Summary Basis of Decision for Niopeg

Niopeg was developed as a biosimilar of the reference biologic drug Neulasta. 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 Niopeg is considered to be representative of the mechanism of action and pharmacological effect of Neulasta.

A New Drug Submission (NDS) for Niopeg was filed with Health Canada on March 23, 2022. During the review of the NDS, Health Canada observed gaps in the Standard Analytical Procedures (SAPs) and the transfer of the SAPs to testing facilities. The SAPs form the basis for the release and stability testing for this product, and are therefore an essential component of the control strategy. In addition, concerns were raised during the virtual site evaluation regarding the inability of the drug product manufacturing facility to demonstrate that the current drug product fill weight strategy supported the ability to consistently meet the label claim. Given these observations, on March 9, 2023, Health Canada issued a Notice of Deficiency (NOD) to the sponsor, requesting further information. On June 8, 2023, Health Canada received a response to the NOD from the sponsor, providing updated SAPs, method transfers, and an analysis to adequately demonstrate that the filling process consistently meets the label claim. The concerns in the NOD were considered to be satisfactorily resolved and on April 17, 2024, a Notice of Compliance was issued to Nora Pharma Inc. for the drug product Niopeg.

Comparative Structural and Functional Studies

Niopeg (pegfilgrastim) was developed as a proposed biosimilar to match the strength and product characteristics of Neulasta authorized in the European Union (referred to as Neulasta-EU). Niopeg is being proposed as a biosimilar to Canadian-authorized Neulasta. Neulasta-EU is declared as the non-Canadian reference biologic drug and is a suitable proxy for the Canadian reference biologic drug, as it meets the requirements outlined in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The sponsor performed head-to-head biosimilarity assessments to demonstrate that Niopeg is similar to Neulasta-EU with regard to most of the quality attributes pertaining to physicochemical properties, biological activity, and product stability. Differences were noted with respect to some physicochemical quality attributes. The Niopeg drug substance (pegfilgrastim) showed a higher molecular weight compared to Neulasta-EU. This was attributed to the molecular weight of pegaldehyde and had no meaningful impact in pharmacokinetic/pharmacodynamic studies. Niopeg pegfilgrastim batches have lower levels of product-related impurities, which has no meaningful impact on safety or biological activity. Comparative stability and forced degradation studies using different stress conditions generated similar degradation profiles for Niopeg and Neulasta-EU, further supporting the similarity assessment. Taken together, these results support the assertion that Niopeg is similar to Neulasta-EU, and therefore support the quality requirements for Niopeg to be considered a biosimilar to Neulasta.

Characterization of the Drug Substance

Pegfilgrastim, the drug substance, is a covalent conjugate of recombinant methionyl human granulocyte-colony stimulating factor (G-CSF; filgrastim) and a single 20 kDa monomethoxypolyethylene glycol propionaldehyde (mPEG). Pegfilgrastim binds to the cellular receptor of G-CSF in myeloid precursor cells in a dose-dependent manner, resulting in cellular proliferation and differentiation of neutrophils.

Detailed characterization studies were performed to provide assurance that pegfilgrastim consistently exhibits the desired characteristic structure and biological activity.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The Niopeg drug substance is manufactured in two stages: the manufacturing of the filgrastim intermediate, and the addition of a PEG moiety to produce a pegylated filgrastim (pegfilgrastim). Filgrastim is expressed in Escherichia coli cells as histidine-tagged filgrastim. The resulting culture is harvested and purified, and the histidine tag is cleaved. The resulting filgrastim is subsequently purified by tangential flow filtration, ion exchange chromatography, and affinity chromatography. The resulting eluate is concentrated and diafiltered, followed by filtration into bags. The final filgrastim critical intermediate is stored 5 °C ± 3 °C for up to 9 months. The pegylated filgrastim manufacturing process begins with the pooling of the filgrastim intermediate, followed by concentration and diafiltration. Next, filgrastim is pegylated with the addition of monomethoxypolyethylene glycol propionaldehyde (mPEG), then purified, concentrated, and diafiltered by ion exchange chromatography and tangential flow filtration into a buffer. Polysorbate 20 is subsequently added and the final bulk drug substance is filtered into sterile bags and stored at 5 °C ± 3 °C for up to 12 months.

The drug product manufacturing process uses an aseptic manufacturing process that includes the preparation of formulation buffer and bulk drug product, bioburden reduction filtration, sterile filtration, aseptic filling, visual inspection, and secondary packaging. The drug product is stored at 5 °C ± 3 °C for up to 36 months.

Process performance qualification data demonstrated that the manufacturing processes are capable of consistently manufacturing the filgrastim intermediate, drug substance, and drug product of acceptable quality. Process parameters, in-process controls, in-process tests, release testing results, and stability results met pre-defined criteria, acceptance limits, and specifications for all process validation batches/lots.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by 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 filgrastim intermediate, drug substance, and drug product manufacturing processes are controlled by process parameters, in-process controls, and in-process tests with defined operating ranges, action limits, and acceptance criteria. The criticality of each of these processes were appropriately defined, and were based on risk assessments, process characterization studies, and previous experience gained during development. Any results outside of specified ranges or limits were identified and investigated.

During the initial review, it was noted that the Standard Analytical Procedures (SAPs) lacked important details that could lead to inconsistencies in method performance and drift in assay results. As a result, an NOD was issued from a quality perspective. In the NOD, the sponsor was requested to include an appropriate level of detail to ensure that the method can be executed consistently. These issues were resolved satisfactorily in the NOD response, and the SAPs are now considered to contain the level of detail required to ensure consistent quality control testing.

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.

Niopeg is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the filgrastim intermediate, drug substance, and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 36 months at 5 °C ± 3 °C for Niopeg is considered acceptable. Niopeg may be stored at room temperature for up to 4 days. Additional storage and special handling instructions are included in the Niopeg Product Monograph.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

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.

A virtual assessment of the facilities involved in the manufacture and testing of Niopeg was performed. The virtual assessment was conducted to provide additional regulatory oversight and to mitigate any residual risks identified during review.

Adventitious Agents Safety Evaluation

Control of non-adventitious agents is routinely performed on an on-going basis for the drug substance and drug product. No raw materials of animal origin are used during filgrastim, drug substance, nor drug product manufacturing.

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 pharmacokinetic and pharmacodynamic profile of pegfilgrastim, the medicinal ingredient in Niopeg, was evaluated in a non-clinical comparative study in healthy and neutropenic rats. A 4-week repeat-dose toxicity study including toxicokinetic assessments was performed in Sprague-Dawley rats as well as a dedicated local tolerance study in New Zealand White rabbits.

Overall, there was no significant difference in the pharmacodynamic, toxicokinetic, or toxicological effects of Niopeg compared to the reference product Neulasta.

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). At all dose levels, ADAs were identified in animals given either Niopeg or Neulasta at the end of the 4-week dosing period and 4-week recovery period. However, ADA formation had no apparent impact on the pharmacodynamic parameters of pegfilgrastim.

There were no reproduction toxicology, mutagenicity, or carcinogenicity studies as such studies are not routinely required for non-clinical testing of similar biological medicinal products containing recombinant granulocyte-colony stimulating factor as active substance.

The non-clinical database submitted for Niopeg was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. The results of the comparative non-clinical studies as well as the potential risks to humans have been included in the Niopeg Product Monograph. In view of the intended use of Niopeg, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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.

The clinical profile of Niopeg was evaluated in two comparative pharmacokinetic and pharmacodynamic studies (Study PEGF/USV/P1/001 [Study P1/001] and Study PEGF/USV/P1/003 [Study P1/003]) and one clinical efficacy and safety study (Study PEGF/USV/P3/003 [Study P3/003]).

Comparative Pharmacokinetic and Pharmacodynamic Studies

Study P1/001 was a pivotal, randomized, double-blind, two-period, two-sequence, crossover study in healthy male and female subjects (number of subjects [n] = 156) to assess the pharmacokinetic and pharmacodynamic profiles of Niopeg and Neulasta after a single 6 mg subcutaneous dose. The pharmacokinetic results showed that the ratio of geometric means for the maximum serum concentration (C_max) between Niopeg and Neulasta was 98.3%, and the 90% confidence interval (CI) of the ratio of geometric means for the area under the concentration-time curve from time zero to time of last quantifiable concentration (AUC_T) was 93.9% to 111.4%. These results were contained within the equivalence margins of 80.0% to 125.0% and demonstrated comparable pharmacokinetic profiles between the biosimilar and reference biologic drug. The results of the primary pharmacodynamic endpoint, absolute neutrophil count, showed that the ratio of geometric means for maximum effect (E_max) was 100.4% and the 95% CI of the ratio of geometric means for area under effect in plasma versus time curve from time zero to the last measurable effect (AUEC) was 97.5% to 101.9%. The results were within the pre-defined equivalence margins of 90.00% to 111.11%. The E_max and AUEC results of the secondary pharmacodynamic endpoint, CD34+ viable cell counts, also met the equivalence criteria. No apparent differences in safety between the two treatment arms were observed in the study. No deaths were reported. Four subjects withdrew from the study after experiencing adverse events; however, no apparent relationship between these events and their pharmacokinetic profiles has been established. No confirmed positive anti-drug antibodies (ADAs) were detected from blood samples.

Study P1/003, a supportive study, had a similar design as Study P1/001, but differed in the dose and the primary objective. The primary objective of Study P1/003 was to confirm the comparable pharmacodynamics of Niopeg and Neulasta after a single 2 mg subcutaneous dose in 64 adult healthy male subjects. The results of the primary pharmacodynamic endpoint of absolute neutrophil count showed that the ratio of geometric means for E_max between Niopeg and Neulasta was 97.1%, and the 95% CI of the ratio of geometric means for AUEC was 94.0% to 105.8%. These values were within the predefined equivalence margins of 80.0% to 125.0%. The E_max and AUEC results of the secondary pharmacodynamic endpoint, CD34+ viable cell counts, also met the equivalence criteria. Comparable pharmacodynamics between Niopeg and Neulasta has been demonstrated after a single 2 mg subcutaneous dose of pegfilgrastim. No clinically meaningful differences in safety were observed between the two treatment arms. Three subjects were confirmed to be positive for ADAs, but all samples tested negative for neutralizing antibodies.

Overall, the comparative bioavailability studies indicated that there are no clinically meaningful differences between the biosimilar and the reference biologic drug.

Comparative Clinical Efficacy and Safety

The comparative clinical efficacy and safety of Niopeg and its reference biologic drug Neulasta were evaluated in Study P3/003, a randomized, assessor-blinded, active-controlled, parallel-group study in breast cancer patients undergoing adjuvant myelosuppressive chemotherapy therapy after surgical resection of breast cancer. Mean duration of severe neutropenia (DSN) in Cycle 1 of treatment was 1.58 and 1.65 days in the Niopeg (n = 166) and Neulasta (n = 82) treatment arms, respectively. The 95% CI of mean ratio for DSN between the Niopeg and Neulasta treatment arms was 0.78 to 1.18 and were entirely contained within the pre-defined equivalence margins of 0.65 to 1.55.

Overall, no clinically meaningful differences in the safety profiles between the two treatment arms were observed during the treatment period and the safety follow-up period. No new adverse events were observed compared with the known safety profile for Neulasta. The immunogenicity findings confirmed the low immunogenic potential of Niopeg, and supported the biosimilarity of the biosimilar and the reference biologic drug.

Appropriate warnings and precautions to those found in the Product Monograph for Neulasta are in place in the approved Niopeg Product Monograph to address the identified safety concerns.

Indications

Niopeg is considered to be biosimilar to Neulasta, the reference biologic drug. Neulasta is authorized and marketed in Canada to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-neoplastic drugs.

Within this drug submission, the sponsor requested the authorization of Niopeg for the indication that is currently authorized for Neulasta.

Similarity between Niopeg and Neulasta was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. 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 studies are not required to support each indication. The indication has been authorized on the basis of demonstrated similarity between Niopeg and the reference biologic drug, in comparative structural and functional studies, comparative non-clinical studies, comparative pharmacokinetic and pharmacodynamic studies, and a clinical trial in patients undergoing adjuvant myelosuppressive chemotherapy therapy after surgical resection of breast cancer.

Indication

Niopeg (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-neoplastic drugs.