Summary Basis of Decision for Omlyclo

Omlyclo was developed as a biosimilar of the reference biologic drug, Xolair. The weight of evidence of similarity between a biosimilar and the reference biologic drug 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.

Comparative Structural and Functional Studies

The biosimilarity evaluation included a two-way comparison between Omlyclo and the reference biologic product approved in the European Union (herein referred to as EU-Xolair). Health Canada considers EU-Xolair a suitable proxy for Xolair authorized in Canada, as it meets all of the requirements for a non-Canadian reference biologic drug set forth in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Ten batches of Omlyclo were evaluated according to similarity criteria, derived from a statistical assessment (mean ± 3 standard deviations) of thirteen batches of EU-Xolair. The results of the similarity studies demonstrate that Omlyclo is identical to EU-Xolair in terms of primary structure and highly similar with respect to higher order structure, purity, and biological activities. Some differences were observed with respect to the N-glycosylation profile, size and charge variants, and post-translational modifications. In all cases, appropriate justifications were provided, and the observed differences between Omlyclo and EU-Xolair are not expected to impact clinically relevant attributes. Additionally, comparative stability studies show that Omlyclo and EU-Xolair have comparable pathways and rates of degradation. Overall, the results support the biosimilarity of Omlyclo and EU-Xolair from a quality perspective.

Characterization of the Drug Substance

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

Comparability of omalizumab lots produced by different processes was performed and comparable physicochemical characteristics and biological activities were demonstrated.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.

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

The drug substance is manufactured from using recombinant deoxyribonucleic acid (rDNA) technology in Chinese hamster ovary cells. The manufacturing process is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated the stability of these cell banks.

The upstream drug substance manufacturing process involves thawing of a single vial of the working cell bank, cell culture expansion through shake flasks, seed bioreactors, followed by production culture in a production bioreactor. The cell culture fluid from the production bioreactor is harvested through continuous centrifugation and depth filtration and then forward-processed to the downstream purification process. The clarified harvest is purified by affinity chromatography and the eluates are held at a low pH for viral inactivation. The product is further purified through anion exchange chromatography and viral filtration, followed by concentration and diafiltration into the final formulation buffer. The bulk drug substance is filled into polycarbonate bottles and stored frozen. The drug substance bottles are thawed under controlled conditions at 15 to 25 °C and are stored at 2 to 8 °C for at least 24 hours prior to shipment to the drug product manufacturing facility.

The drug product manufacturing process consists of drug substance thawing, microbial filtration, pooling, mixing, sterile filtration, aseptic filling, stoppering, inspection, and storage at 2 to 8 ˚C. The unassembled drug product consists of the drug product in pre-filled syringes without plunger rods. Once the unassembled drug product is manufactured, it is assembled with a finger flange, a plunger rod, and a safety guard.

Omlyclo drug product (150 mg/mL) is formulated for subcutaneous administration as a sterile liquid solution in a pre-filled syringe with safety guard. It is available in two strengths: 75 mg/0.5 mL and 150 mg/1.0 mL. In addition, each syringe of product contains the following excipients: L-histidine, L-histidine hydrochloride (HCl) monohydrate, L-arginine HCl, polysorbate 20, and water for injection. 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 the omalizumab with the excipients is supported by the stability data provided.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered suitable and/or meet standards appropriate for their intended use. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits. Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. The sponsor has successfully completed the appropriate supportive validation activities to ensure product quality, including shipping, hold time, and aseptic processing studies.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with ICH guidelines.

The control strategy consists of product and process understanding and commercial controls including quality attribute criticality, product/process characterization, process development, process validation, release/stability testing, in-process test/control, process parameter control, raw material control, facility controls, and post-approval stability testing. This multi-level control strategy as part of the overall process performance and product quality monitoring system assures the consistent manufacture of acceptable product and mitigates risk of failures in process performance.

The results of the safety assessment demonstrated that the purification process is capable of consistently reducing the levels of process-related impurities, product-related variants, and contaminants within the specification or validation criteria. The in-house analytical methods were validated according to ICH Q2(R1) and compendial methods complied with pharmacopeial standards. The specifications for the drug substance and the drug product were appropriately set and justified.

Each lot of Omlyclo drug product is tested for appearance, identity, content, potency, and purity. Established test specifications and validated analytical test methods are considered acceptable.

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).

Through Health Canada's lot release testing and evaluation program, three lots of 75 mg drug product were tested using a stability-indicating method. The testing process confirmed that the method used in-house is acceptable for its intended use.

Omlyclo 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.

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 to 8 °C for Omlyclo, protected from light is considered acceptable. This may include a period of no more than 7 days at 25 °C. 

The compatibility of the drug product with the container closure system was demonstrated through stability studies and extractables and leachables studies.

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.

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and the drug product manufacturing facilities were not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The omalizumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

One raw material of animal origin is used in the drug substance manufacturing process (the cell culture media is derived from cod liver oil and cholesterol from sheep’s wool). In addition, dialyzed fetal bovine serum and Trypsin-ethylenediaminetetraacetic acid (EDTA) (porcine pancreas, bovine lactose) were used during cell line development. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) agents or other human pathogens. All animal-derived raw materials were subject to a TSE risk assessment in accordance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3).

The excipients used in the drug product formulation are not of animal or human origin.

For biosimilars, the degree of similarity to the reference biologic drug 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 data submitted consisted of one four-week repeat dose study in cynomolgus monkeys. The animals were dosed every 4 weeks with subcutaneous injections of omalizumab or the reference biologic drug, Xolair, at 5 or 75 mg/kg bodyweight. No toxicologically significant findings or distinct toxicities were observed when comparing the omalizumab and Xolair groups. Free serum immunoglobulin E (IgE) was reduced to below the limit of quantitation by study day (SD) 8 in animals receiving either omalizumab or Xolair at a dose of 75 mg/kg bodyweight. Total serum IgE increased over the study period beginning on SD 8 through to SD 29 at all dose levels for both treatment groups in accordance with the expected pharmacological effect.

On SD 22, in animals administered Xolair, increases in systemic exposure based on maximum concentration (C_max) or area under the concentration versus time curve from 0 to 168 h post-dose (AUC_0-168) were greater than dose-proportional, while increases were approximately dose-proportional for those administered omalizumab. Omalizumab to Xolair exposure ratios were not equivalent at the low dose (5 mg/kg bodyweight), however, the exclusion of low-dose group animals with low Xolair serum concentrations resulted in equivalent ratios at the low and high dose. In consideration of the low number of animals in this study (total number of 3 per group), these data are considered secondary to the clinical pharmacology conclusions based on human data.

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

The non-clinical data submitted for Omlyclo were 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. For more information, refer to the Omlyclo Product Monograph, approved by Health Canada and available through the Drug Product Database.

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.

Omlyclo is the first biosimilar submission to the omalizumab reference biologic drug (Xolair) in Canada. Xolair sourced from the United States and Europe were both utilized as reference biologic drugs in the Omlyclo clinical development programme. The Sponsor declared Xolair authorized in the European Union (EU-Xolair) as the non-Canadian reference biologic drug.

Comparative Pharmacokinetics and Pharmacodynamics

Immunoglobulin E (IgE) plays a central role in the pathophysiology of inflammatory diseases in the airway. Omlyclo (omalizumab) binds to IgE and prevents binding of IgE to the high-affinity IgE receptor (FcεRI), thereby reducing the amount of free IgE that is available to trigger the allergic-inflammatory cascade. Subsequently, FcεRI receptors on cells downregulate.

The Phase I, randomized, double-blind, three-arm, parallel group, single-dose Study CT‑P39 1.1 was performed in healthy subjects to compare the pharmacokinetics and safety of three formulations of omalizumab: Omlyclo, EU-Xolair, and Xolair licensed in the United States (US-Xolair). The primary objective was to demonstrate pharmacokinetic similarity of Omlyclo, EU‑Xolair, and US-Xolair, in terms of the area under the concentration-time curve from time zero to infinity (AUC_0‑inf), the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC_0-last), and the maximum serum concentration (C_max) following a single 150 mg subcutaneous dose. Serum samples were collected up to Day 127 (3,024 hours) after dosing. Serum omalizumab concentration profiles were used to calculate pharmacokinetic parameters.

The study demonstrated that Omlyclo, EU-Xolair, and US-Xolair were bioequivalent, as the calculated 90% confidence interval of the geometric mean ratio for C_max and AUC_0-last for each comparison (Omlyclo versus EU-Xolair and Omlyclo versus US-Xolair) was contained entirely within Health Canada’s prespecified comparative pharmacokinetic biosimilarity margin of 80.0% to 125.0%. In addition, the safety and immunogenicity profiles were similar between the groups administered Omlyclo and the reference products EU-Xolair and US-Xolair.

Comparative Clinical Efficacy and Safety

The clinical efficacy and safety of Omlyclo was evaluated in comparison to its reference biologic drug, EU-Xolair in Study CT-P39 3.1, a Phase III, double-blind, randomized, active-controlled (reference biologic drug) parallel-group study. The primary objective of this study was to demonstrate the clinical similarity and relative potency of Omlyclo to EU-Xolair in participants with chronic spontaneous urticaria (CSU; synonym for chronic idiopathic urticaria) refractory to H1-antihistamines.

The primary efficacy endpoint of the study was the change from baseline in the Itch Severity Score over 7 days (ISS7) at Week 12. The co-primary endpoint was a comparison of the relative potency of two dose strengths of Omlyclo and EU-Xolair. There were multiple secondary endpoints including the change from baseline in the ISS7 at Week 24, the use of rescue medications, and quality of life measures. At baseline, study participants were randomized 2:2:1:1 to receive three monthly subcutaneous doses of either Omlyclo 300 mg, EU-Xolair 300 mg, Omlyclo 150 mg or EU-Xolair 150 mg. At Week 12, subjects in the EU-Xolair 300 mg treatment arm were re-randomized to continued treatment with EU-Xolair or to change to treatment with Omlyclo 300 mg to assess the impact of switching from the reference biologic drug to Omlyclo. The participants in the other treatment arms continued treatment with the same product assigned at baseline, but the dose was increased to 300 mg for participants in the 150 mg treatment arms. All subjects received three further monthly doses of study drug for a total of six doses over the two treatment periods. The final dose was at Week 20. Study subjects were followed off treatment from Week 20 to Week 40 (the end of study). Of the 619 subjects randomized at baseline, 578 (93.3%) completed the first 12‑week treatment period, 562 (90.8%) completed the second 12‑week treatment period (up to Week 20) and 518 (83.7%) completed the entire study (up to Week 40), including the follow-up period. The study duration and exposure to study drug were similar between participants who were exposed to Omlyclo and EU-Xolair.

Omlyclo met its primary objective as the 90% confidence interval of the difference in mean change from baseline in ISS7 at Week 12 of the Omlyclo 300 mg and Xolair 300 mg groups was contained within the pre-defined clinical biosimilarity margin (modified-intention-to-treat and per protocol analyses).

The study was not able to fulfil its co-primary endpoint of the relative potency of two doses (300 mg and 150 mg) of Omlyclo compared to Xolair. The difference in mean change from baseline in ISS7 at Week 12 between the Omlyclo 300 mg and 150 mg treatment arms was not statistically significant. This was attributed to the potential variability of treatment response in CSU patients. The pharmacokinetic data supported the difference between the two dosing regimens, demonstrating the expected difference in serum trough drug concentrations between the two dosing groups.

The study was not powered to demonstrate a difference between the exposure groups for the secondary endpoints. However, all of these endpoints demonstrated a similar trend to the primary endpoint with no meaningful difference observed between Omlyclo and Xolair. There was no observed negative treatment effect following the switch from EU-Xolair to Omlyclo at Week 12.

A review of the safety data, including treatment-emergent adverse events, did not reveal any new safety signals or any meaningful differences in the reporting of adverse events, abnormal laboratory tests, electrocardiogram or physical exam findings between the Omlyclo and EU-Xolair treatment groups.

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). A numerical imbalance in the frequency of treatment-emergent ADAs was identified between Omlyclo-exposed participants (approximately 10%) and EU-Xolair-exposed participants (approximately 2%). As there was no demonstrable effect of the ADAs on the clinical efficacy or safety of Omlyclo, the observed difference in ADA frequency was considered acceptable.

Overall, Study CT-P39 3.1 indicated there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The safety profile of Omlyclo is considered to be comparable to that which has been established for the reference biologic drug Xolair. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the Omlyclo Product Monograph, as they are in the Product Monograph for Xolair.

Indications

Within this drug submission, the sponsor requested the authorization of Omlyclo for all of the indications that are currently authorized for Xolair.

Similarity between Omlyclo and Xolair was established in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. Importantly, the demonstration of similarity between a proposed biosimilar and its reference biologic drug enables the sponsor’s submission for the proposed biosimilar to rely on the safety and efficacy information already generated for the reference biologic drug, and therefore clinical trials are not required to support each indication.

Considering the totality of evidence submitted, including results of structural, functional, and clinical pharmacokinetic, pharmacodynamic, immunogenicity, and safety comparisons between Omlyclo and Xolair, Health Canada authorized Omlyclo for the same indications held by Xolair, as follows:

Allergic Asthma

Omlyclo (omalizumab) is indicated for adult and pediatric patients (6 years of age and above) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.

• Adults and adolescents (12 years of age and older): Omlyclo has been shown to significantly decrease the incidence of asthma exacerbations and improve control of asthma symptoms in these patients.

• Children (6 to less than 12 years of age): Omlyclo, used as add-on therapy, has been shown to significantly decrease asthma exacerbation rates in children who are inadequately controlled and have a documented history of exacerbation.

Chronic Rhinosinusitis with Nasal Polyposis

Omlyclo (omalizumab) is indicated as an add-on maintenance treatment with intranasal corticosteroids in adult patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) inadequately controlled by intranasal corticosteroids alone.

Chronic Idiopathic Urticaria

Omlyclo (omalizumab) is indicated for the treatment of adults and adolescents (12 years of age and above) with chronic idiopathic urticaria (CIU) who remain symptomatic despite H1 antihistamine treatment.

The safety and efficacy of Omlyclo have not been established in other conditions.