Summary Basis of Decision for Ranopto

As outlined in the What steps led to the approval of Ranopto? section, the review of the quality component of the New Drug Submission for Ranopto was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

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

Comparative Structural and Functional Studies

Ranopto was developed to match the strength and product characteristics of the United States (US)‑licensed Lucentis product (US‑Lucentis) and the European Union (EU)‑licensed Lucentis product (EU‑Lucentis). Lucentis sourced from the US market 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.

Multiple lots of Ranopto and US‑Lucentis were included in the biosimilarity assessment, along with multiple lots of EU‑Lucentis as supportive data. The results of the biosimilarity assessment demonstrate that Ranopto is identical to US‑Lucentis with respect to primary structure, and highly similar with respect to higher order structure, purity, and biological activity. Differences in levels of norleucine and low molecular weight species were observed between Ranopto, US‑Lucentis, and EU‑Lucentis, but did not result in differences in binding to vascular endothelial growth factor (VEGF)‑A or in biological activity.

Comparative forced degradation (temperature, mechanical, pH, light, and oxidation), accelerated (25 °C), and stressed (40 °C) stability studies generated similar degradation profiles for Ranopto, US‑Lucentis, and EU‑Lucentis.

Collectively, the results indicate that Ranopto is highly similar to Lucentis and support the quality requirements for Ranopto to be considered a biosimilar to Lucentis.

Characterization of the Drug Substance

The drug substance, ranibizumab (the medicinal ingredient in Ranopto), is a recombinant, humanized antibody antigen-binding fragment (Fab) that binds selectively to VEGF‑A. The binding prevents the interaction of VEGF‑A with VEGF receptor (VEGFR)-1 and VEGFR-2, which are present on the surface of endothelial cells. The inhibition of this interaction reduces neovascularization and vascular permeability, as well as macular edema and subsequent loss of vision. Like Lucentis, the reference product, Ranopto is intended for treating macular degeneration and other visual impairments due to neovascularization.

Detailed characterization studies were performed to provide assurance that ranibizumab consistently exhibits the desired characteristic structure and biological activity. The structure, functional activity, and other characteristics were delineated during the biosimilarity assessment described above.

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

The drug substance, ranibizumab, is produced in Escherichia coli cells which have been genetically engineered to express this antibody through recombinant deoxyribonucleic acid (DNA) technology. The manufacturing process begins with the initiation of a cell culture from a single working cell bank vial which is transferred to progressively larger bioreactors as it undergoes expansion. Protein expression is induced when the cell culture reaches the required density. Cells are then harvested and homogenized to release the active ingredient into the cell lysate. Following clarification and filtration, the cell lysate is purified through multiple chromatography steps. Ultrafiltration/diafiltration is performed to concentrate the in‑process material and exchange the buffer, followed by the addition of polysorbate 20. The bulk drug substance is filtered, filled into bottles, and stored at ≤ -65 °C.

Manufacturing of the drug product, Ranopto, begins with thawing of the bulk drug substance at 2 °C to 8 °C. The excipient solution is prepared, followed by compounding to the target formulation. Bioburden reduction and sterile filtration steps are performed before aseptic filling in vials, stoppering, and crimping. The vials are then visually inspected and stored at 2 °C to 8 °C. 

Process validation was conducted with multiple batches of the drug substance and drug product manufactured at the intended commercial scale and facilities. Process performance qualification data reflect consistency in the manufacturing processes of the drug substance and drug product. All process parameters were run within their demonstrated operating ranges. In‑process attributes, release testing results, and stability results met pre‑defined criteria, acceptance limits, and specifications for all validation lots. All lab‑scale and process validation studies were deemed successful and supportive of hold times, impurity clearance, resin/membrane lifetimes, filters, extractables and leachables, shipping, and other supporting activities and equipment.

None of the non-medicinal ingredients (excipients) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of ranibizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy around raw material sourcing and testing and cell bank qualification ensures the quality, safety, and efficacy of the product. A risk‑based approach was used to establish the criticality of quality attributes, process parameters, and in‑process controls to ensure process and quality consistency. Release and stability data from historical and commercial batches were used to establish appropriate specifications. Controlled quality attributes include general characteristics (colour, clarity, visible particles, sub‑visible particles, pH, osmolality, and filling volume), identity, purity, impurities, protein concentration, polysorbate 20 concentration, potency, and microbial safety. Non‑compendial methods were all successfully validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and deemed suitable for their intended purpose. A two‑tiered reference standard system has been implemented. Overall, the reference standard qualification program was found to be appropriate to maintain consistent quality and mitigate the risk of drifting.

Ranopto 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. 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 process confirmed that the methods used in-house are acceptable for their intended use, and the results support the consistency of the manufacturing process.

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 at 2 °C to 8 °C for Ranopto is considered acceptable. Prior to use, the unopened vial may be stored at temperatures up to a maximum of 30 °C for a maximum of 24 hours.

Additional storage and special handling instructions are included in the Ranopto Product Monograph.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, an on‑site evaluation (OSE) was initially recommended for the drug substance manufacturing site. However, Health Canada reassessed its position on conducting an OSE of this site following a pre‑license inspection conducted at the same site by the United States Food and Drug Administration (FDA). The inspection report from the FDA was provided in this submission, and additional documentation was also requested and reviewed to address issues identified in the report. All issues were found to be properly addressed by the sponsor and the facility.

Adventitious Agents Safety Evaluation

The ranibizumab drug substance is manufactured in E. coli cells, and therefore the risk of viral contamination derived from production cell banks is very low. As bacterial systems do not support the replication of mammalian viruses, viral clearance studies are not applicable. No materials of animal origin are used during the cell banking and manufacturing of the ranibizumab drug substance. The biological materials used are from certified non-animal sources and therefore considered safe with respect to viral contamination. Testing of the end of production, master, and working cells banks adequately demonstrated that the cell banks were free of bacterial and fungal contaminants. Additionally, bioburden, endotoxin, and sterility testing are routinely performed throughout the drug substance and drug product manufacturing processes, where applicable.

Overall, appropriate controls are in place to ensure low risk for the introduction of non-viral adventitious agents during ranibizumab drug substance and drug product manufacturing.

As outlined in the What steps led to the approval of Ranopto? section, the review of the non-clinical component of the New Drug Submission for Ranopto was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

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.

No comparative in vivo pharmacodynamic studies were conducted with the Ranopto test article, FYB201. In a pivotal single-dose toxicity study, a 0.5 mg dose of FYB201, ranibizumab sourced from the European Union (EU), or ranibizumab sourced from the United States (US), was administered to New Zealand white albino rabbits bilaterally by intravitreal injection, followed by a two‑week observation period. An additional control group received intravitreal injection of the vehicle. No toxicologically relevant ocular/local tolerability or systemic effects were attributed to any of the products tested. All ocular reactions observed were classified as slight and transient, with no difference in incidence between the groups. A histological analysis of study animal organs and ocular tissues revealed no pathological findings which were attributable to any of the intravitreal injections of FYB201, the ranibizumab comparators (EU‑ or US‑sourced), or the vehicle. Pharmacokinetic parameters measured in the serum and vitreous/aqueous humor demonstrated similar systemic and local exposure. Overall, a 0.5 mg dose of FYB201 administered by intravitreal injection was well tolerated and its safety profile in animals is similar to those of the EU‑ and US‑sourced ranibizumab reference products.

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

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

As outlined in the What steps led to the approval of Ranopto? section, the review of the clinical component of the New Drug Submission for Ranopto was conducted as per Methods 2 (for the review of the bioanalytical methods) and 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

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.

Comparative Efficacy, Safety, and Pharmacology Study

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor (VEGF)‑A. Ranibizumab is designed to penetrate all retinal layers. It binds with high affinity to all active VEGF‑A isoforms (e.g., VEGF110, VEGF121, and VEGF165), thereby preventing binding of VEGF‑A to its receptors, VEGF receptor (VEGFR)‑1 and VEGFR‑2. The binding of VEGF‑A to its receptors leads to endothelial cell proliferation, neovascularisation, and vascular leakage. All of these are thought to contribute to the progression of the neovascular form of age‑related macular degeneration, macular edema causing visual impairment in diabetes and retinal vein occlusion, and choroidal neovascularization secondary to pathologic myopia.

Data from the Phase III clinical study FYB201‑C2015‑01‑P3 were submitted to support the biosimilarity of Ranopto to the reference product, Lucentis. This study was conducted in patients with neovascular (wet) age‑related macular degeneration (AMD), and a justification was also submitted for data extrapolation to the other indications that have been authorized in adults for Lucentis.

In study FYB201‑C2015‑01‑P3, 477 patients were randomized 1:1 to receive treatment with either 0.5 mg Ranopto (number of patients [n] = 238) or Lucentis (n = 239) in the study eye every 4 weeks, up to Week 48. The primary efficacy endpoint was the change from baseline in best‑corrected visual acuity (BCVA) at Week 8. The pre‑defined equivalence margin was ± 3.5 BCVA letters. Secondary endpoints included the change from baseline in BCVA at Week 24 and Week 48.

The least squares mean difference for the change from baseline in BCVA between Ranopto and Lucentis at Week 8 (primary endpoint) was ‑0.4 BCVA letters (95% confidence interval [CI]: ‑1.9, 1.1). The 95% CI fell within the pre‑defined equivalence margin of ± 3.5 BCVA letters. The results from the Per Protocol Set (PPS) and from sensitivity analyses were consistent with the results of the primary efficacy analysis. The mean changes from baseline in BCVA at Week 24 and Week 48 (secondary endpoints) were similar between the groups treated with Ranopto and Lucentis, with a mean change of ‑0.0 letters (95% CI: ‑1.9, 1.8) at Week 24 and ‑0.1 letters (95% CI: ‑2.2, 2.1) at Week 48.

The clinical pharmacology data presented and reviewed in this submission are limited to a purely qualitative evaluation of serum pharmacokinetic data within a subgroup of 59 neovascular AMD patients in the main comparative clinical study, FYB201‑C2015‑01‑P3. This subgroup includes 29 patients treated with Ranopto and 30 patients treated with Lucentis. The drugs were administered through intravitreal injection, and serum concentrations were measured at the time of maximum concentration (T_max) to ensure detectable levels of both Ranopto and Lucentis. The geometric means between the Ranopto‑ and Lucentis‑treated patients were consistent after the first dose and at steady‑state. At Week 20 (after Visit 6), the geometric mean was 2.33 ng/mL for the Ranopto‑treated patients and 2.79 ng/mL for the Lucentis‑treated patients.

The incidence of anti‑drug antibodies (ADAs) appeared consistent between patients treated with Ranopto and Lucentis. A total of 14 of 237 patients (5.9%) treated with Ranopto and 14 of 238 patients (5.9%) treated with Lucentis were found to be ADA‑positive. The time course, titre, and persistence of ADAs appeared consistent between the two groups. The ADAs were not found to consistently impact the efficacy, safety, or pharmacokinetic profile of either Ranopto or Lucentis in study FYB201‑C2015‑01‑P3.

In the clinical safety evaluation, the frequencies of ocular treatment‑emergent adverse events (TEAEs) in the study eye and non‑ocular TEAEs over 48 weeks were similar between the Ranopto and Lucentis groups. In the Ranopto and Lucentis groups, respectively, ocular TEAEs were observed in 36% and 41% of patients, ocular serious TEAEs were observed in 0.8% and 1.3% of patients, non‑ocular TEAEs were observed in 44% and 54% of patients, and non‑ocular serious TEAEs were observed in 7% and 12% of patients. The TEAEs observed in study FYB201‑C2015‑01‑P3 were generally consistent with the known safety profile of Lucentis. No new safety signals were identified.

The justification for extrapolation of the study data to other indications was acceptable, as ranibizumab has the same mechanism of action and a similar safety profile across all indications sought, and similar safety profiles were observed between Ranopto and Lucentis in study FYB201-C2015-01-P3.

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

Indications

Ranopto is considered to be biosimilar to Lucentis, the reference biologic drug. In adult patients, Lucentis is authorized and marketed in Canada for:

• the treatment of neovascular (wet) age related macular degeneration (AMD).

• the treatment of visual impairment due to diabetic macular edema (DME).

• the treatment of visual impairment due to macular edema secondary to retinal vein occlusion (RVO).

• the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM).

• the treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to ocular conditions other than AMD or PM, including but not limited to angioid streaks, post-inflammatory retinochoroidopathy, central serous chorioretinopathy or idiopathic chorioretinopathy.

Additionally, Lucentis is indicated in preterm infants for:

• the treatment of retinopathy of prematurity (ROP) with zone I (stage 1 with plus disease [1+], stage 2 with plus disease [2+], or stage 3 with or without plus disease [3 or 3+]), or zone II (stage 3 with plus disease [3+]) or aggressive posterior ROP (AP‑ROP) disease.

Within this drug submission, the sponsor requested the authorization of Ranopto for all of the indications for adult patients that are currently authorized for Lucentis. An indication for preterm infants was not sought for Ranopto.

Similarity between Ranopto and Lucentis 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 trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Ranopto and the reference biologic drug, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases or conditions involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.