Summary Basis of Decision for Ruxience

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. Accordingly, the clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacokinetics

The sponsor submitted one pivotal comparative pharmacokinetic study (B3281001) to establish equivalence in the pharmacokinetic parameters between Ruxience and the reference product, MabThera (rituximab sourced from the European Union [EU]). Mabthera (hereafter referred to as rituximab-EU) was considered a suitable proxy for Rituxan authorized in Canada as it met all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Study B3281001 was a randomized, double-blind, 3-arm, parallel-group study in patients with active rheumatoid arthritis on a background of methotrexate who had an inadequate response to one or more tumour necrosis factor (TNF) antagonist therapies. Patients continued with receiving stable doses of methotrexate (10 mg/week to 25 mg/week) and were required to receive supplementary folate. The study was designed to compare the pharmacokinetics of Ruxience to rituximab-EU and rituximab sourced from the United States, rituximab-US.

The study enrolled 220 subjects who were randomized in a ratio of 1:1:1 to Ruxience, rituximab-EU or rituximab-US. Patients received their assigned treatment, which included two doses of 1,000 mg administered two weeks apart (on days 1 and 15). Sampling occurred over a period of 168 days (covering both doses). The sampling time was sufficient to characterize an adequate portion of the concentration versus time curve.

The sponsor's primary analysis of comparative pharmacokinetics was conducted on the per-protocol population, defined as all subjects who were randomized to and received the full dose of the planned study treatment and who had no major protocol violations that would affect the analysis. The analysis included 63, 67, and 68 subjects who received Ruxience, rituximab-EU, and rituximab-US, respectively. Similarity in pharmacokinetics was demonstrated by the 90% confidence intervals (CI) of the ratios of the geometric means of the area under the serum concentration versus time curve from time 0 to the last measured concentration at time T (AUC_T) and the maximum observed serum concentration (C_max) (point estimate) falling entirely within the predefined similarity margins of 80.0% to 125.0%.

The per-protocol population analysis excluded the data for 22 subjects. Although the sponsor purposefully overpowered the study to account for loss of subjects, there remained concern that the assessment could be biased due to imbalances that might have arisen through exclusions. Another concern arose due to the exclusion of 9 subjects, enrolled at a single site, who were excluded because of unexplained inconsistencies in their pharmacokinetic data. Given that Health Canada's Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies clearly states that all subjects who have evaluable data should be included in the analyses, the reviewer of the submission performed an analysis on the intention-to-treat (ITT) population (all randomized subjects) using nominal sampling times. This analysis demonstrated pharmacokinetic similarity, as the ratios of the geometric means of AUC_T and C_max and their 90% CIs fell entirely within the predefined similarity margins of 80.0% to 125.0%. Finally, the sponsor was asked to recalculate the ratios after including all evaluable subjects and considering actual sampling times. The results of these analyses were also demonstrative of pharmacokinetic similarity. Therefore, pharmacokinetic similarity has been adequately demonstrated in compliance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document and the Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies.

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

Comparative Clinical Efficacy, Safety, and Immunogenicity

The efficacy, safety, and immunogenicity of Ruxience in comparison to the innovator version of rituximab were assessed in patients with low tumour burden follicular lymphoma (study B3281006) and patients with rheumatoid arthritis (study B3281001 and its extension, study B3281004).

Comparative Clinical Efficacy

Patients with low tumour burden follicular lymphoma (study B3281006)

One pivotal comparative study was submitted to support the sponsor's assertion that no clinically meaningful differences exist between the biosimilar (Ruxience) and the innovator version of rituximab. The study, B3281006, was a multicentre, randomized, double-blind study of Ruxience versus innovator rituximab sourced from the EU (rituximab-EU), for the first-line treatment of patients with CD20-positive, low tumour burden follicular lymphoma. The study population was considered a suitable test population for a comparison of response rates to support a demonstration of biosimilarity. While treatment options for patients with low tumour burden follicular lymphoma often include a watch-and-wait approach, the use of rituximab as a first-line monotherapy is also considered a reasonable option and is associated with a high overall response rate (ORR) of approximately 77%. Based on these previous findings and on discussions with international regulators, the sponsor predefined margins for equivalence in ORR of -16% to 16%.

The study randomized 198 patients to rituximab-EU and 196 patients to Ruxience, 197 and 196 of whom, respectively, received at least one dose of study treatment. Randomization was stratified by the Follicular Lymphoma International Prognostic Index 2 (FLIPI2) classification (low, medium and high risk). A review of the baseline patient demographics and disease characteristics demonstrated that the treatment arms were well balanced.

Patients were to receive the study drug to which they were randomized once weekly for 4 weeks at a dose of 375 mg/m², the usual dose of rituximab administered to adult patients with non-Hodgkin's lymphoma.

The primary outcome was the ORR by treatment arm, based on blinded central review, among the ITT population at study week 26. The primary objective was to demonstrate equivalence in the ORR within the predefined margins. The blinded central review applied the 2007 International Working Group response criteria in the assessment of response. The estimated ORRs were 70.7% (95% CI: 63.8%, 76.9%) and 75.5% (95% CI: 68.9%, 81.4%) in the rituximab-EU and Ruxience treatment arms. The risk difference was 4.66% (95% CI: -4.16%, 13.47%). As the 95% CI of the risk difference was entirely contained within the predefined equivalence margins (-16%, 16%), the trial was determined to have met its primary objective.

Subgroup analyses of the ORR demonstrated consistency across patients with various baseline demographic and disease characteristics.

Rheumatoid arthritis (study B3281001)

Supportive comparative efficacy data stem from the pivotal comparative pharmacokinetic study B3281001 (see Comparative Pharmacokinetics) conducted in patients with active rheumatoid arthritis and inadequate response to anti-TNF treatment. In this study, efficacy was compared descriptively and included assessments of the American College of Rheumatology (ACR) response endpoints (ACR20/50/70) and the 28-joint disease activity score with C-reactive protein (DAS28-CRP) at various time points. The assessments were supportive of biosimilarity, considering that the study was not designed to make any definitive conclusions regarding similarity beyond pharmacokinetic similarity.

Comparative Clinical Safety

Patients with low tumour burden follicular lymphoma (study B3281006)

In the pivotal study B3281006 (described in Comparative Clinical Efficacy), the safety population included all patients with low tumour burden follicular lymphoma who received at least one dose of study medication (n = 393). One patient randomized to the rituximab-EU arm did not receive any study medication and was therefore not included in the safety population.

The extent of exposure was similar in the treatment arms as 390 out of 393 subjects received all four doses of study medication.

Adverse events were observed in most subjects. There were 79.6% and 73.6% of patients in the Ruxience and rituximab-EU treatment arms, respectively, who had an adverse event regardless of relationship to treatment. Serious adverse events were experienced by 8.7% of patients receiving Ruxience and 7.6% of patients receiving rituximab-EU. Adverse events that were considered grade 3 or higher occurred in 14.3% of patients who received Ruxience and 13.2% of those who received rituximab-EU. Treatment discontinuation, due to an adverse event, was required for 1.5% and 1.0% of patients in the Ruxience and rituximab-EU treatment arms, respectively. Temporary treatment discontinuation due to an adverse event was required for 25.9% of patients treated with rituximab-EU compared to 18.9% of patients treated with Ruxience.

Infusion-related reactions were slightly more common among patients who received rituximab-EU in comparison to those who received Ruxience (29.9% vs. 25.0%).

Overall, the adverse event profile was similar for the two treatments and did not suggest a difference that could be attributable to product-related differences.

Patients with rheumatoid arthritis (study B3281001 and its extension, study B3281004)

Supportive comparative safety data were derived from the pivotal pharmacokinetic study B3281001 (described in the Comparative Pharmacokinetics). The extent of exposure was similar in the three arms of the study (Ruxience, rituximab-EU, rituximab-US). Of the 220 treated subjects, 217 received the full course of rituximab (1,000 mg administered on days 1 and 15).

Adverse events were reported for 68.5%, 61.6%, and 55.4% of patients receiving Ruxience, rituximab-US, and rituximab-EU, respectively. Serious adverse events were experienced by 6.8% of patients in the Ruxience treatment arm, compared to 1.4% of patients in the rituximab-EU treatment arm, and 5.5% of patients in the rituximab-US treatment arm. Grade 3 and higher adverse events occurred in 21 patients. The reported rates were 13.7%, 13.7%, and 1.4% in the Ruxience, rituximab-US, and rituximab-EU treatment arms, respectively. The sponsor was asked to provide any available information to explain the discrepancy in the rates of grade 3 or higher adverse events observed between the rituximab-EU arm and the remaining treatment arms. In the response, the sponsor acknowledged the differences, but pointed out that there was no common adverse reaction that accounted for the differences, with each grade 3 or higher adverse event preferred term occurring in 1 or 2 patients. The sponsor also provided information demonstrating that 7 out of 10 subjects in the Ruxience arm and 5 out of 10 subjects in the rituximab-US arm had medical histories that would suggest a predisposition to the adverse events that were observed. Importantly, no grade 4 events occurred in any of the three treatment arms.

The rate of withdrawal from treatment due to adverse events was low and similar between treatment arms (2.7% in the Ruxience arm, 1.4% in the rituximab-EU arm, and 1.4% in the rituximab-US arm).

Infusion-related reactions were reported for 13.7% of patients in each of the Ruxience and rituximab-US arms, while the rate of infusion-related reactions was 6.8% in the rituximab-EU arm.

Overall, the safety profile of Ruxience observed in study B3281001 is consistent with the known safety profile for Rituxan when used to treat patients with rheumatoid arthritis who have had inadequate response to anti-TNF therapies.

Study B3281004 was an extension study for subjects with active rheumatoid arthritis who had participated for at least 16 weeks in study B3281001 and had not received intervening treatment with investigational agents or other biologics (including rituximab-US and rituximab-EU) in the period between completing study B3281001 and entering study B3281004. This study evaluated the safety (including immunogenicity) of treatment with Ruxience, as well as the safety and immunogenicity occurring after transitioning from rituximab-US or rituximab-EU to Ruxience. Fifty-nine patients who received Ruxience in B3281001 continued to be treated with Ruxience in B3281004. Of the subjects who were randomized to rituximab-EU in B3281001, 33 were randomized to receive one course of rituximab-EU followed by two courses of Ruxience and 33 were randomized to receive three courses of Ruxience. Similarly, of the subjects randomized to rituximab-US in B3281001, 30 were randomized to receive one course of rituximab-US followed by two courses of Ruxience, while 30 were randomized to receive three courses or Ruxience.

The rates of adverse events and the rates of serious adverse events in study B3281004 were comparable between each of the treatment sequences.

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

Comparative Immunogenicity

Immunogenicity of Ruxience was evaluated in patients with low tumour burden follicular lymphoma (study B3281006) and patients with rheumatoid arthritis (study B3281001 and its extension, study B3281004). The patients with low tumour burden follicular lymphoma were considered a suitable population for immunogenicity assessment. These patients had not received prior chemotherapy regimens and received rituximab as monotherapy, whereas the rheumatoid arthritis patients in study B3281001 could have had prior treatment with a variety of products including disease-modifying antirheumatic drugs and TNF antagonists. In addition, rheumatoid arthritis patients in study B3281001 received concomitant methotrexate, which may affect the immune response.

In study B3281006, patients were followed for up to 52 weeks. The overall rate of anti-drug antibody positivity observed at any time post-baseline was 19.8% for patients who received rituximab-EU and 22.1% for patients who received Ruxience. Anti-drug antibodies against Ruxience were cross-reactive with rituximab-EU in 93% of cases suggesting that the former were elicited by epitopes common to both products. The majority of anti-drug antibodies against rituximab-EU were also cross-reactive with Ruxience (76.9%).

The rates of anti-drug antibody positivity in study B3281001 (or later) were 12.3%, 13.5%, and 9.6% for rituximab-US, rituximab-EU, and Ruxience, respectively. Of note, the follow-up could be variable for patients in this study due to the extension study enrollment that was available, but not required, beginning at week 16. In the extension study, B3281004, the overall results of immunogenicity testing gave no clear indication that continuing with a single treatment (Ruxience) or switching between Ruxience and the reference product (rituximab-EU or rituximab-US) was associated with an impact on the rate of immunogenicity.

Overall, the assessments of immunogenicity are considered adequate and supportive of biosimilarity.

Indications

Similarity between Ruxience and the reference biologic drug, Rituxan, was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug and therefore clinical trials are not required to support each indication.

Within this drug submission, the sponsor provided a rationale for requesting the authorization of indications that were not specifically studied in the clinical development program for Ruxience. The sponsor addressed each of the critical points including the mechanism of action in each indication, pharmacokinetic and biodistribution differences between populations, immunogenicity, and potential toxicity differences between indications. The primary focus of the scientific justification was on the similarity demonstrated through comparative physicochemical and functional assessments, non-clinical comparisons and clinical pharmacokinetic, safety, and efficacy comparisons.

Based on the evidence submitted, Ruxience was authorized for the same indications currently held by the reference drug Rituxan, as follows:

• Non-Hodgkin's Lymphoma (NHL)
  
  
• Ruxience (rituximab for injection) is indicated for:
  
  
• the treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma.
  
  
• the treatment of patients with CD20-positive, diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
  
  
• the treatment of patients with previously untreated stage III/IV follicular, CD20-positive, B-cell non-Hodgkin's lymphoma in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy.
  
  
• the maintenance treatment of patients with follicular non-Hodgkin's lymphoma who have responded to induction therapy with either CHOP or CHOP plus Ruxience.
  
  
• single-agent maintenance treatment of previously untreated patients with advanced follicular non-Hodgkin's lymphoma with high tumour burden and who have responded to induction therapy with either CHOP plus Ruxience or CVP plus Ruxience.
  
  
• Chronic Lymphocytic Leukemia (CLL)
  
  
• Ruxience (rituximab for injection) is indicated for the treatment of patients with previously untreated or previously treated B-cell chronic lymphocytic leukemia (B-CLL), Binet stage B or C, in combination with fludarabine and cyclophosphamide.
  
  
• The use of rituximab in CLL is based on an improvement in progression-free survival. Overall survival benefit has not been demonstrated in patients with previous treatment for CLL. The efficacy of treatment with R-FC (rituximab-fludarabine and cyclophosphamide) in CLL patients who were previously treated with rituximab in combination with fludarabine and cyclophosphamide has not been studied.
  
  
• Rheumatoid Arthritis (RA)
  
  
• Ruxience in combination with methotrexate is indicated in adult patients:
  
  
• to reduce signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more tumour necrosis factor (TNF) inhibitor therapies.
  
  
• Rituximab in combination with methotrexate has been shown to reduce the rate of progression of joint damage as measured by X-ray.
  
  
• Granulomatosis with Polyangiitis (GPA, also known as Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
  
  
• Ruxience in combination with glucocorticoids is indicated for the induction of remission in adult patients with severely active granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) and microscopic polyangiitis (MPA).
  
  
• Consideration should be given to current treatment guidelines for vasculitis.