Summary Basis of Decision for Lapelga

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 Lapelga is located below.

Recent Activity for Lapelga

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 Lapelga

Updated:  2023-08-24

The following table describes post-authorization activity for Lapelga a product which contains the medicinal ingredient pegfilgrastim. 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 AnchorManagement of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN)

  • DIN 02474565 - 6 mg (10 mg/mL), pegfilgrastim, solution, subcutaneous administration (pre-filled syringe)
  • DIN 02529343  - 6 mg (10 mg/mL), pegfilgrastim, solution, subcutaneous administration (pre-filled autoinjector)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 273956 2023-03-31 Issued NOL 2023-07-07 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for updates to in-process controls, analytical procedures, and specifications for the drug substance and intermediate. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 271705 2023-01-24 Issued NOL 2023-02-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the parameters of an approved holding step. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02529343) market notification Not applicable Date of first sale: 2022-11-28 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 267210 2022-08-19 Issued NOL 2022-10-07 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 259222 2021-12-01 Issued NOC 2022-07-22 Submission filed as a Level I – Supplement for the addition of a secondary container closure system. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02529343) was issued for the new presentation.
SNDS # 261230 2022-02-04 Issued NOC 2022-07-06 Submission filed as a Level II – Supplement (Safety) to update the PM with the new safety information and migrate the PM to the 2020 format to align with that of the reference biologic drug, Neulasta. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 252960 2021-05-20 Issued NOC 2021-12-23 Submission filed as a Level I – Supplement for a change to the primary container closure system, with corresponding labelling updates. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 249975 2021-02-25 Issued NOL 2021-06-09 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug substance release and shelf‐life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 251056 2021-03-22 Issued NOL 2021-04-26 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance manufacturing process The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 243187 2020-08-21 Issued NOC 2020-12-17 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 241793 2020-07-15 Cancellation Letter 2020-08-18 Submission filed as a Level I – Supplement to update the PM with new safety information. The change was not in scope of a Level I change but was considered to be a Level II (Safety) change. The sponsor cancelled the submission administratively.
SNDS # 232877 2019-10-25 Issued NOC
2019-12-27		 Submission filed as a Level I - Supplement for labelling updates. . The updates to the labels were reviewed and considered acceptable. An NOC was issued.
NC # 228607 2019-06-12 Issued NOL
2019-08-01		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02474565) market notification Not applicable Date of first sale:
2019-02-27		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 217389 2018-06-18 Issued NOL
2018-09-18		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 219156 2018-08-13 Issued NOL
2018-08-24		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with the safety labelling language for aortitis so the PM aligns with the PM for Neulasta (pegfilgrastim) and to provide corresponding updates to the package insert. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 204841 2017-04-21 Issued NOC
2018-04-05		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Lapelga

Date SBD issued: 2018-07-06

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

Pegfilgrastim
6 mg (10 mg/mL), solution, subcutaneous

Drug Identification Number (DIN):

  • 02474565

Apotex Inc.

New Drug Submission Control Number: 204841

 

On April 5, 2018, Health Canada issued a Notice of Compliance (NOC) to Apotex Inc. for Lapelga, a biosimilar to Neulasta (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. Lapelga contains a highly similar version of pegfilgrastim to the innovator drug Neulasta.

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. 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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

In this drug submission, Neulasta is the reference biologic drug. Similarity between Lapelga and Neulasta 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 Lapelga for the same indication that is currently authorized for Neulasta.

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. According to Health Canada's review, the benefit-risk profile of Lapelga is considered to be positive based on Lapelga being highly similar to the reference biologic drug. Lapelga is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.

 

1 What was approved?

 

Lapelga, an immunostimulant, was authorized with an indication to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.

Lapelga is a biosimilar to Neulasta. Both drugs contain the medicinal ingredient, pegfilgrastim. Pegfilgrastim is a long-acting, covalent conjugate of recombinant methionyl human granulocyte-colony stimulating factor (G-CSF, filgrastim) and monomethoxypolyethylene glycol (PEG).

Similarity between Lapelga and the reference biologic drug, Neulasta, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, and comparative clinical studies including a pharmacokinetic and pharmacodynamics study and an efficacy and safety study in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Lapelga is contraindicated in patients with known hypersensitivity to Escherichia coli-derived proteins‚ pegfilgrastim‚ filgrastim, or any other component of the product.

Lapelga 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.

Lapelga (6 mg [10 mg/mL] pegfilgrastim) is presented as a solution for injection for subcutaneous use only. In addition to the medicinal ingredient, the solution contains glacial acetic acid, sodium hydroxide, sorbitol, polysorbate 20 and water for injection.

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

 

2 Why was Lapelga approved?

 

Health Canada considers the benefit-risk profile of Lapelga to be positive based on Lapelga being highly similar to the reference biologic drug Neulasta. Lapelga is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs. Similarity between Lapelga and Neulasta was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Lapelga is considered to be a biosimilar to Neulasta. Neulasta, a pegylated filgrastim (pegfilgrastim), has been authorized in Canada since 1994 and has an established favourable benefit-risk profile for the treatment of cancer patients with non-myeloid malignancies undergoing myelosuppressive chemotherapy.

The New Drug Submission (NDS) filed for Lapelga requested authorization for the only indication that is currently authorized for Neulasta. The indication has been authorized on the basis of demonstrated similarity between Lapelga and the reference biologic drug.

Lapelga is a pegylated version of filgrastim (referred to as pegfilgrastim), which is a recombinant form of human granulocyte-colony stimulating factor (G-CSF) produced in and purified from Escherichia coli. The pegylation increases the residence time of pegfilgrastim in the circulation allowing for less frequent dosing compared to filgrastim. The G-CSF acts on hematopoietic cells by binding to specific cell surface receptors thereby stimulating proliferation, differentiation, commitment, and end-cell functional activation, including proliferation of neutrophils.

The results of the assessment indicated that Lapelga and Neulasta are highly similar with respect to their physicochemical and biological properties and support the quality requirements for Lapelga to be considered a biosimilar to Neulasta.

To support the quality assessment that Lapelga was highly similar to Neulasta, the sponsor provided evidence of comparable pharmacokinetic (PK) and pharmacodynamic (PD) activity of Lapelga and Neulasta in a healthy volunteer comparative two-way crossover study. The ratios of the geometric means of Lapelga/Neulasta (test/reference) were within the predefined acceptance range of 80% to 125% for the area under the curve (AUC) from time zero up to the sampling time for the last non-zero concentration (AUCt), the AUC from time zero to infinity (AUCinf) and the maximum plasma concentration (Cmax). In addition, the 90% confidence interval of the geometric mean ratio for AUCs was also contained within this acceptance range for the potency corrected data. For PD comparisons, the area under the effect curve for absolute neutrophil counts from time zero measured up to the last sampling time (AUECt), as well as the maximum effective concentration (Emax), were determined for Lapelga and Neulasta. The ratios of AUECt and Emax of Lapelga/Neulasta as well as the 95% confidence intervals of the ratios were also contained within the predefined acceptance range of 80% to 125%.

The safety and immunogenicity comparisons of Lapelga to Neulasta were assessed in a randomized, assessor-blinded, active-controlled study in patients with early breast cancer receiving docetaxel, doxorubicin, and cyclophosphamide (the TAC regimen) anticancer chemotherapy in the adjuvant setting. No clinically meaningful differences in safety and immunogenicity between Lapelga and Neulasta were observed. Bone pain was the most commonly reported adverse drug reaction related to pegfilgrastim. There were no discontinuations due to severe bone pain. Bone pain was generally reported as mild to moderate and could be controlled in most patients with non-narcotic analgesia.

A Serious Warnings and Precautions box describing splenic rupture and severe sickle cell crises has been included in the Product Monograph for Lapelga, as is found in the Product Monograph for Neulasta.

A Risk Management Plan (RMP) for Lapelga was submitted by Apotex 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 Lapelga was accepted.

Overall, the therapeutic benefits of Lapelga therapy were consistent with the known benefits of the reference biologic drug Neulasta and no clinically meaningful differences in safety were reported. On the basis of the submitted results, and taking into consideration the similarity demonstrated in comparative structural, functional, and non-clinical studies, the totality of data supports the authorization of Lapelga for the same indication as Neulasta.

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 Basis for Decision sections.

 

3 What steps led to the approval of Lapelga?

 

Submission Milestones: Lapelga

Submission Milestone Date
Pre-submission meeting: 2014-10-30
Submission filed: 2017-04-21
Screening  
Screening Acceptance Letter issued: 2017-06-09
Review  
Review of Risk Management Plan complete: 2018-03-01
Quality Evaluation complete: 2018-03-21
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-03-21
Clinical Evaluation complete: 2018-04-05
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-04-05

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Lapelga was based on a critical assessment of the data package submitted to Health Canada. Questions and answers from the United States Food and Drug Administration (FDA) were 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?

 

The onus is on the Lapelga 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 Lapelga 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 Lapelga, 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):

  • Clarification of the measures planned to be undertaken in Canada in order to distinguish adverse event reports for the biosimilar from those for other authorized products.
  • Revision of the proposed follow-up questionnaires to increase their clarity and ease of use, in order to minimize barriers to the reporting of adverse reactions and to encourage the reporting of high-quality post-marketing/adverse reaction data.

 

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

 

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's life cycle.

The PAAT for Lapelga 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

 

Lapelga (pegfilgrastim) was developed as a biosimilar to the reference biologic drug, Neulasta. For biosimilars, the weight of evidence is provided by structural and functional studies. 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 Lapelga is considered to be representative of the mechanism of action and pharmacological effect of Neulasta.

Comparative Structural and Functional Studies

The sponsor performed head-to-head characterization, stability (under accelerated and stressed conditions) and forced degradation studies to compare the drug substance (pegfilgrastim) and drug product (Lapelga) to the reference biologic drug, Neulasta.

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 Lapelga and Neulasta.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that pegfilgrastim 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

Lapelga (pegfilgrastim) is a long-acting, covalent conjugate of recombinant methionyl human granulocyte-colony stimulating factor (G-CSF, filgrastim) and monomethoxypolyethylene glycol (PEG).

The manufacture of the Lapelga drug substance is performed using the following steps: pegylation of the filgrastim critical intermediate, purification by chromatography, ultrafiltration/diafiltration, and filtration. A single monomethoxypolyethylene glycol (PEG) molecule is bound to filgrastim via an amine bond. The critical intermediate, filgrastim, is produced in Escherichia coli cells through use of standard recombinant deoxyribonucleic acid (DNA) technology. The manufacture of the filgrastim critical intermediate consists of a series of steps which include cell culture, harvest, purification stages, and formulation. The sponsor has demonstrated that the manufacturing facility is capable of consistently producing pegfilgrastim drug substance of acceptable quality.

The Lapelga drug product is manufactured using common methodologies for the production of aseptic protein products. The drug product manufacturing process consists of the following steps: preparation of the filtered formulation buffer, preparation of the formulated bulk solution, sterile filtration of the formulated bulk solution, and aseptic filling. The sponsor has demonstrated that the drug product manufacturing facility is capable of consistently producing Lapelga of acceptable quality at the commercial scale.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.

Lapelga is available as a sterile, clear, colourless preservative-free solution (acetate buffered, pH 4.0, isotonic solution) for injection. It is supplied in a 1 mL glass, single-use, prefilled syringe with needle-guard at a protein concentration of 10 mg/mL (6 mg/0.6 mL). Lapelga will be packaged in a single blister package and further packaged in a carton along with the patient information leaflet.

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 pegfilgrastim 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 and analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing results support the consistency of the manufacturing process and suitability of the assays for their intended purpose.

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 for Lapelga is considered acceptable, when stored at 5oC ± 3oC and protected from light. The proposed in-use shelf life for Lapelga of one single period of up to 15 days when stored at 25oC ± 2oC within the authorized long-term shelf-life is adequately supported and considered to be satisfactory.

The proposed packaging and components are considered acceptable.

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 facility involved in the manufacture and testing of Lapelga drug product was waived as a successful OSE had been recently performed for another product whose manufacturing process was similar.

Adventitious Agents Safety Evaluation

The pegfilgrastim 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 and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

There is no risk of viral adventitious agents from the fermentation process. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy or other human pathogens. There are no excipients of human or animal origin used in the manufacture of the Lapelga drug substance or drug product.

 

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 Lapelga 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 toxicology program included a pivotal 28-day comparative repeat-dose and toxicokinetic study in rats, a comparative local tolerance study in rabbits, and a comparative dermal sensitization study in guinea pigs.

A dose-dependent increase in white blood cells, particularly neutrophils, was comparable for groups of rats treated with similar doses of Lapelga and Neulasta. An increase in alkaline phosphatase and in spleen weight was reported in animals dosed with the Lapelga as well as Neulasta. The findings were dose dependent (from low dose up to the high dose) in frequency and severity and comparable for both products. Dose-dependent joint swelling and limping, noted during treatment, subsided in animals administered 30 µg/kg Lapelga or Neulasta and lessened in animals treated with 1,100 g/kg. The incidences and severities of the effects of the two products were indistinguishable.

The toxicokinetic profiles of Neulasta and Lapelga were also similar. Additionally, no local tolerance toxicity or irritation potential of Lapelga or Neulasta was observed in rabbits. Most observations were sporadic and/or graded as slight to very slight with the exception of hematoma observed after intra-arterial injections. The hematomas were generally considered moderate or severe. Histopathologically, there were no signs of treatment-related intolerance with the administration of Lapelga or Neulasta at the local injection site.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Lapelga Product Monograph. In view of the intended use of Lapelga, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Lapelga 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 biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.

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 degree of similarity at the quality level determines 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.

Comparative Pharmacokinetic and Pharmacodynamic Studies

Comparative pharmacokinetics and pharmacodynamics of Lapelga and the reference biologic drug, Neulasta, were studied in a Phase I single-dose, randomized, assessor-blinded, two-way crossover study (APO-Peg-02) with healthy male and female subjects. Single subcutaneous doses of Lapelga 6 mg (6 mg/0.6 mL) or Neulasta 6 mg (6 mg/0.6 mL) were administered to 66 healthy subjects. The study duration included two study periods of 28 days each with an 8-week washout between treatment administrations. Of the 66 subjects that received the study drug or the reference biologic drug, 56 subjects were included in the assessment of similarity. Pegfilgrastim concentrations for the primary pharmacokinetic analysis were determined by a validated enzyme-linked immunosorbent assay (ELISA). Absolute neutrophil counts were measured over time as a direct indicator of the response to pegfilgrastim, which was the basis for the primary pharmacodynamic analysis.

Pharmacokinetics

The systemic exposure parameter, area under the curve (AUC), for pegfilgrastim following administration of Lapelga and Neulasta were calculated by the linear trapezoidal rule from time zero up to the last measureable sampling time, known as AUCt. The maximum plasma concentrations (Cmax) for the respective formulations were determined from the pharmacokinetic time course. The two one-sided hypotheses at the α = 0.05 level of significance were tested for AUCt and Cmax by constructing the 90% confidence interval (CI) for the ratio (test/reference) of the geometric means for Lapelga and Neulasta. Similarity of the test to reference formulation could be assumed when the ratio of the geometric means of the AUC and Cmax as well as the 90% CI (for the ratio) of AUCt was within 80% to 125% range.

The sponsor demonstrated that the ratios for the geometric means of Cmax and AUCt were within the predefined acceptance range of 80% to 125%, while the upper bound of the 90% CI for AUCt was slightly outside the predefined range. This slightly higher upper value (125.5%) was attributed to a smaller than listed drug content for Neulasta (less than 95% of the label claim). In the potency corrected data, the ratios for Cmax and AUCt and the 90% CI for the AUCt ratio were all well within the 80% to 125% range. Overall, the pharmacokinetic parameters were considered acceptable for a similarity assessment.

Pharmacodynamics

The primary pharmacodynamic endpoint parameters for the absolute neutrophil count were the area under the effect curve from time zero measured up to the last sampling time defined as AUECt and the maximum effective concentration defined as Emax. As demonstrated by the pharmacodynamic results, the 95% CI of the ratio (Lapelga/Neulasta) of geometric means of each of the primary pharmacodynamic endpoint parameter were fully contained within the predefined acceptance margins of 80% to 125%. The 6 mg therapeutic dose used in the study was considered acceptable in terms of sensitivity to detect similarities (or differences if they existed) between the Lapelga and Neulasta in healthy volunteers.

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

Comparative Clinical Safety, Immunogenicity, and Efficacy

The comparative clinical safety, immunogenicity, and efficacy were evaluated in a Phase III, randomized, assessor-blinded, active-controlled study (APO-Peg-03) of subcutaneously administered Lapelga, and United States-licensed or European Union-approved Neulasta in patients with early breast cancer receiving TAC (docetaxel, doxorubicin, cyclophosphamide) anticancer chemotherapy in an adjuvant setting.

There were 595 patients enrolled and randomized to treatment. Of the 595 patients, 589 patients were given the study drug Lapelga or the reference biologic drug Neulasta (294 received Lapelga; 148, US-Neulasta; and 147, EU-Neulasta). A total of 547 (92.9%) patients completed the treatment phase of the study for all 6 cycles (single dose per cycle); 268 (91.2%) in the Lapelga arm, 142 (95.9%) in the US-Neulasta arm and 137 (93.2%) in the EU-Neulasta treatment arm.

Safety

The types, frequency, and severity of adverse events were comparable between Lapelga and Neulasta. Bone pain was the most commonly reported adverse drug reaction related to pegfilgrastim. In the APO-Peg-03 treatment phase, bone pain was reported in 139 patients (47.3%) that received Lapelga, 73 patients (49.3%) that received US-Neulasta, and 78 patients (53.1%) that received EU-Neulasta. Severe bone pain was reported in 46 patients (15.6%) in the Lapelga arm, which was similar to the US-Neulasta and EU-Neulasta arms where 23 (15.5%) and 20 (13.6%) patients had reported events of severe bone pain, respectively. There were no discontinuations due to severe bone pain. The majority of these events were controlled with non-opioid analgesics. No significant differences were identified between Lapelga and Neulasta in other adverse events including laboratory evaluations (clinical chemistry, etc.).

Appropriate warnings and precautions are in place in the approved Lapelga Product Monograph to address identified safety concerns based on Part I of the Neulasta Product Monograph including a Serious Warnings and Precautions box describing splenic rupture and severe sickle cell crises.

Overall, the safety profile of Lapelga is considered to be comparable to that which has been established for the reference biologic drug Neulasta.

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

Immunogenicity

In the APO-Peg-03 study, samples were tested in an assay using a multi-tiered approach to first screen, then confirm and provide a relative anti-pegfilgrastim anti-drug antibody (ADA) concentration (titre). Any confirmed positive samples were then further characterized to determine if the anti-pegfilgrastim antibodies present in a sample were specific for the protein moiety (G-CSF) or PEG moiety by competition with Lapelga (Apo-Filgrastim, G-CSF) and PEG, respectively. Lastly, the assay was also used to determine whether the confirmed anti-pegfilgrastim antibodies were bound to the endogenous counterpart of the drug. The confirmed positive samples were also tested in a neutralizing antibody assay.

In Study APO-Peg-03, 18 of 589 (3.1%) patients assessed for immunogenicity were confirmed to be positive for ADA at one or more time points. Incidence of treatment-emergent ADA was low and similar between the three treatment groups: 1.0% (3/294) in the Lapelga arm, 0.7% (1/148) in the US-Neulasta arm and 0.7% (1/147) in the EU-Neulasta arm. The samples from the 18 patients with confirmed ADA positive results were tested in the cell-based assay to evaluate the presence of antibodies with neutralizing activity.

Neutralizing activity could have been specific to pegfilgrastim or G-CSF. Neither Lapelga nor Neulasta exposure resulted in the induction of neutralizing antibodies to pegfilgrastim. Neutralizing antibodies to endogenous G-CSF were detected in 3 patients (0.5%). Two of these patients were positive at the screening visit, of which one was negative at all post-dosing time points and one was only positive for G-CSF neutralizing antibodies at one other time point (Week 20). The third patient was positive for G-CSF neutralizing antibodies at two post-treatment time points. The G-CSF neutralizing antibodies were transient and all 3 patients were negative for neutralizing antibodies at their last time points tested.

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

Indication

Lapelga is a biosimilar to the reference biologic drug Neulasta. The sponsor requested authorization of Lapelga for the one indication that is currently authorized for Neulasta. Lapelga is authorized to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.

Similarity between Lapelga and Neulasta was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. On the basis of the safety and immunogenicity results and considering the similarity between Lapelga and Neulasta that was demonstrated in comparative structural, functional, and non-clinical studies, the totality of data supports the authorization of Lapelga for the same indication currently held by Neulasta.

 

 

 

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