Summary Basis of Decision for Sylvant

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 Sylvant is located below.

Recent Activity for Sylvant

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 Sylvant

Updated:

2022-11-24

The following table describes post-authorization activity for Sylvant, a product which contains the medicinal ingredient siltuximab. 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 Management of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN):

  • DIN 02435128 - 100 mg/vial, siltuximab, lyophilized powder for solution, intravenous administration
  • DIN 02435136 - 400 mg/vial, siltuximab, lyophilized powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DINs 02435128 and 02435136) market notification Not applicable Date of first sale: 2021-08-12 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 247027 2020-12-10 Issued NOC 2021-01-26 Submission filed to transfer ownership of the drug product from Janssen Inc to EUSA Pharma (UK) Limited. An NOC was issued.
NC # 213668 2018-02-14 Issued NOL
2018-04-24		 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.
NC # 212952 2018-01-19 Issued No Objection Letter
2018-03-16		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 211982 2017-12-11 Issued No Objection Letter
2018-03-07		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug substance. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 191297 2016-01-11 Issued No Objection Letter
2016-04-15		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to convert from campaign to concurrent manufacturing. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 187995 2015-09-24 Issued No Objection Letter
2016-01-06		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to revise the Dosage and Administration section of the Product Monograph to include additional compatible materials. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DINs 02435128 and 02435136) market notification Not applicable Date of first sale:
2015-03-03		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 174291 2014-05-12 Issued NOC
2014-12-03		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Sylvant

Date SBD issued: 2015-05-15

The following information relates to the new drug submission for Sylvant.

Siltuximab, 100 mg/vial and 400 mg/vial, Lyophilized powder for solution, intravenous

Drug Identification Number (DIN):

  • 02435128 100 mg/vial, lyophilized powder for solution
  • 02435136 400 mg/vial, lyophilized powder for solution

Janssen Inc.

New Drug Submission Control Number: 174291

 

On December 3, 2014, Health Canada issued a Notice of Compliance to Janssen Inc. for the drug product Sylvant.

The market authorization was based on quality (chemistry and manufacturing), non clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Sylvant is favourable for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)-negative.

1 What was approved?

Sylvant, an interleukin 6 antagonist, was authorized for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)-negative.

The safety and efficacy of Sylvant have not been studied in pediatric patients.

Sylvant is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Sylvant was approved for use under the conditions stated in the Sylvant Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Sylvant (100 mg/vial and 400 mg/vial siltuximab) is presented as lyophilized powder for solution. In addition to the medicinal ingredient, the lyophilized powder contains L-histidine, L-histidine monohydrochloride monohydrate, polysorbate-80 and sucrose.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Sylvant Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Sylvant approved?

Health Canada considers that the benefit/risk profile of Sylvant is favourable for the treatment of patients with multicentric Castleman's disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)-negative.

Castleman's disease (CD) involves an abnormal overgrowth of cells of the lymph system that is similar in many ways to lymphomas but is not considered to be a form of cancer. The global incidence of CD is rare and estimated at <1 in 100,000. It usually is presented as a single enlarged lymph node, and less commonly as symptomatic multicentric disease (MCD) with infections, night sweats, fatigue, hepatosplenomegaly, neuropathy and/or fluid overload. There is no specific therapy for MCD and the current standard of care for alleviating debilitating symptoms and disease burden results in a disease-free survival rate for MCD after 3 years of 50%. Treatment includes splenectomy /debulking surgery, radiotherapy, corticosteroids, and combination chemo and immunotherapy including thalidomide, interferons and Rituxan and Actemra.

Sylvant has been shown to be efficacious in MCD patients who are human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)-negative. The market authorization was based on a pivotal Phase II study (MCD2001) in MCD patients who were HIV-negative and HHV-8-negative and a supporting Phase I study (C0328T03) that included a group of patients with MCD who were treated with the recommended dose of Sylvant. The pivotal study was multinational, randomized, double-blind and placebo-controlled, and evaluated the effect of Sylvant on a primary endpoint of durable tumour and symptomatic response. The supporting study was single-arm and open-label in which the patients with MCD who were treated at the target dose and schedule were assessed for clinical benefit and radiologic response. The Phase II Sylvant clinical study met the pre-specified statistical and clinical criteria for durable response rate in patients treated with Sylvant, including complete response and partial response, with at least stable disease in all other evaluable disease in the absence of treatment failure, sustained for at least 18 weeks. The results of both studies support the efficacy of Sylvant for the specified indication.

The safety issues with Sylvant have been appropriately captured in the Sylvant Product Monograph. A higher incidence of adverse events leading to dose delay or dose interruption were reported in Sylvant-treated patients (32.9%, 27/82) compared with placebo-treated patients (19.2%, 5/26). The most common adverse drug reactions (ADRs) observed during treatment with Sylvant in the MCD clinical studies were upper respiratory tract infections (37.8%), pruritus (29.3%), and maculopapular rash (23.2%). The most common adverse drug reactions (ADRs) of Grade 3 or higher in the pivotal study MCD2001 included hypertension (6.1%), neutropenia (4.5%), hypertriglyceridemia (3.0%), thrombocytopenia (3.0%) and renal impairment (3.0%). There was one case of anaphylaxis reported.

No patients with hyaline vascular pathology demonstrated a durable tumour and symptomatic response. However, a consistent treatment effect favouring Sylvant-treated patients in the secondary endpoints of best tumour response and median time to treatment failure was shown in this subgroup.

A Risk Management Plan (RMP) for Sylvant was submitted by Janssen 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 Sylvant has been deemed appropriate and acceptable.

Overall, the therapeutic benefits seen in the pivotal study are promising and the benefits of Sylvant therapy are considered to outweigh the risks. Sylvant has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Sylvant Product Monograph to address the identified safety concerns.

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 Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Sylvant?

The drug submission for Sylvant was reviewed under the Priority Review Policy. Sufficient evidence was provided demonstrating that Sylvant provides an effective treatment of a disease for which no drug is presently marketed in Canada.

 

Submission Milestones: Sylvant

Submission Milestone Date
Pre-submission meeting: 2014-01-16
Request for priority status  
Filed: 2014-02-19
Approval issued by Director, Centre for the Evaluation of Radiopharmaceuticals and Biotherapeutics: 2014-03-28
Submission filed: 2014-04-28
Screening  
Screening Acceptance Letter issued: 2014-06-06
Review  
Quality Evaluation complete: 2014-12-03
Clinical Evaluation complete: 2014-11-28
Labelling Review complete: 2014-11-27
Notice of Compliance issued by Director General: 2014-12-03

 

The Canadian regulatory decision on the non clinical and clinical review of Sylvant was based on a critical assessment of the Canadian data package. The European Medicines Agency (EMA) review (Day 120 Questions and Responses) and the United States Food and Drug Administration (FDA) (Summary of FDA Information Requests and Responses) documents were reviewed and considered during the evaluation and recommendation for the chemistry and manufacturing of Sylvant.

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?

As part of the marketing authorization for Sylvant, 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):

  • Provide Health Canada the following study reports:
    • Final study report for Study MCD2002 (long term safety study) when it becomes available.
    • Final overall survival results for MCD2001 when it becomes available.
    • In Europe, a post-marketing patient registry is currently being conducted. The sponsor will provide Health Canada the final report for the registry when it becomes available.
  • Inform Health Canada about any safety signals, including an increased rate of any serious adverse events (SAEs), identified from pharmacovigilance, on-going or future clinical studies, and post-market assessments. The SAEs of particular interest in this population include:
    • Gastrointestinal perforation;
    • Renal impairment;
    • Infections including atypical infectious agents;
    • Infusion reactions.
  • Implement, as soon as practicable, a primary reference standard representative of the proposed manufacturing process using the stringent pooling criteria for the direct product capture (DPC) process intermediate product.
5 What post-authorization activity has taken place for Sylvant?

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Sylvant 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 Clinical basis for decision

Clinical Pharmacology

Castleman's disease (CD) involves an abnormal overgrowth of cells of the lymph system that is similar in many ways to lymphomas but is not considered to be a form of cancer. In the multicentric form of Castleman's disease (MCD), the body often makes too much of a protein called interleukin-6 (IL-6). Siltuximab, the active ingredient in Sylvant, is a human-mouse chimeric monoclonal antibody that binds human IL-6 and prevents it from binding to IL-6 receptors. Interleukin-6 is a pro-inflammatory cytokine that is produced by a variety of cell types including T-cells and B-cells, lymphocytes, monocytes and fibroblasts, as well as malignant cells. Normally, IL-6 is involved in the induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. Overproduction of IL-6 in chronic inflammatory diseases and malignancies has been linked to anemia and cachexia and has been hypothesized to play a central role in driving plasma cell proliferation and symptoms in patients with CD.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Sylvant for the specified indication.

Serum C-reactive protein (CRP) was selected as a biomarker to represent serum IL-6 concentrations since the latter formed complexes during treatment which interfered with the analytical method. The dosing regimen was designed with a population pharmacokinetics (PK) model coupled with a pharmacodynamics (PD) model of an inhibitory indirect response. The model suggested an adjusted dose of 11 mg/kg every 3 weeks to maintain drug concentrations (PK) that would keep serum CRP (PK) under the desired level of 1 µg/mL. Clinically, rapid and sustained suppression of serum CRP was observed and, from simulation studies, it was expected that steady-state serum concentration of siltuximab would be reached by the end of the sixth cycle throughout the remainder of the treatment period and for 3 weeks after the last dose for over 90% of the patient population.

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

Clinical Efficacy

The efficacy and safety of Sylvant were assessed in a pivotal Phase II, multinational, randomized, double-blind, placebo-controlled study (MCD2001), and in a supportive Phase I, single-arm, open-label study (C0328T03).

The pivotal study MCD2001, compared Sylvant plus best supportive care (BSC) versus (vs.) BSC in 79 male and female patients with symptomatic MCD who were human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)-negative. Patients were randomized (2:1 to Sylvant + BSC or placebo + BSC), and stratified for baseline corticosteroid use (yes vs. no). There were 53 patients randomized to receive Sylvant and 26 patients randomized to receive placebo. Of the 26 patients who received placebo, 13 subsequently crossed-over to receive Sylvant. The study was conducted in 38 study centres in 19 countries including the United States, Canada, and Eastern and Western Asia. The patients were 20-78 years of age (median 48 years), 48% were Asian, and 39% were Caucasian. The majority of the patients (66%) were men; however, the placebo group was imbalanced with 85% male patients.

Symptomatic disease was defined with National Cancer Institute Common Terminology Criteria Adverse Event (NCI CTCAE) grading ≥1. Treatment (Sylvant 11 mg/kg every 3 weeks or placebo) was to be continued until treatment failure (defined as disease progression based on increase in symptoms, deterioration in performance status, or radiologic progression), discontinuation of treatment, withdrawal from the study, or until 48 weeks after the last patient started study treatment.

Patients were evaluated with radiologic imaging, assessment of skin lesions, and signs and symptoms related to the disease. Independent radiologists blinded to treatment assignment reviewed all imaging studies. Tumour response was assessed based on index lesions (measurable) and nonindex lesions (nonmeasurable).

The primary efficacy endpoint was durable tumour and symptomatic response, defined as a complete response (CR, complete disappearance of all measurable and evaluable disease and resolution of baseline symptoms attributed to MCD, sustained for at least 18 weeks) or a partial response (PR, a ≥50% decrease in the sum of the product of the diameters of index lesion(s), with at least stable disease in all other evaluable disease in the absence of treatment failure, sustained for at least 18 weeks), assessed by independent central radiology review and investigator-assessed symptomatic response. The primary analysis was to occur when the last patient had completed 48 weeks of treatment.

The intent-to-treat population was used for the primary endpoint analysis. The response rate in the 2 treatment groups was compared using an exact Cochran-Mantel-Haenszel test, adjusted for the stratification factor (corticosteroid use). A hierarchical testing procedure of select major secondary endpoints was pre-specified, and included the endpoints tumour response rate and time to treatment failure. Ninety-five percent confidence intervals and p-values were calculated to compare the two groups. The safety population for this study included 79 patients who were randomized and received at least 1 dose of Sylvant or placebo.

Independent review showed a statistically significant improvement in durable tumour and symptomatic response rate in the Sylvant group compared with the placebo group (34% vs. 0%, respectively; difference in response rates of 34% with 95% CI: 11.1, 54.8; p = 0.0012). The overall tumour response rate was 38% in the Sylvant group and 4% in the placebo group (difference in response rates of 33.9% with 95% CI: 11.1, 54.8; p = 0.0022). In the subset of patients with baseline anemia, hemoglobin response (change from baseline of ≥15 g/L at Week 13) was reported in 61% of patients in the Sylvant group and 0% of patients in the placebo group (95% CI 28.3, 85.1; p = 0.0002). At the time of analysis, overall survival data were not mature.

The supportive Study C0328T03 was a single-arm, open-label Phase I study where the primary objective was to assess the safety and pharmacokinetics of multiple dosing regimens of Sylvant administered as an intravenous (IV) infusion in patients with B-cell non-Hodgkin's lymphoma, multiple myeloma, or Castleman's disease. A total of 16 patients with MCD were treated at the target dose and schedule (11 mg/kg every 3 weeks) for a median of 92 weeks (range 8.1, 252.3). In these patients, overall tumour response rate evaluated by independent review was 43.8% with a 6.3% complete response. Eleven of these patients moved into a long-term extension study and have been treated for a median duration of 68 months (range 40.9, 85.1). All tumour responses were durable for >18 weeks.

Overall, the efficacy data submitted supports the use of Sylvant for the treatment of patients who are (HIV)-negative and (HHV-8)-negative.

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

Clinical Safety

The clinical safety evaluation of Sylvant was primarily based on data obtained from both the Phase II pivotal study (MCD2001) and the Phase I supporting study (C0328T03) discussed in the Clinical Efficacy section. In the pivotal study, 53 patients with MCD were randomized to the Sylvant treatment arm and received 11 mg/kg Sylvant every 3 weeks and 26 patients were randomized to the placebo arm. Of the 26 placebo-treated patients in the pivotal study, 13 subsequently crossed-over to receive Sylvant. The supporting study included 16 patients with MCD whom received the target dose of 11 mg/kg Sylvant every 3 weeks. Additional data were available from patients who received 11 mg/kg Sylvant in other disease types including malignant solid tumours, metastatic renal cell carcinoma, myelodysplastic syndrome and smoldering multiple myeloma.

The safety of Sylvant treatment was compared with placebo in various subsets of the integrated safety dataset, including all patients with MCD who received the target dose (MCD target dose group), and all patients with MCD who received any dose (integrated MCD group). The safety profile for the integrated monotherapy studies in various disease types was similar to that seen in the integrated MCD studies for those patients treated with Sylvant at the target dose and no dose-related safety issues were identified. In combination therapy studies in multiple myeloma, no additional safety issues were observed.

All patients in the MCD target dose group had a treatment-emergent adverse event (TEAE) (100% in the MCD target dose group vs. 96% in the placebo group). Adverse events leading to dose delay or interruption in MCD studies were reported in 32.9% (27/82) of patients in the Sylvant group vs. 19.2% (5/26) in the placebo group. Adverse events leading to discontinuation were reported in 18.3% (15/82) of patients in the Sylvant group vs. 38.5% (10/26) in the placebo group. The most frequent adverse drug reactions (ADRs), affecting ≥20% of patients during treatment with Sylvant in the MCD clinical studies, were upper respiratory tract infection (37.8%), pruritus (29.3%), and maculo-papular rash (23.2%). The most serious ADR associated with the use of Sylvant was anaphylactic reaction (1.2%). Two patients (4%) died due to disease progression after Sylvant was discontinued in the treatment group. Four patients (15%) in the placebo group died (1 patient died of pneumonia and congestive heart failure, and the other 3 due to disease progression or the development of myelodysplastic syndrome). The Sylvant Product Monograph includes identified ADRs from the pivotal clinical study, MCD2001, TEAEs observed in at least 3% of the MCD target dose group, abnormal hematology parameters of Grade 3 or higher in the integrated MCD group, and TEAEs of Grade 3 or higher observed in at least 5% of patients who received Sylvant at the target dose with any condition.

Infections

In the MCD clinical studies, Sylvant was associated with upper respiratory tract infections in 37.8% (31/82) of patients vs. 15.4% (4/26) of placebo-treated patients. Nasopharyngitis occurred in 13.4% (11/82) of patients treated with Sylvant vs. 3.8% (1/26) of placebo-treated patients. Serious infections, including pneumonia and sepsis were observed during clinical studies.

Sylvant may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). The Sylvant Product Monograph includes guidance to practitioners to diligently monitor patients receiving Sylvant for signs of infection, and to withhold Sylvant until any infection resolves.

Infusion-related reactions and hypersensitivity

Anaphylaxis has occurred during infusion with Sylvant. In the MCD2001 clinical study, Sylvant was associated with an infusion-related reaction or hypersensitivity reaction in 7.5% of patients treated with Sylvant monotherapy vs. 0% in the placebo group. The most common infusion-related reactions reported in Sylvant-treated patients (≥2 patients) were pruritus, erythema, chest pain, and nausea. In Sylvant monotherapy studies, infusion-related reactions, among those patients with infusion-related reactions collected, were low at 1.9% (1/52) in the placebo group vs. 4.9% (4/81) in the target dose group. These were generally low grade and manageable. Dose delays or dose interruptions were infrequent. There were no deaths due to infusion-related reactions reported across the groups. The Sylvant Product Monograph includes guidance to practitioners regarding the management of infusion-related reactions and hypersensitivity.

Cardiovascular

Hypertension has been reported as an adverse event in Sylvant clinical trials in MCD patients (13.4% vs. 3.8% in the placebo group, 7.3% Grade 3 or 4 vs. 0% in the placebo group).

Hypotension (grade 3 or higher) has been reported as an adverse event in clinical trials in MCD patients (1.2% vs. 0% in the placebo group).

An assessment of the cardiovascular safety of Sylvant has been performed and no safety issues have been identified among Sylvant-treated patients. There were no effects on the QT interval and no increased risk for cardiac arrhythmias observed in Sylvant-treated patients with MCD.

Endocrine and Metabolism

In the MCD clinical studies, Sylvant was associated with a higher incidence of hypertriglyceridemia compared with placebo-treated patients [13.4% (11/82) vs. 0% (0/26), respectively]. In the MCD2001 clinical study, 5.7% of Sylvant-treated patients were administered a lipid-modifying agent in association with an adverse event of hypertriglyceridemia.

In MCD studies, hyperuricemia was reported in 14.6% vs. 0% in the placebo group (grade 3 or higher: 3.7% vs. 0% in the placebo group). An increase in uric acid levels was reported in MCD studies (13.4% grade 4 vs. 15.4% grade 4 in the placebo group).

Gastrointestinal

Gastrointestinal (GI) perforation has been reported in Sylvant clinical studies (0.75%) although not in MCD studies.

Hematologic

Polycythemia was reported as a serious adverse event in Sylvant clinical trials in MCD patients (1.2%).

Immune

In MCD clinical trials, grade 3 or grade 4 neutropenia was reported as an adverse event in 3/82 (3.7%) of Sylvant-treated patients vs. 1/26 (3.8%) in placebo-treated patients.

All clinical studies with Sylvant excluded patients with clinically significant infections, including those known to be hepatitis B surface antigen positive. Two cases of reactivated hepatitis B have been reported when Sylvant was administered concomitantly with high dose dexamethasone, and bortezomib, melphalan and prednisone in multiple myeloma patients.

Sylvant did not bind to virally produced IL-6 in a nonclinical study. Patients should be tested to confirm they are not HIV or HHV-8 positive before treatment.

Renal Impairment

Renal impairment was reported in 12.2% vs. 0% in the placebo group (2.4% grade 3 or higher vs. 0% in the placebo group).

Overall, the safety profile of Sylvant is acceptable and manageable for patients with MCD who are HIV-negative and HHV-8-negative. Appropriate warnings and precautions are in place in the approved Sylvant Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

The non-clinical database for siltuximab, the active ingredient in Sylvant, is complete, and is in accordance with the International Conference on Harmonisation (ICH) Guidance S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals document.

In vitro, siltuximab dose-dependently inhibited the growth of an IL-6-dependent murine plasmacytoma cell line in response to human IL-6. In cultures of human hepatoma cells, IL-6-stimulated production of the acute phase protein serum amyloid A was dose-dependently inhibited by siltuximab. Similarly, in cultures of human Burkitt's B-lymphoma cells, the production of immunoglobulin M (IgM) protein in response to IL-6 was dose-dependently inhibited by siltuximab.

Siltuximab demonstrated comparable activity in the neutralization of human and non-human primate IL-6, whereas little or no activity was seen against IL-6 from other species, supporting the use of non-human primates in the non-clinical studies. The surrogate anti-mouse IL-6 mAb, CNTO 345, exhibited a similar binding and neutralization activity profile for mIL-6 as siltuximab demonstrated against hIL-6, and was therefore used in supportive mouse toxicology studies.

Siltuximab was well-tolerated in cynomolgus monkeys in the 3- and 6-month repeat-dose toxicity studies. Reproductive toxicity testing revealed that siltuximab was well-tolerated during pregnancy, and was not teratogenic nor embryotoxic in cynomolgus monkeys. Treatment of mice with the surrogate antibody CNTO 345 had no adverse effects on maternal or paternal fertility. No tumours or pre-neoplastic changes were observed in the repeat-dose studies. Based on the weight of evidence, inhibition of IL-6 has a low probability of increasing tumorigenesis in patients. Pharmacological effects indicative of inhibition of specific immune responses were noted that were consistent with the known pharmacology of IL-6 inhibition; the magnitude of these findings were minimal and were not considered to be toxicologically significant.

In conclusion, siltuximab was well-tolerated in cynomolgus monkeys at a dose and exposure level that exceeded the anticipated human exposure by at least 10-fold. The non-clinical toxicology database was considered adequate to assess the safety profile of siltuximab and support its use for the treatment of adults with Castleman's disease.

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

7.3 Quality Basis for Decision

Siltuximab, the active ingredient in Sylvant, is a chimeric (human-murine) monoclonal antibody of the immunoglobulin G1κ (IgG1κ) isotype that binds to human Interleukin-6 (IL-6). Siltuximab is biosynthesized in cell substrate engineered by recombinant deoxyribonucleic acid (DNA) techniques from a Chinese Hamster Ovary (CHO) cell line.

Characterization of the Drug Substance

Siltuximab was extensively analyzed to determine its structural, physicochemical, and functional characteristics. Siltuximab is comprised of two identical heavy chains and two identical light chains that associate through non covalent interactions and covalent heavy heavy and heavy light chain disulfide bonds.

Detailed characterization studies were performed to provide assurance that siltuximab 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

Siltuximab (the drug substance) is biosynthesized in cell substrate engineered by recombinant DNA techniques from a Chinese hamster ovary (CHO) cell line. Cell substrate, suspended in chemically defined medium without components of human or animal origins, is cultivated using bioreactors operated in perfusion mode. Siltuximab is purified from the collected supernatant pool in a series of chromatographic, filtration, and chemical treatment steps that are designed and validated to remove specific impurities, including viruses. Key process intermediate is isolated following virus inactivation; the material is filtered, dispensed into containers, and stored frozen until further processing. The manufacturing process is operated under conditions that are defined as nested ranges of normal operating ranges and proven acceptable ranges established using the design of experiments approach. The manufacturing process was validated at the manufacturing scale and/or characterized using qualified small scale models. The performance of the manufacturing process is routinely monitored by in process testing against justified acceptance criteria.

The process for the manufacture of the drug product (Sylvant) includes thawing of bottles containing the formulated bulk, pooling and mixing, pre filtration, in line sterilizing filtration and aseptic filling. Following aseptic filling, the vials are partially stoppered, lyophilized and fully stoppered, capped and visually inspected. There are no process intermediates. The performance of the manufacturing process is routinely monitored through in process testing against justified acceptance criteria. The manufacturing process performance was validated at the manufacturing scale to establish the overall consistency and effectiveness of aseptic operations. The performance of the manufacturing process is routinely monitored by in process testing against justified acceptance criteria.

Control of the Drug Substance and Drug Product

The quality of the drug substance is assessed against respective release specifications, which incorporate tests to assess identity, purity, potency, and relevant characteristics of the dosage form. The associated analytical methods were validated or qualified and the acceptance criteria were appropriately justified. The provided batch analysis data confirm that the proposed manufacturing process consistently yields drug substance of acceptable quality.

The quality of Sylvant drug product lots is routinely assessed against a release specification, which incorporates tests to assess relevant characteristics of the dosage form, the identity, purity, and potency of the reconstituted active ingredient, excipient composition and conformance with compendial requirements. The associated analytical methods were validated or qualified, and the acceptance criteria were appropriately justified. The provided batch analysis data confirm that the proposed manufacturing process consistently yields drug product of acceptable quality.

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 shelf life of 24 months at 2-8°C for both the 100 mg and 400 mg vials is considered acceptable. Furthermore, in-use stability was demonstrated, considering the compatibility of reconstituted and diluted Sylvant with infusion devices and exposure to environmental conditions associated with routine dose administration.

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.

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of Sylvant was not conducted due to the short timeline associated with this priority submission and because Health Canada had recently performed an OSE at each of the facilities with respect to other drug products.

All sites involved in the production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

Materials of animal origin were used early in the development of the cell substrate and were subjected to appropriate risk assessment. No materials of human or animal origin are used in the manufacture of Sylvant.

Report a problem or mistake on this page
Please select all that apply:
Date modified: