Summary Basis of Decision for Simponi ™
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:
SimponiTM
Golimumab, 50 mg/0.5 mL, Solution, Subcutaneous
Centocor Ortho Biotech Inc.
Submission control no: 120525
Date issued: 2009-09-02
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02324776
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number: 120525
Date of Submission:
Date of authorization:
2 Notice of decision
On April 7, 2009, Health Canada issued a Notice of Compliance to Centocor Ortho Biotech Inc. for the drug product Simponi.
Simponi contains the medicinal ingredient golimumab, which is a tumour necrosis factor alpha (TNF-α) inhibitor.
Simponi is indicated for the conditions described below:
Rheumatoid arthritis (RA) - Simponi, in combination with methotrexate (MTX), is indicated for:
- Reducing signs and symptoms in adult patients with moderately to severely active RA.
Psoriatic arthritis (PsA) - Simponi is indicated for:
- Reducing signs and symptoms in adult patients with moderately to severely active PsA, alone or in combination with MTX. Simponi can be used in combination with MTX in patients who do not respond adequately to MTX alone.
Ankylosing spondylitis (AS) - Simponi is indicated for:
- Reducing signs and symptoms in adult patients with active AS who have had an inadequate response to conventional therapies.
Rheumatoid arthritis, PsA, and AS are autoimmune disorders of unknown etiology, however, it is known that the proinflammatory cytokine TNF-α mediates inflammation in each of these conditions. Simponi is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody that prevents the binding of TNF-α to its receptor, thereby producing an immunosuppressant effect.
The market authorization was based on quality, non-clinical, and clinical information submitted. Safety and efficacy were evaluated using 24-week data obtained from five large multicentre, randomized, double-blind, placebo-controlled, Phase III clinical studies. An additional 8 months of Simponi exposure data from the extension of these studies was submitted to support the long-term safety of this product. Each of these studies examined subcutaneous (SC) Simponi injections in patients with the chronic inflammatory disorders: RA (3 studies), PsA (1 study), and AS (1 study). For several of these studies, a primary efficacy endpoint was the percent of patients achieving an American College of Rheumatology 20 (ACR 20) response by Week 14 of treatment. An ACR 20 response requires a patient to have a 20% reduction in the number of swollen and tender joints, and a 20% reduction in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire (HAQ) score.
A total of 1542 patients with moderately to severely active RA took part in three studies assessing the safety and efficacy of Simponi treatment. Simponi was administered subcutaneously at doses of 50 mg or 100 mg, with or without MTX, every 4 weeks. Primary endpoints for two of the studies included the percent of patients achieving an ACR 20 response at Week 14. As well, a co-primary endpoint for one of the studies was improvement from baseline in HAQ at Week 24 as compared to placebo. Simponi treatment with or without concomitant treatment with MTX in patients with active RA (previously treated or not treated with anti-TNF agents) resulted in improvement in signs and symptoms as demonstrated by the percent of patients achieving an ACR 20 response at Week 14. Patients treated with Simponi also exhibited significantly greater improvement in several aspects of the HAQ.
In a separate study, 405 patients with PsA were randomly assigned to receive placebo or Simponi (50 mg or 100 mg). Treatment with 50 mg of Simponi resulted in the first co-primary endpoint of the study being met, in that significant improvement in signs and symptoms were observed based on the percent of patients achieving an ACR 20 response at Week 14. The analysis is ongoing for the second co-primary endpoint of change from baseline in radiographic score.
An additional study evaluated 356 patients with AS. Patients were randomly assigned to receive placebo or Simponi (50 mg or 100 mg). The primary endpoint was Assessment in Ankylosing Spondylitis 20 (ASAS 20) response at Week 14. ASAS 20 responses were achieved by 59% of patients receiving 50 mg Simponi compared with 22% of patients receiving placebo at Week 14. Improvement in signs and symptoms as measured by ASAS 20 was observed at first assessment (Week 4) following the first administration of Simponi, and was maintained through Week 24.
The safety of Simponi is further supported by clinical data beyond 24 weeks in the five Phase III studies together with safety data from Phase I and II studies in RA patients, completed and ongoing studies in other indications, and Phase I studies in healthy subjects. The safety data submitted did not pose unique concerns beyond those applicable to other biologic products approved for the treatment of RA, PsA or AS including other members of this class. Simponi is a member of the TNF-inhibitors class, which has been associated with severe risks of serious infections, including opportunistic infections, development of lymphoma and other malignancies, and development of demyelinating disorders and autoimmune disorders in RA, PsA and AS.
Simponi (50 mg/0.5 mL, golimumab) is presented in a pre-filled syringe or autoinjector as a solution for SC injection. The recommended dose of Simponi for adult patients with RA, PsA and AS is 50 mg given subcutaneously once a month, on the same date each month. Dosing guidelines are available in the Product Monograph.
Simponi is contraindicated for patients with severe infections such as sepsis, tuberculosis, and opportunistic infections. As well, Simponi is contraindicated in patients who are hypersensitive to golimumab, latex, or to any other ingredient in the formulation or component of the container. Simponi should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Simponi are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Simponi is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Golimumab, the medicinal ingredient of Simponi is a TNF-α inhibitor. The elevated expression of the cytokine TNF-α has been linked to chronic inflammatory diseases such as rheumatoid arthritis (RA), as well as spondyloarthropathies such as psoriatic arthritis (PsA) and ankylosing spondylitis (AS). It is an important mediator of the articular inflammation and structural damage that are characteristic of these diseases. Golimumab is a human IgG1κ monoclonal antibody that binds with high affinity to human TNF-α. Through the formation of stable complexes with both soluble and transmembrane forms of human TNF-α, golimumab prevents the binding of TNF-α to its receptor, thereby neutralizing its biological activity and producing an immunosuppressant effect.
Manufacturing Process and Process Controls
Golimumab is manufactured using a continuous perfusion mammalian cell culture process. The purification process consists of a combination of chromatography and viral inactivation/removal steps. Process validation data demonstrate that the manufacturing process operates in a consistent manner, yielding product of acceptable quality.
The drug substance manufacturing process has been scaled-up and optimized during development. The process changes introduced at each generation of the process were adequately described and comparatively assessed. Lot release and characterization data have also been used to support the comparability assessment.
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that golimumab consistently exhibits the desired characteristic structure and biological activity.
Comparability of golimumab lots produced by different processes was performed and comparable physicochemical characteristics were demonstrated.
Control of Drug Substance
The drug substance specifications and analytical methods used for the quality control of golimumab are considered acceptable.
The levels of product- and process-related impurities are adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The impurities that were reported and characterized were found to be within acceptable limits.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The proposed packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Simponi (50 mg/0.5 mL, golimumab) is supplied as a sterile, clear to slightly opalescent, preservative-free solution in a single-use, Type I glass 1-mL pre-filled syringe with a fixed stainless steel needle. The syringe is stoppered with a coated stopper and the needle is covered with a needle shield. The fixed needle is a 5-bevel, 27-gauge, half-inch stainless steel needle. The needle shields are manufactured using a dry natural rubber containing latex. The syringe is assembled into either the Centocor Autoinjector or the UltraSafe Passive® Delivery System for single-use by SC injection.
Each 1.0 mL of Simponi contains 100 mg of golimumab, 0.87 mg L-histidine and L-histidine hydrochloride, 41.0 mg sorbitol, 0.15 mg polysorbate 80, and water for injection. Simponi is available in one-strength: 50 mg of golimumab in 0.5 mL.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of golimumab with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
The release specifications and stability specifications for the drug delivery devices assure device quality, performance, and safety of the finished combination product with respect to drug delivery and post-use needle stick protection when used according to their labelled Instructions for Use.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The Simponi drug product manufacturing process essentially consists of pooling formulated bulk from the individual bulk containers, and filling into syringes. The manufacturing process has been adequately validated.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
The validated process is capable of consistently generating product that meets release specifications.
Control of Drug Product
Simponi is tested to verify that its identity, appearance, content uniformity, assay, pH, particle size, viscosity, fill volume, particulates, sterility, protein content, osmolality, colour, clarity, levels of degradation products, drug-related impurities, bacterial endotoxins, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 24-month shelf-life for Simponi, when stored at 2 to 8°C in the proposed container closure system, protected from light, is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of golimumab drug substance has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The facility was rated as compliant and no observations were made. An OSE of the facilities involved in the manufacture and testing of Simponi drug product was not warranted as the facility was recently evaluated for another product.
The design, operations, and controls of the facilities and equipment that are involved in the production of Simponi are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Cell culture, fermentation steps, and purification steps are performed in almost closed systems to avoid microbiological contamination. Open steps are performed under laminar flow and/or apply additional contamination precaution measures. Transmissible spongiform encephalopathy infectivity is excluded as no animal-derived raw materials are used in the manufacture and formulation of Simponi. During cell line development, foetal bovine serum has been used, however, no animal-derived materials were used to prepare the cell banks. The cell bank systems have been tested for the absence of microbial, fungal and viral contaminants. Unprocessed bulk harvest for each run is tested for the absence of viral contaminants by in vitro assay using four indicator cell lines.
Mycoplasma and microbial bioburden are monitored by in-process testing. Bioburden and endotoxin levels are monitored as part of routine release testing. Manufacturing procedures and 0.2 µm filtration steps are used throughout the process to minimize the risk of microbial contamination.
Potential viral agents include endogenous retrovirus and adventitious agents. Raw material controls minimize the risk of contamination by adventitious agents. Clearance studies provide further assurance that any potential endogenous or adventitious agents will be removed or inactivated by the manufacturing process.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Simponi has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
In vitro pharmacodynamic (PD) studies revealed that golimumab binds with high affinity to soluble human TNF-α (monomer and trimer) and to transmembrane TNF-α. The affinity of soluble TNF-α trimer for golimumab was 2.4-fold greater compared to the affinity of TNF-α for infliximab. Infliximab is a chimeric anti-human IgG1 monoclonal antibody that has a pharmacological profile similar to that of golimumab. Evidence from these studies demonstrated that the primary mechanism of action of golimumab is the prevention of binding of human TNF-α to TNF-α receptors.
The binding of TNF-α to p55 and p75 TNF-α receptors was inhibited by golimumab in a concentration-dependent manner. It was shown that TNF-α rapidly dissociates from TNF-α/TNF-α-receptor complexes in the presence of golimumab, as the binding of dissociated TNF-α to golimumab prevents reassociation with its receptor.
In further in vitro tests, golimumab effectively neutralized several TNF-α-mediated cellular responses including cytotoxic effects on a human tumour cell line and TNF-α- induced cell-surface expression of the adhesion proteins E-selectin, vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1 by human endothelial cells. The TNF-α- induced secretion of cytokines by primary human endothelial cells was also inhibited by golimumab as was the proliferation and secretion of cytokines by primary human fibroblasts. In the majority of in vitro assays, golimumab consistently showed a 2- to 5-fold higher potency compared to infliximab.
The effect of golimumab in vivo was evaluated for efficacy in a human TNF transgenic mouse model of experimental arthritis. Treatment with golimumab produced a statistically significant delay in the onset of clinical symptoms compared to untreated mice, as well as a significant reduction in joint pathology. The effect on clinical symptoms was observed with golimumab at doses of 1 and 10 mg/kg bodyweight (bw), while the effect of infliximab was only seen at the 10 mg/kg bw dose.
Golimumab was capable of neutralizing TNF-α from several non-human primates, including cynomolgus monkeys, but little or no neutralization of TNF-α could be detected in dog, rabbit, mouse, or rat.
3.2.2 Pharmacokinetics
The doses and the dose regimens selected for the toxicology studies were sufficient to produce sustained high serum concentrations of golimumab that were greatly in excess of the concentrations required to neutralize all TNF-α in monkey serum. Serum concentrations obtained in the repeated-dose studies were at least 2400-fold in excess of the concentrations required to neutralize cynomolgus monkey TNF-α in vivo. In addition, serum concentrations were greatly in excess of clinical exposure levels, with peak serum concentrations obtained at steady-state being in excess of 1000-fold greater than the peak serum concentration obtained in patients that received 50 mg golimumab SC injections every 4 weeks.
Pharmacokinetic (PK) analysis in the repeat-dose studies conducted in cynomolgus monkeys did not reveal any apparent gender differences. In the 6-month SC-dose study with twice weekly administrations, the overall mean terminal half-life for both the 25 and 50 mg/kg bw dose was estimated to be between 14 and 16 days. Systemic exposure increased in a dose-proportional manner. Steady-state serum golimumab concentrations were reached at or between Day 81 and Day 92 with an estimated area under the curve (AUC) accumulation ratio of 5.71 estimated for the 25 mg/kg bw dose group. Steady-state serum golimumab concentrations were reached between Day 92 and Day 141 with an estimated AUC accumulation ratio of 8.90 in the 50 mg/kg bw dose group.
3.2.3 Toxicology
In PD studies it was demonstrated that golimumab neutralizes the activity of cynomolgus monkey TNF-α, but does not neutralize rodent TNF-α. Hence, toxicology studies with golimumab were conducted in cynomolgus monkeys, and supportive toxicology studies were conducted in mice using an analogous anti-mouse TNF-α monoclonal antibody (cV1q). These mouse toxicity studies were also conducted in support of the infliximab (Remicade®) toxicology program but were provided by the sponsor as supportive information for the effects of anti-TNF-α treatment on reproduction, development and chronic toxicity.
The doses and the dose regimens selected for the toxicology studies were sufficient to produce sustained high serum concentrations of golimumab that were greatly in excess of the concentrations required to neutralize all TNF-α in monkey serum.
Safety pharmacology endpoints were incorporated into the single- and repeated-dose toxicology studies conducted with golimumab in cynomolgus monkeys. These included measures of heart rate, blood pressure and electrocardiograms (ECGs) to assess cardiovascular safety; respiratory rate to assess respiratory safety; and body temperature and daily clinical cage side observations to evaluate central nervous system (CNS) safety. No adverse events (AEs) of golimumab were observed in the safety pharmacology evaluations following single- and repeated-dosing of cynomolgus monkeys via intravenous (IV) or SC routes of administration at doses up to 50 mg/kg twice weekly.
Repeat-Dose Toxicity
Sub-chronic testing in CD-1 mice was carried out for 6 months, with IV administration of cV1q at dose levels of 0, 10, or 40 mg/kg bw/week. Dose levels were well-tolerated and there were no adverse treatment-related findings at either dose level tested. The only finding was an increase in the incidence of lymphocytolysis for male mice in the 50 mg/kg bw group. However, this finding was not observed at the end of the recovery period, and in the absence of any other treatment-related findings, is of uncertain toxicological significance.
Sub-chronic testing for 1 month (IV administration) and chronic toxicity testing for 6 months (IV and SC administration) in cynomolgus monkeys was carried out at dose levels of 10 (1-month study), 25 (6-month studies) and 50 (all studies) mg/kg bw/week. Dose levels were generally well-tolerated after 1 or 6 months of exposure. However, in the 6-month IV study, one male in the 25 mg/kg bw group exhibited disseminated histoplasmosis, which was considered to be likely a secondary effect associated with the administration of golimumab. In addition, Keyhole Limpet Hemocyanin (KLH) analysis revealed a reduced humoral response (after IV administration only), with a more pronounced effect observed at 50 mg/kg bw. IgG antibody production was more affected than immunoglobulin M (IgM). Based on these findings, it was concluded that the risk of infection is increased with golimumab administration. There were no other treatment-related effects observed in these studies.
Genotoxicity
Genotoxicity tests have not been conducted with golimumab. Due to their large molecular size, monoclonal antibodies are not expected to pass through cellular and nuclear membranes and therefore are not expected to gain access to or interact with deoxyribonucleic acid (DNA) or other chromosomal material. The range and type of genotoxicity studies routinely conducted for pharmaceuticals are generally not considered applicable to biotechnology-derived pharmaceuticals according to the International Conference on Harmonisation (ICH) Guidance S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals document (ICH S6).
Carcinogenicity
Carcinogenicity studies have not been conducted with golimumab. Direct evaluation of carcinogenic potential of golimumab in carcinogenicity studies or rodent tumour immune surveillance models is precluded since golimumab does not neutralize rodent TNF-α. It is worth noting that in the 6-month chronic toxicity monkey study there were no proliferative changes (such as hyperplasia) in any animal after up to 9-months of exposure to golimumab. In addition, the 6-month chronic toxicity study conducted in mice with cV1q showed no proliferative changes.
Reproductive and Developmental Toxicity
Reproductive toxicity studies were conducted in cynomolgus monkeys at dose levels of 25 and 50 mg/kg bw. There were no treatment-related effects on embryo-foetal development, pre- and post-natal development (including the development of the foetal immune system, and functioning of the infant immune system) nor on maternal function. Golimumab was not teratogenic at any dose level tested.
Supportive reproductive/developmental studies were conducted in mice at dose levels of 10 and 40 mg/kg bw. In these studies, there were no treatment-related effects on viability or growth and development in the offspring through production of the second filial (F2) generation foetuses. Treatment with cV1q did not adversely affect the immune response of CD-1 first filial (F1) generation male and female mice, with the exception of effects on humoral immunity where treatment at a dose level of 40 mg/kg bw resulted in slight decreases in humoral immune parameters. It was reported that decreases in IgM antibody forming cell (AFC) response to sheep red blood cell (sRBC) have been observed previously in adult mice treated with anti-TNF antibody.
In a general fertility and reproductive study, pregnancy rates were 92%, 91%, and 76% of the female mice in the 0 (vehicle control), 10, and 40 mg/kg bw dose groups, respectively. This finding was not considered to be treatment-related since the pregnancy rate was only slightly lower than the historical control range (83 to 100%) and there was no effect on semen parameters or on fertility parameters evaluated at Caesarean section. In addition, this effect was not reproducible in a peri-/post-natal reproduction study in mice, in which the pregnancy rates for the F1 generation females were 95.8%, 91.3%, and 100% for the 0, 10, and 40 mg/kg bw groups, respectively.
Local Tolerance
Local tolerance after SC injections of golimumab was evaluated in a single injection study and in 3-week and 4-week twice weekly injection studies in cynomolgus monkeys. In these studies, mild skin irritation and inflammation at the SC injection-site were seen which were similar to that following SC injection of human IgG. This local injection-site reaction was considered to likely be related to the development of immune antibody responses detected in the monkeys as a result of the injection of a foreign protein.
Immunohistochemical Tissue Cross-Reactivity
In an immunohistochemical tissue cross-reactivity study, golimumab did not stain the majority of the normal human tissues evaluated. There was slight to moderate staining of the adnexal epithelium of the skin from 2 out of 3 donors and slight staining of the keratinocytes in the epidermis (stratum malpighii) of nipple skin overlying the breast (mammary gland) from 1 out of 3 donors. The reactivity was observed at a concentration of 10 µg/mL but not at 1 µg/mL. The positive staining of these tissues was not unexpected, as it has been reported that human surface epidermal and adnexal keratinocytes may express TNF-α.
Antigenicity
The incidence of antibodies to golimumab was greater at lower doses. High serum concentrations of golimumab observed in the multiple-dose studies may have interfered with the detection of antibodies to golimumab, or the animals may have developed high-dose tolerance.
3.2.4 Summary and Conclusion
In summary, in vitro PD studies revealed that golimumab binds with high affinity to soluble human TNF-α (monomer and trimer) and to transmembrane TNF-α and is capable of effectively neutralizing several TNF-α-mediated cellular responses. Golimumab was capable of neutralizing TNF-α from several non-human primates.
Pharmacokinetic analysis revealed that the serum concentrations obtained in the repeated-dose studies in cynomolgus monkey were greatly in excess of clinical exposure levels, with peak serum concentrations obtained at steady-state being in excess of 1000-fold greater than the peak serum concentration obtained in patients that received 50 mg golimumab SC injections every 4 weeks.
In general, golimumab was well-tolerated in repeat-dose toxicity studies and local tolerance studies at doses up to 50 mg/kg bw, which is up to 1000-fold higher than the median steady-state maximum plasma concentration (Cmax) value in humans (1.71 µg/mL) receiving 50 mg every 4 weeks. However, in the 6-month repeat dose monkey IV toxicity study, one male exhibited disseminated histoplasmosis which was considered most likely to be a secondary effect associated with the administration of golimumab. In addition, KLH analysis in this study revealed a reduced humoral response. Hence, it was concluded that the risk of infection is increased with golimumab administration.
Although lymphocytolyis was observed in male mice at the dose level of 50 mg/kg bw, this finding was totally reversed by the end of the recovery period. In addition, lymphocytolysis was not observed in cynomolgus monkeys after dosing for up to 6 months. Hence, the weight of evidence indicates that lymphocytolyis is not a safety concern for humans.
There was no evidence of golimumab-associated maternal toxicity, teratogenicity, or developmental delays observed in developmental and reproductive toxicity studies in cynomolgus monkeys. For reproduction studies in mice, the only finding was slight decreases in humoral immune parameters in the F1 generation mice at a dose level of 40 mg/kg bw.
The toxicity database for Simponi (golimumab) is in accordance with the ICH S6 and is considered adequate to assess the safety profile of Simponi (golimumab) and to support its use in humans, provided that adequate safety precautions are taken against the immunomodulatory activity which may be seen in patients undergoing treatment.
3.3 Clinical basis for decision
3.3.1 Pivotal Studies
The pharmacodynamics, pharmacokinetics, safety, and efficacy of Simponi were evaluated on the basis of 24-week data obtained from 5 large multicentre, randomized, double-blind, placebo-controlled, Phase III clinical studies. An additional 8 months of Simponi exposure data from the extension of these studies were submitted to support the long-term safety of this product. Each of these pivotal studies examined SC injections of Simponi in patients with the chronic inflammatory disorders: RA (3 studies), PsA (1 study), and AS (1 study).
Rheumatoid Arthritis
Three pivotal studies [RA-1 (GO-FORWARD), RA-2 (GO-AFTER), and RA-3 (GO BEFORE)] of Simponi treatment for RA were conducted in over 1500 patients ≥18 years of age. Enrolled patients had moderately to severely active RA diagnosed according to American College of Rheumatology ACR criteria for at least 3 months prior to screening with at least 4 swollen and 4 tender joints. Simponi was administered subcutaneously at doses of 50 mg or 100 mg, with or without MTX, every 4 weeks.
Psoriatic Arthritis
One pivotal study (GO-REVEAL) evaluated Simponi treatment in 405 adult patients with active PsA. Patients received 50 or 100 mg of Simponi administered as SC injections every 4 weeks. Enrolled patients had a diagnosis of PsA for at least 6 months with a psoriatic skin lesion of at least 2 cm in diameter and active disease with at least 3 swollen and 3 tender joints despite disease-modifying antirheumatic (DMARD) or nonsteroidal anti-inflammatory (NSAID) therapy. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%).
Ankylosing Spondylitis
One pivotal study (GO-RAISE) evaluated Simponi treatment in 356 adult patients with active AS. Patients received 50 or 100 mg of Simponi administered as SC injections every 4 weeks. Enrolled patients had symptoms of active disease [defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 and a visual analogue scale (VAS) for total back pain of ≥4, each on a scale of 0 to 10 cm] despite current or previous DMARD or NSAID therapy. Patients with complete ankylosis of the cervical and lumbar spine were excluded from study participation.
3.3.2 Pharmacodynamics
Simponi was effective in modulating select markers of inflammation and bone metabolism across the indications. Improvement in C-reactive protein (CRP) levels were observed relative to placebo groups and treatment with Simponi resulted in significant reductions from baseline in serum levels of interleukin-6 (IL 6), ICAM 1, matrix metalloproteinase-3 (MMP 3), and vascular endothelial growth factor (VEGF) compared to placebo treatment. In addition, levels of TNF-α were significantly reduced in RA and AS patients and levels of IL 8 were reduced in PsA patients. These changes were observed at the first assessment (Week 4) after the initial Simponi administration and were generally sustained through Weeks 14 and/or 24. Simponi with or without MTX resulted in significant changes in serum levels of select markers of bone metabolism [increases in osteocalcin and procollagen type I N-terminal propeptide (PINP) and decreases in deoxy-pyridinolin (DPD) levels] at Week 4. All of these biomarker changes are consistent with an improvement in the disease processes with reduced inflammation, increased bone growth, and decreased bone resorption.
3.3.3 Pharmacokinetics
Simponi exhibited dose-proportional pharmacokinetics in patients with RA over the dose range of 0.1 to 10.0 mg/kg following a single IV dose. As well the mean systemic clearance of Simponi was estimated to be 4.9 to 6.7 mL/day/kg, and the mean volume of distribution ranged from 58 to 126 mL/kg in these patients. The volume of distribution for Simponi indicates that Simponi is distributed primarily in the circulatory system with limited extravascular distribution. Median terminal half-life values were estimated to be approximately 2 weeks in healthy subjects and patients with RA, PsA, or AS.
Following SC administration of Simponi in 237 healthy subjects, the following PK parameters were obtained:
- The mean maximum observed serum concentration (Cmax) = 3.1 µg/mL;
- The mean time to reach Cmax (Tmax)a = 4 days (range = 1 to 10 days);
- The mean area under the curve from time 0 to infinity (AUCinf) = 49.7 µg·day/mL;
- The mean terminal half-life (T1/2) = 12 days;
- The mean apparent systemic clearance (CL/F) = 15.3 mL/day/kg;
- The mean apparent volume of distribution (Vz/F) = 248 mL/kg.
By cross-study comparisons of mean AUCinf values following an IV or SC administration of Simponi, the absolute bioavailability of SC Simponi was estimated to be 44% to 58%. When 50 mg Simponi was administered SC to patients with RA, PsA or AS every 4 weeks, serum concentrations reached steady-state by Week 12. With concomitant use of MTX, treatment with 50 mg Simponi SC every 4 weeks resulted in a median steady-state trough serum concentration of approximately 0.6 µg/mL in patients with active RA despite MTX therapy, approximately 0.5 µg/mL in patients with active PsA, and approximately 0.6 µg/mL in patients with AS. Patients with RA, PsA or AS who did not receive concomitant use of MTX had approximately 30% lower steady-state trough concentrations of Simponi than those who received Simponi with MTX. Population PK analysis in patients with RA also indicated that concomitant use of MTX could reduce the apparent clearance of Simponi by 17.1%. However, concomitant use of NSAIDs, oral corticosteroids or sulfasalazine did not influence the apparent clearance of Simponi.
Special Populations
Population PK analyses showed there was a trend toward higher apparent clearance of Simponi with increasing bodyweight. As a result, heavier patients tended to have lower steady-state trough concentrations of Simponi. However, across the RA, PsA, and AS populations, a treatment benefit of Simponi 50 mg and 100 mg was observed for all subgroups by weight quartiles with no meaningful differences in clinical efficacy among these subgroups. Therefore, there is no need to adjust the dosage of Simponi based on bodyweight.
No gender-related PK differences were observed with Simponi after correction for patients' bodyweights.
The PK parameters of Simponi were not influenced by age in adult patients. Patients ≥65 years of age had apparent clearance of Simponi similar to patients <65 years of age.
No ethnicity-related PK differences were observed between Caucasians and Asians.
Patients who developed anti-Simponi antibodies generally had low steady-state trough serum concentrations of Simponi.
3.3.4 Clinical Efficacy
Rheumatoid Arthritis
RA Study 1 (GO-FORWARD)
Study RA-1 (GO-FORWARD) evaluated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with an anti-TNF agent. Patients were randomized to receive placebo + MTX (n = 133), Simponi 50 mg + MTX (n = 89), Simponi 100 mg + MTX (n = 89) or Simponi 100 mg monotherapy + placebo (n = 133). The co-primary endpoints were the percent of patients achieving an ACR 20 response at Week 14 and improvement from baseline in HAQ score at Week 24. Major secondary endpoints included Disease Activity Score 28 (DAS28) (using CRP) response at Week 14, ACR 20 response at Week 24, and improvement from baseline in HAQ at Week 14.
Treatment with Simponi in patients with active RA despite MTX resulted in improvement in signs and symptoms as demonstrated by the percent of patients achieving an ACR 20 response at Week 14. A significantly greater percent of patients achieved an ACR 20 response in the Simponi 50 mg + MTX group than in the placebo + MTX group (p≤ 0.001) at Weeks 14 and 24. The percent of patients achieving ACR 50 and ACR 70 responses was also greater in the Simponi 50 mg + MTX group than in the placebo + MTX group at Weeks 14 and 24. When ACR 20 responses over time were considered, improvement was observed at the first assessment (Week 4) after the first Simponi 50 mg + MTX administration, and was maintained through Week 24.
In addition, the percent of patients achieving a DAS28 (using CRP) response was significantly greater for those patients treated with Simponi 50 mg + MTX compared with those who received placebo + MTX at Week 14 and at Week 24.
Patients treated with Simponi 50 mg showed significantly greater (p<0.001) improvement in the Disability Index of the HAQ score compared with placebo at Week 14.
RA Study 2 (GO AFTER)
Study RA-2 (GO-AFTER) evaluated 461 patients who were previously treated with one or more of the anti-TNF agents adalimumab, etanercept, or infliximab. Reasons for discontinuation of prior anti-TNF therapies included lack of efficacy (58%), intolerance (17%), and/or reasons other than safety or efficacy (40%). Patients were randomized and were allowed to continue concomitant DMARD therapy with MTX, sulfasalazine, and/or hydroxychloroquine during the study. The primary endpoint was the percent of patients achieving an ACR 20 response at Week 14. Major secondary endpoints included an ACR 50 response at Week 14, DAS28 (using CRP) response at Week 14, ACR 20 response at Week 24, and improvement from baseline in HAQ score at Week 24.
Treatment with Simponi 50 mg in patients with active RA, previously treated with anti-TNF agent(s), resulted in significant improvement in signs and symptoms as demonstrated by ACR 20, 50, and 70 responses at Week 14 and 24. When ACR 20 responses over time were considered, improvement was observed at the first assessment (Week 4) after the first Simponi 50 mg + MTX administration, and was maintained through Week 24. The percent of patients achieving an ACR 20 response was greater for patients receiving Simponi 50 mg than for patients receiving placebo, regardless of the reason reported for discontinuation of one or more prior anti-TNF therapies. The difference from placebo reached statistical significance in the subset of patients who discontinued their prior anti-TNF agent for lack of efficacy. The proportion of patients achieving ACR 20 responses was numerically greater in patients who were receiving MTX at baseline (39.8% with MTX and 26.0% without MTX respectively).
Patients' and physicians' assessments and HAQ score were also significantly improved for the group receiving Simponi 50 mg compared with placebo at Week 14 and 24. For Simponi 50 mg, there was a 33% improvement in CRP compared with 0% improvement for placebo at Week 14, and 14% compared with 0% at Week 24.
The percent of patients achieving a DAS28 (using CRP) response was significantly greater for those patients treated with Simponi 50 mg compared with those who received placebo at Week 14 (56% compared with 30%; p<0.001) and at Week 24 (49% compared with 23%; p<0.001).
A specific claim for the use of Simponi in patients previously treated with TNF inhibitors has not been granted; the effect of a switch from one TNF inhibitor to another is still unclear scientifically and controversial in common medical practice.
RA Study 3 (GO-BEFORE)
Study RA-3 (GO-BEFORE) evaluated 637 patients with active RA who were MTX-naïve and had not previously been treated with an anti-TNF agent. Patients were randomized to receive placebo + MTX (n = 160), Simponi 50 mg + MTX (n = 159), Simponi 100 mg + MTX (n = 159) or Simponi 100 mg monotherapy + placebo (n = 159). For patients receiving active MTX, a dose of 10 mg/week MTX was administered at the beginning of Week 0 and was increased to 20 mg/week by Week 8. There were two co-primary endpoints. The first co-primary endpoint was the percent of patients achieving an ACR 50 response at Week 24 and the second was the change from baseline in van der Heijde Modified Sharp score at Week 52. Major secondary endpoints included ACR 20 response at Week 24, and the percent of patients with abnormal CRP at baseline achieving an ACR 50 response at Week 24.
The co-primary endpoint of the percent of randomized patients achieving an ACR 50 response with Simponi + MTX compared to MTX plus placebo was not reached. The proportion of randomized patients who achieved an ACR 50 response at Week 24 was numerically greater in the Simponi 50 mg + MTX group (40.3%) and in the Simponi 100 mg group (36.5%) than in the placebo + MTX group (29.4%), but did not reach statistical significance. The percent of patients achieving an ACR 20 response at Week 24 (major secondary endpoint) was 62% for the SIMPONI 50 mg + MTX group compared with 49% for the placebo + MTX group (p = 0.028). In other measures of efficacy at Week 24, including the major secondary efficacy endpoints and other efficacy endpoints, results suggested that treatment with Simponi + MTX resulted in a numerically better response than treatment with placebo + MTX for the majority of endpoints evaluated, with no suggestion of an increased treatment benefit in the Simponi 100 mg + MTX group when compared with the Simponi 50 mg + MTX group. Despite the inability to meet the primary endpoint, the results of this study suggest that to ensure maximum efficacy, Simponi should be administered in combination with MTX.
The data pertaining to the second co-primary endpoint (change from baseline in van der Heijde Modified Sharp score at Week 52) will be submitted in a future report.
Psoriatic Arthritis
PsA Study (GO-REVEAL)
The GO-REVEAL study evaluated 405 patients with PsA. Patients were randomly assigned to receive placebo (n = 113), Simponi 50 mg (n = 146), or Simponi 100 mg (n = 146). A co-primary endpoint was the percent of patients achieving an ACR 20 response at Week 14. Analysis of the second co-primary endpoint, change from baseline in radiographic score, is ongoing. Major secondary endpoints included the percent of patients achieving an ACR 20 response at Week 24, Psoriasis Area Severity Index (PASI) 75 response at Week 14 in a subset of patients with ≥3% Body Surface Area (BSA) psoriasis skin involvement at baseline, improvement from baseline in HAQ scores at Week 24, and change from baseline in the Physical Component Summary (PCS) score of the Short Form 36 (SF-36) Health Survey at Week 14.
Treatment with Simponi 50 mg resulted in significant improvement in signs and symptoms as demonstrated by the percent of patients achieving ACR 20 response at Week 14 (p<0.001). ACR 20 improvement was observed at the first assessment (Week 4) after the first Simponi administration and was maintained through Week 24. Among patients with ≥3% BSA psoriasis skin involvement at baseline, a significantly greater percent of patients achieved PASI 75 response at Week 14 when treated with Simponi 50 mg compared with placebo.
Patients treated with Simponi 50 mg showed significantly greater (p<0.001) improvement in the HAQ score compared with placebo at Week 14 and Week 24. The percent of patients who achieved clinically meaningful improvements in HAQ of ≥0.30 change from baseline was also significantly greater in those patients receiving Simponi 50 mg when compared with placebo (p<0.001). In addition, these patients showed significantly greater improvement (p<0.001) from baseline in the SF-36 PCS score compared to the placebo group at Week 14.
Ankylosing Spondylitis
AS Study (GO-RAISE)
The GO-RAISE study evaluated 356 patients with AS. Patients were randomly assigned to receive placebo (n = 78), Simponi 50 mg (n = 138), and Simponi 100 mg (n = 140). Placebo-controlled efficacy data were collected and analyzed through Week 24. The primary endpoint was ASAS 20 response at Week 14. Major secondary endpoints included ASAS 20 response at Week 24, Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14, and Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 14.
At Week 14, ASAS 20 and ASAS 40 responses were achieved by 59% and 45% respectively, of patients receiving Simponi 50 mg compared with 22% and 15% respectively of patients receiving placebo (p<0.001). Improvement in signs in symptoms as measured by ASAS 20 was observed at the first assessment (Week 4) after the first Simponi administration, and was maintained through Week 24.
Median improvement in the BASFI at Week 14 was 1.4 in the Simponi 50 mg group, compared with worsening by 0.1 in the placebo group (p<0.001). The improvement in physical function was maintained at Week 24 in Simponi-treated patients.
No significant change in BASMI was observed at Weeks 14 or 24 in the Simponi 50 mg group compared with the placebo group. However, in the 50 mg Simponi group versus the placebo group, significant median improvements from baseline were observed at Week 14 and 24 for lumbar flexion, lumbar side flexion at Week 24, and intermalleolar distance measurements at both Week 14 and 24 (p<0.05).
3.3.5 Clinical Safety
The safety of Simponi was evaluated based on data provided from the pivotal clinical studies described in section 3.3.1 Pivotal Studies and data from Phase II and III clinical studies. Altogether, safety data were obtained from 2522 Simponi-treated patients including 1544 with RA, 394 with PsA, 353 with AS, and 231 with severe persistent asthma.
After analyzing the submitted data, the most important safety concern to be highlighted is the risk of serious infections including sepsis, tuberculosis (TB), invasive fungal, and other opportunistic infections which have been observed with the use of anti-TNF antagonists including Simponi. Some of these serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections. Simponi should not be given to patients with a clinically important active infection and caution should be exercised when considering the use of Simponi in patients with chronic infection or a history of recurrent infection. A Black Box Warning describing serious warnings and precautions has been included in the Product Monograph for Simponi.
In all studies, treatment with Simponi was generally well-tolerated. Adverse events reported with Simponi treatment (whether in combination with MTX or without concomitant MTX) were similar to those reported with other anti-TNF-α therapies. Upper respiratory tract infection (URI) was the most common AE reported in the combined Phase III RA, PsA, and AS studies through Week 16, occurring in 7.2% of Simponi-treated patients as compared with 5.8% of placebo-treated patients. In addition to Simponi, patients who experienced AEs may have also taken concomitant MTX, sulfasalazine, hydroxychloroquine, low dose corticosteroids (≤10 mg of prednisone/day or equivalent), and/or NSAIDs during the studies.
In the Phase III studies, the most frequently reported AEs leading to discontinuation of Simponi treatment were those in the infections and infestation system-organ class for the RA studies, the neoplasms system-organ class for the PsA study, and the investigations system-organ class for the AS study.
Adverse Events in the Rheumatoid Arthritis Studies
In the three RA studies, the proportion of patients experiencing ≥1 AE was generally similar across all treatment groups both at Week 16 and Week 24, with no notable differences between Simponi-treatment groups nor among patients receiving or not receiving MTX at baseline.
In Study RA-2, through Week 16, the proportion of patients with serious adverse events (SAEs) was lower in patients receiving Simponi (3.9%) compared with those receiving placebo (7.1%). However, patients in Study RA-1 who received Simponi + MTX had a higher proportion of SAEs at Week 16. The Simponi 100 mg + MTX group had the highest proportion of patients with ≥1 SAE (9.0%) followed by the Simponi 50 mg + MTX group (5.6%), the Simponi 100 mg + placebo group (3.8%), and the placebo + MTX group (2.3%). In Study RA-3, the incidence of SAEs and other significant AEs was generally similar in patients treated with Simponi + MTX and those treated with placebo + MTX.
The combined analysis of AEs from all patients treated with Simponi in the Phase III RA studies through to Week 16 indicated that the most commonly reported AEs were URIs (7%), injection-site erythaema (4%), nasopharyngitis (4%), hypertension (3%), increased alanine aminotransferase (ALT) levels (3%) and aspartate aminotransferase (AST) levels (2%), bronchitis (2%), pharyngitis (2%), dizziness (2%) and sinusitis (2%). One percent of Simponi-treated patients reported AEs of influenza, pyrexia, paraesthesia, oral herpes, cellulitis, rhinitis, and pneumonia.
Adverse Events in the Psoriatic Arthritis Study
Through Week 24, the proportion of patients experiencing ≥1 AE was 64.7% in the all Simponi groups and 67.1% in the combined Simponi group with similar proportions in the Simponi 50 mg (67.8%) and 100 mg (65.1%) groups.
The combined analysis of AEs from all patients treated with Simponi in the Phase III study of PsA through to Week 16 indicated that the most commonly reported AEs were URI (7%), nasopharyngitis (7%), increased ALT (3%) and AST (2%) levels, injection-site erythaema (2%), hypertension (2%) bronchitis (2%), and rhinitis (2%). %). One percent of Simponi-treated patients reported AEs of oral herpes, pharyngitis, dizziness, sinusitis, influenza, cellulitis, and pyrexia.
Adverse Events in the Ankylosing Spondylitis Study
Through Week 16, prior to early escape, the proportions of patients experiencing ≥1 AE were similar in the placebo (74.0%) group and the combined Simponi (77.3%) group. Furthermore, the proportion of patients with ≥1 AE was comparable between Simponi 50 mg (79.0%) and 100 mg (75.7%) group.
Through Week 24, the proportion of patients experiencing ≥1 AE was 76.6% in the placebo group versus 85.6% in the combined Simponi group. Similar proportions of patients experienced AEs in the Simponi 50 mg (84.8%) and 100 mg (85.7%) groups. The overall incidence of AEs was greater for patients not receiving DMARDs at baseline (80.1% in the combined Simponi group and 81.6% in the placebo group) than for patients receiving DMARDs.
The combined analysis of AEs from all patients treated with Simponi in the Phase III study of AS through to Week 16 indicated that the most commonly reported AEs were nasopharyngitis (11%), URI (10%), increased ALT (7%) and AST (5%) levels, dizziness (5%), sinusitis (3%), injection-site erythaema (3%), hypertension (3%), influenza (3%), and rhinitis (3%). %). One percent of Simponi-treated patients reported AEs of bronchitis, pyrexia, pharyngitis, oral herpes, injection-site irritation, laryngitis, and injection-site pruritus.
Tuberculosis
Patients who were diagnosed with latent TB at baseline were eligible for enrollment if they started treatment for latent TB prior to or simultaneously with the first study agent administration. Most patients were treated with isonicotinyl hydrazine. There were 6 cases of active TB in the entire Simponi clinical program, including 4 cases of pulmonary/pleural TB reported in an RA study.
Patients receiving Simponi should be monitored closely for signs and symptoms of active TB during and after treatment, including patients who tested negative for latent TB infections.
Injection-Site Reactions
In the Phase III RA, PsA, and AS studies through Week 16, injection-site reactions occurred in 5.8% of Simponi-treated patients, and the majority of these were mild to moderate. There was one serious injection-site reaction (injection-site erythaema which led to discontinuation of study agent), and an additional patient who discontinued study agent due to injection-site erythaema.
In the Phase III RA, PsA, and AS studies with Simponi, no patient who received Simponi-treatment developed anaphylaxis or serum sickness-like reactions.
Laboratory Test Results
In the Phase III RA, PsA, and AS studies, markedly abnormal haematology values were observed in a small proportion of patients treated with Simponi. A decrease in neutrophil counts was the most frequently reported abnormal haematology value by Simponi-treated patients, compared to placebo-treated patients.
The most frequently reported markedly abnormal chemistry by Simponi-treated patients was increased total bilirubin. Post-baseline ALT or AST elevations > upper limit normal (ULN) were frequently observed in Simponi-treated patients. The majority of these elevations were asymptomatic. Among patients with baseline ALT levels ≤ ULN, elevated ALT abnormalities were noted with a greater incidence in patients who received treatment for latent TB than in patients who did not receive treatment for latent TB.
Antigenicity
In the Phase III RA, PsA, and AS studies, through Week 24, antibodies to Simponi were detected in 4.3% of Simponi-treated patients. Treatment with concomitant MTX resulted in a lower proportion of patients with antibodies to Simponi than patients receiving Simponi without MTX (approximately 2% versus 7%, respectively). The vast majority of patients who were positive for antibodies to Simponi (98.2%) had antibodies capable of neutralizing Simponi bioactivity in vitro. Based on the small number of patients with antibodies to Simponi, the presence of neutralizing antibodies to Simponi did not preclude a clinically meaningful ACR and ASAS response and were not associated with an increased frequency of injection-site reactions.
The small number of patients positive for antibodies to Simponi limits the ability to draw definitive conclusions regarding the relationship between antibodies to Simponi and clinical efficacy or safety measures.
Infections
In the Phase III RA, PsA, and AS studies, through Week 16, 12.7% to 16.8% of Simponi-treated patients were treated for infections as compared to 11.5% to 13.6% of the placebo-treated patients. Serious infections were observed in 1.4% of Simponi-treated patients and 1.3% of placebo-treated patients. In Simponi-treated patients, serious infections included sepsis, pneumonia, cellulitis, abscess, and TB.
Serious infections were most frequently observed in patients receiving Simponi 100 mg + MTX.
Malignancies
In Study RA-1, malignancies were reported for 5 patients through Week 24 [1 with basal cell cancer in the placebo + MTX group, 1 with basal cell cancer in the Simponi 100 mg + placebo group, 1 with breast cancer in the Simponi 100 mg + MTX group, 1 with squamous cell skin cancer, and 1 with squamous cell skin cancer in situ (Bowen's disease), both in the Simponi 100 mg + placebo group].
In Study RA-2, malignancies were reported for 3 patients through Week 24 (1 with lymphoma in the Simponi 100 mg group, 1 with squamous cell skin cancer in the Simponi 50 mg group, and 1 with pancreatic carcinoma in the placebo group).
In Study RA-3, malignancies were reported for 4 patients through Week 24 (1 with breast cancer in situ in the Simponi 50 mg + MTX group, 1 with Hodgkins's disease in the Simponi 100 mg + MTX group, 1 with squamous cell skin cancer in the placebo + MTX group, and 1 with breast cancer in the placebo + MTX group).
In the PsA study, malignancies were reported for 3 patients (2 with basal cell carcinoma and 1 with prostate cancer), all in the Simponi 100 mg group.
In the AS study, through Week 24, malignancies were reported in 2 patients. One patient in the placebo group had basal cell carcinoma of moderate severity that was not considered to be related to the study agent. An additional patient in the Simponi 100 mg group had basal cell carcinoma considered mild and not related to study agent.
The incidence of lymphoma in Simponi-treated patients with RA, PsA, and AS during the controlled portions of the Phase II and Phase III clinical trials was higher than expected in the general population. The incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the Simponi and the placebo groups.
The potential role of TNF-blocking therapy in the development of malignancies is unknown.
Deaths
As of July 31, 2008, there were 18 deaths in the entire Simponi clinical program (17 Simponi-treated patients and 1 placebo-treated patient). The most frequently reported causes of death included malignancies in 3 patients (including 1 placebo patient), myocardial infarction in 3 patients, unknown cause in 2 patients, and sepsis in 2 patients. When the incidence of death in all Simponi studies was calculated per 100 patient years of follow-up, the incidences were not statistically different between the Simponi and placebo group.
Based on the clinical data submitted, Simponi has a safety profile similar to that of other TNF-α inhibitors in similar indications and patient populations. The safety profile is acceptable.
3.3.6 Additional Issues
As part of the marketing authorization for Simponi, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) providing:
- 1-year safety data for infections, malignancies, liver enzyme elevations, injection-site reactions, and antinuclear antibody (ANA) test results;
- A final Risk Management Plan including Progressive Multifocal Leukoencephalopathy (PML) (as a serious opportunistic infection) and serious liver toxicity as topics, and a pharmacovigilance plan by which additional safety information will be collected about these topics;
- 1-year efficacy and safety (for example, effects on the progression of structural damage) and safety data/analyses for the approved indications in RA, PsA, and AS;
- Notification of all SAEs including malignancies, other autoimmune diseases, serious infections, et cetera, that occurred in all clinical trials with Simponi.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Simponi is a member of the TNF-inhibitors class. The safety data submitted did not pose unique concerns beyond those applicable to other biologic products approved for the treatment of RA, PsA or AS including other members of this class. The TNF-inhibitors class has been associated with severe risks of serious infections, including opportunistic infections, development of lymphoma and other malignancies, and development of demyelinating disorders and autoimmune disorders in RA, PsA and AS. The efficacy of Simponi has been judged to be acceptable for these three indications.
Based on the data submitted, the benefit/risk of Simponi is favourable.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Simponi is favourable in the treatment of:
Rheumatoid arthritis - Simponi, in combination with methotrexate (MTX), is indicated for:
- Reducing signs and symptoms in adult patients with moderately to severely active RA.
Psoriatic arthritis - Simponi is indicated for:
- Reducing signs and symptoms in adult patients with moderately to severely active PsA, alone or in combination with MTX. Simponi can be used in combination with MTX in patients who do not respond adequately to MTX alone.
Ankylosing spondylitis - Simponi is indicated for:
- Reducing signs and symptoms in adult patients with active AS who have had an inadequate response to conventional therapies.
The 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 (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: SimponiTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-05-08 |
| Submission filed: | 2008-04-29 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-06-11 |
| Review | |
| On-Site Evaluation: | 2009-02-16 - 2009-02-20 |
| Biopharmaceutics Evaluation complete: | 2009-04-07 |
| Quality Evaluation complete: | 2009-04-07 |
| Clinical Evaluation complete: | 2009-04-07 |
| Biostatistics Evaluation complete: | 2009-04-07 |
| Labelling Review complete: | 2009-04-07 |
| NOC issued by Director General: | 2009-04-07 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SIMPONI | 02324776 | JANSSEN INC | GOLIMUMAB 50 MG / 0.5 ML |