working cell banks, which have been thoroughly characterized and tested for microbial contamination in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

 

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 studies compared Trurapi insulin aspart to reference insulin aspart (from European Union [EU]‑sourced NovoRapid) and insulin aspart from United States (US)‑sourced Novolog, and included pharmacodynamic and toxicology comparability studies.

The non-clinical database submitted for Trurapi 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.

In in vitro pharmacodynamic studies, Trurapi insulin aspart and reference insulin aspart demonstrated comparable binding affinities and binding kinetics with insulin receptor (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 glucose uptake, and gene regulation of glucose 6-phosphatase), and mitogenic potency of Trurapi insulin aspart and reference insulin aspart were also comparable. No in vivo pharmacodynamic studies were conducted.

In two pivotal comparative repeat-dose toxicity studies, rats were administered Trurapi insulin aspart or reference insulin aspart at doses of 5, 25, or 100 U/kg body weight, or vehicle control, by subcutaneous injection twice daily (equal to 10, 50, or 200 U/kg body weight/day, respectively) for 1 month. Rats given Trurapi insulin aspart did not develop any unique adverse effects. In one study, one rat from each of the treatment groups died, potentially from hypoglycemia, which is consistent with the pharmacological activity of insulin aspart. Insulin aspart pharmacokinetics (total drug exposure across time [area under the concentration time curve; AUC] and maximum serum concentration [Cmax]) were dissimilar between Trurapi insulin aspart and reference insulin aspart. Anti-drug antibodies developed in a higher percentage of animals administered Trurapi insulin aspart than those receiving the corresponding dose of reference insulin aspart. Overall, no toxicity or tolerability concerns were reported for Trurapi insulin aspart 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 Trurapi Product Monograph. Considering the intended use of Trurapi, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Clinical basis for decision

 

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 support of the indications sought. Therefore, clinical trials are not required to support each indication.

For biosimilars, the purpose of the clinical program 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.

Trurapi was developed as a biosimilar to the reference product, NovoRapid 100 units (U)/mL, marketed in Canada since 2001 and in the European Union since 1999. It is proposed for the treatment of diabetes mellitus in adults, adolescents, and children over the age of two, and is to be used in conjunction with an intermediate or long-acting insulin. This indication is the same as one of the therapeutic indications currently approved for NovoRapid.

Comparative Pharmacokinetic and Pharmacodynamic Studies

The primary activity of Trurapi is the regulation of glucose metabolism. Insulins, including Trurapi, bind to insulin receptors on muscle and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.

As part of the clinical development program, a Phase I study (Study PDY12695) was conducted to demonstrate the similarity in pharmacokinetic (PK) exposure and pharmacodynamic (PD) activity between Trurapi and the reference biologic drug, NovoRapid. The biologic drug NovoLog, which also has insulin aspart as its medicinal ingredient, was also included in this comparison. Study PDY12695 was a randomized, double-blind, single-dose, three-treatment, three-period, six-sequence, crossover study that used the euglycemic clamp technique in subjects with Type 1 Diabetes Mellitus (T1DM). The primary objectives of this study were to compare the exposure and activity of Trurapi to those of NovoRapid and NovoLog. Each subject, under fasted conditions, received single subcutaneous doses of 0.3 U/kg of the three versions of insulin aspart: Trurapi, NovoRapid, and NovoLog. As this was the pivotal PK and PD comparability study for the Trurapi development program, the evaluation of the results focused on the comparison between Trurapi and the declared Canadian Reference Product, NovoRapid.

Serum samples were collected up to 12 hours after dosing and a linear mixed effects model was used to estimate PK and PD parameters. The study demonstrated PK comparability between Trurapi and NovoRapid; the point estimate of the geometric mean ratio for the maximum concentration (Cmax) and the 90% confidence intervals (CI) of the geometric mean ratio for the area under the concentration versus time curve to the time of the last quantifiable concentration (AUCT) were within the comparability margins of 80.0% to 125.0%. Moreover, the study demonstrated PD comparability between Trurapi and NovoRapid; 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 (GIR‑AUC0-12h) 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 patients with T1DM established comparable PK and PD between Trurapi and NovoRapid.

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

Comparative Clinical Efficacy and Safety

Study EFC15081 was a Phase III study conducted to compare the clinical efficacy, safety, and immunogenicity of Trurapi to NovoRapid (the reference biologic drug) and NovoLog in adult patients with diabetes mellitus also using insulin glargine. Study EFC15081 was a 26‑week, multinational, multicentre, randomized, active-controlled, two-arm parallel-group, open-label study with a 6‑month extension. United States (US)‑sourced NovoLog was used in the US, and European Union (EU)‑sourced NovoRapid was used in the other countries.

The primary objective was to demonstrate the non-inferiority of Trurapi to NovoRapid/NovoLog in hemoglobin A1c (HbA1c) change from baseline to Week 26 in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) also using insulin glargine.

Study EFC15081 enrolled 597 patients with T1DM or with T2DM diagnosed for at least 12 months. All patients had measurements of HbA1c in the range of 7% to 10%. Among the 597 randomized patients (301 in the Trurapi group and 296 in the NovoLog/NovoRapid group), 83.2% had T1DM and 16.8% had T2DM. The study participants had a mean age of 48 years and a mean duration of diabetes of 19.5 years. Patient demographics were as follows: 59.6% of patients were male, 82.6% were Caucasian, 3.2% were Black or African American, and 12.5% were Asian. The mean body-mass index was 27.45 kg/m2 and 45.9% of patients had a glomerular filtration rate (GFR) ≥90 mL/min/1.73 m2.

The primary efficacy endpoint was the change in HbA1c from baseline to Week 26 using a non-inferiority margin of 0.3%. The safety assessment included analysis of the immunogenicity of Trurapi and NovoRapid.

At Week 26, treatment with Trurapi provided a mean reduction in HbA1c that was non-inferior to that achieved with the reference biologic drug. Fasting plasma glucose decreased from baseline to Week 26 in both treatment groups and no relevant differences were observed in the percentage of patients achieving a target HbA1c <7%. The total daily doses of Trurapi and the reference biologic drug and the incidence of severe hypoglycemia were similar in the two treatment groups.

The clinical study indicated there are no clinically meaningful differences between the biosimilar and the reference biologic drug with respect to efficacy.

The clinical safety of Trurapi relative to its reference biologic drug, NovoRapid, was evaluated as a secondary objective in Study EFC15081.

The safety profiles were similar between the Trurapi and the NovoRapid/NovoLog groups in terms of the types of reported treatment-emergent adverse effects (TEAEs) and frequency of occurrence. A total of 156/301 (51.8%) patients in the Trurapi group and 146/296 (49.3%) in the NovoLog/NovoRapid group reported TEAEs during the main 6-month on-treatment period. Serious TEAEs were reported in 25 patients (8.3%) in the Trurapi group and in 18 patients (6.1%) in the NovoRapid/NovoLog group. Serious TEAEs were distributed over a variety of System Organ Classes (SOC) without any clustering by Preferred Term (PT).

Two deaths occurred during the main 6-month study period, both in the NovoRapid/NovoLog group. Two additional deaths were reported after the main 6‑month study period, one in each treatment group. None of these events were considered related to the study drug.

The incidence of TEAEs leading to permanent treatment discontinuation was low and similar in the two treatment groups (Trurapi: 1.7% [5 patients]; NovoRapid/NovoLog: 1.0% [3 patients]). Similar incidences of hypersensitivity reactions (3.7% of patients) were reported in the two treatment groups. None were determined to be serious, but they were considered related to treatment in 2 (0.7%) patients in the Trurapi group and in 1 (0.3%) patient in the NovoRapid/NovoLog group. Hypersensitivity reactions resulted in the permanent treatment discontinuation in two patients in the Trurapi group and in one patient in the NovoRapid/NovoLog group.

Treatment-emergent AEs of injection site reactions were reported in a low and similar percentage of patients in the Trurapi group (0.7% [2 patients]) and in the NovoRapid/NovoLog group (1.4% [4 patients]). None of the events were considered related to Trurapi, whereas events were reported by the Investigator as related to NovoRapid/NovoLog in 3 out of 4 patients.

In patients with T1DM, as in the overall population, no meaningful differences were found with respect to safety and tolerability between the two treatment groups. The size of the T2DM group was considered too small to draw any clinically meaningful conclusions on safety in this population.

Overall, the safety profile of Trurapi 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 Trurapi Product Monograph, as they are in the Product Monograph for NovoRapid.

For more information, refer to the Trurapi 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). The immunogenicity of Trurapi relative to that of its reference biologic drug, NovoRapid, was evaluated as a secondary objective in Study EFC15081 (described in the Comparative Clinical Efficacy and Safety section).

During the 6‑month treatment period, analysis of anti‑insulin aspart antibodies (AIAs) showed an overall similar response to Trurapi and NovoRapid/NovoLog for median titers, treatment-boosted, and treatment-induced AIAs. Similar percentages of patients in the two treatment groups had positive AIA titers at baseline (Trurapi: 35.3%; NovoRapid/NovoLog: 36.7%). The percentages of patients with treatment-emergent AIAs (i.e., treatment-boosted or treatment-induced AIAs) during the main 6‑month on-treatment period were also similar in both groups (Trurapi: 16.9% [50/296]; NovoLog/NovoRapid: 20.5% [60/292]).

An evaluation of the potential effects of treatment-emergent AIAs on efficacy and safety did not suggest an impact of treatment-emergent AIAs on clinical outcomes. Mean change in HbA1c from baseline to Week 26, insulin dose, hypoglycemia, hypersensitivity reactions, injection site reactions, or common TEAEs and serious TEAEs were taken into account in this evaluation. In addition, there was no relationship between the maximal AIA titers and insulin doses or efficacy and safety parameters, regardless of treatment-emergent AIA status. There was also no relationship between the maximal AIA titers and insulin doses or efficacy and safety parameters for patients with treatment-emergent AIAs.

Results of analyses of AIAs in subgroups defined by baseline and screening factors (particularly for type of diabetes, type of comparator, and prior use of NovoRapid/NovoLog) showed similar responses for Trurapi and NovoRapid/NovoLog and were thus consistent with the results observed in the overall study population.

Overall, comparative immunogenicity studies ruled out clinically meaningful differences in immunogenicity between the biosimilar and the reference biologic drug in patients with diabetes mellitus.

Indications

Trurapi is considered to be biosimilar to NovoRapid, the reference biologic drug. NovoRapid is authorized and marketed 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.

Within this drug submission, the sponsor requested the authorization of Trurapi for one of the indications that is currently authorized for NovoRapid.

Trurapi (insulin aspart injection) is indicated for:

  • the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia.
  • Trurapi should normally be used in regimens together with an intermediate or long-acting insulin.

Similarity between Trurapi 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. The indication has been authorized on the basis of demonstrated similarity between Trurapi and the reference biologic drug based on 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.

 

 

 

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