Summary Basis of Decision for Orencia
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:
Orencia
Abatacept, 250 mg/vial, Powder for solution, Intravenous
Bristol-Myers Squibb Canada
Submission control no: 098531
Date issued: 2007-05-07
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):
- 02282097
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
™ of Bristol-Myers Squibb Company, used under licence by Bristol-Myers Squibb Canada
2 Notice of decision
On June 29, 2006, Health Canada issued a Notice of Compliance to Bristol-Myers Squibb Canada for the drug product Orencia.
Orencia contains the medicinal ingredient abatacept which is a selective immunosuppressant. Abatacept is a soluble fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion (hinge, CH2, and CH3 domains) of human immunoglobulin G1.
Orencia is indicated for reducing signs and symptoms, inducing clinical responses, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs) and/or to tumour necrosis factor (TNF) antagonists. Abatacept selectively modulates (inhibits) a key co-stimulatory signal required for full activation of T lymphocytes expressing CD28. Activated T lymphocytes are found in the synovium of patients with RA and contribute to the pathogenesis of RA and other autoimmune diseases.
Orencia met the criteria for, and was granted, Priority Review status as it is intended to be used for the treatment of patients who have had an inadequate response to TNF antagonists.
The market authorization was based on data submitted from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. The efficacy and safety of Orencia were evaluated in six studies. Orencia demonstrated benefit in reducing the signs and symptoms of RA, in improving physical function, and in inhibiting the progression of joint damage as measured by X-ray. The overall safety profile did not reveal significant safety signals during clinical trials.
Orencia (250 mg/vial, abatacept) is presented as a sterile lyophilized powder for intravenous infusion. Orencia should be administered as a 30-minute intravenous infusion at the dose specified based on patient body weight. Orencia should be given at 2 and 4 weeks after the first infusion, then every 4 weeks thereafter. Orencia may be used as monotherapy or concomitantly with DMARDs. Dosing guidelines are available in the Product Monograph.
Orencia is contraindicated for patients with known hypersensitivity to Orencia or any of its components. Orencia 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 Orencia are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Orencia is favourable for reducing signs and symptoms, inducing clinical responses, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis who have had inadequate response to one or more DMARDs and/or to TNF antagonists.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Description
Abatacept, the medicinal ingredient of Orencia, is a recombinant fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion of human immunoglobulin G1. Abatacept selectively blocks a key co-stimulatory signal required for full activation of T-lymphocytes expressing CD28. Activated T lymphocytes are found in the synovium of patients with rheumatoid arthritis and they contribute to the pathogenesis of rheumatoid arthritis and other autoimmune diseases.
Manufacturing Process and Process Controls
Abatacept is produced by recombinant DNA technology in Chinese hamster ovary cells. The manufacture of abatacept is based on a CHO master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents/viral contaminants. Genetic characterization (restriction endonuclease mapping and copy number analysis) also demonstrated stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of abatacept comprises a series of steps which include cell culture, harvest and purification. The purification is performed via a combination of chromatographic and viral inactivation/removal steps. The manufacturing process consistency is ensured through defined production procedures, critical quality tests, in-process limits, and abatacept certificate of analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during manufacture were reviewed and 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 abatacept consistently exhibits the desired characteristic structure. Results from process validation studies also indicate that the methods used during processing adequately control the levels of product and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of abatacept. The drug substance specifications, and analytical methods used for quality control of abatacept are considered acceptable.
Stability
Based upon real-time and accelerated stability studies submitted, the suggested shelf-life and storage conditions for abatacept are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Orencia is supplied as a sterile, white, preservative-free, lyophilized powder for intravenous administration. Following reconstitution with 10 mL of sterile water for injection, USP, the Orencia solution is clear, colourless to pale yellow, with a pH range of 7.0 to 8.0. Each single-use vial of Orencia provides 250 mg abatacept, 500 mg maltose, 17.2 mg sodium phosphate monobasic, and 14.6 mg sodium chloride for administration. The excipients used in the Orencia formulation comply with either the US Pharmacopeia (USP) or National Formulary (NF) specifications, except for maltose monohydrate, which complies to an acceptable non-compendial set of specifications.
During early clinical development, the constituted solutions of Orencia for injection were found to be incompatible with disposable siliconized syringes, which are commonly used for the preparation and administration of intravenous products. An alternate silicone-free syringe was identified to overcome this issue and will be co-packaged with the drug product vial.
Pharmaceutical Development
The quantitative composition (i.e. concentration of medicinal and non-medicinal ingredients) of the Orencia formulation has changed during development. However, the qualitative composition (i.e. type of medicinal and non-medicinal ingredients used) of the Orencia formulation has remained the same. These changes were implemented in order to optimize the stability of the formulation and did not impact the quality of Orencia.
Changes were made to the abatacept manufacturing process during development. Data pertaining to the physicochemical characteristics and biological activity demonstrated biocomparability between development and commercial batches.
Manufacturing Process and Process Controls
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters are adequately described in the submitted documentation and are found acceptable. Orencia is filled into vials using proper aseptic process techniques, and conventional pharmaceutical equipment and facilities.
Control of Drug Product
Orencia is tested to verify its appearance, identity, purity, sterility, and potency, as well as the formulation-relevant parameters: protein content, pH, constitution time, and osmolality. The validation reports submitted for the analytical procedures used for in-process and release testing of Orencia are satisfactory and in compliance with ICH guidelines.
Analytical testing results from final batch analyses were reviewed and considered to be acceptable according to the specifications of the drug product.
Stability
Based upon the real-time and accelerated stability data submitted, the proposed 24-month shelf-life is considered acceptable when stored at 2°C to 8°C and protected from light.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the drug substance facility involved in the manufacture and testing of Orencia has been conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The design, operations, and controls of the facilities and equipment which are involved in the production are considered suitable for the activities and products manufactured. All facilities are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Pre-harvest culture fluid from each lot is tested to ensure freedom of adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of animal and recombinant origin used in the manufacturing process have been adequately tested to ensure freedom of adventitious agents. One raw material, produced from lactose obtained from milk, is the only bovine raw material used for the manufacture of Orencia. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Orencia 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
The mechanism of action of abatacept has been evaluated in various in vitro and in vivo pharmacodynamic (PD) models of T-cell function such as T-cell proliferation, cytokine production, and T-cell-dependent antibody production. The drug was also tested in animal models of disease including the collagen-induced model of rheumatoid arthritis (RA).
In vitro studies
In the mixed lymphocytes reaction (MLR) assay using human cells, abatacept maximally inhibited naive and memory T-cell proliferation by 50 to 80%. The maximum inhibitory effect on T-cell proliferation occurred at drug concentrations that were ~10 to 30 µg/mL. In addition to inhibiting proliferation of T cells, abatacept also suppressed the production of the T-cell cytokine interleukin-2 (IL-2) by ≥90% and, to a lesser extent, TNF-α and interferon (IFN)-γ by 60-80%. TNF-α and IFN-γ are key cytokines that drive the activation of leukocytes and the inflammatory cascade.
A recall response to tetanus toxoid peptide was measured to assess whether abatacept affected memory T-cell proliferation using peripheral-blood mononuclear cells derived from human donors. In this assay, T-cell proliferation in response to tetanus antigen was inhibited up to 80% at abatacept concentrations (~10-30 g/mL) similar to those used in the MLR assay.
Abatacept had no effect on TNF-α production from monocytes/macrophages activated with the bacterial endotoxin lipopolysaccharide, indicating that abatacept does not impact this particular pathway of innate immunity. This is important from a safety perspective, as the innate immune system plays a critical primary role in host responses to infections.
In vivo studies
The effect of abatacept on T-cell-dependent antibody production was studied in rodents and non-human primates. In rodents, abatacept inhibited primary antibody responses to the T-cell-dependent antigens, keyhole limpet hemocyanin (KLH), and sheep red blood cells by >95%. In general, secondary antibody responses to antigens in rodents were also inhibited, but to a lesser extent than the primary antibody response. Studies in non-human primates demonstrated that anti-KLH and anti-bacteriophage primary and secondary antibody responses were inhibited by >80% with abatacept treatment.
The activity of abatacept was assessed in the widely used rat collagen-induced arthritis (CIA) model. Prophylactic administration of abatacept abrogated paw swelling, prevented disease progression, inhibited anti-collagen antibody production, decreased pro-inflammatory cytokine and chemokine production, and inhibited bone destruction as measured by CT-MRI and histology.
No treatment-related finidings were observed in a battery of in vivo safety pharmacology evaluations that included respiratory and neurologic function, electrocardiograms, heart rate and sounds, and blood pressure conducted as part of repeat-dose toxicity studies in monkeys for up to one year. In addition, no treatment-related changes were observed following dosing with respect to anaphylactoid clinical signs or increases in serum or plasma histamine, complement C3a, TNF-α, or IL-6, mediators associated with hemodynamic changes and/or anaphylactoid responses.
The effects of abatacept, CTLA4Ig from non-BMS (Bristol-Myers Squibb) sources on host responses were evaluated with murine cytomegalovirus (MCMV). The studies indicate that the protective in vivo immune responses to the pathogen are largely preserved in animals treated with abatacept.
These results highlight the selectivity of abatacept on CD4+ T cell-mediated processes relative to other aspects of immune function such as innate and CD8+ T-cell immunity. As a result, abatacept may theoretically increase the risk of infection to some pathogens that may be more dependent upon a CD4+ T-cell-mediated mechanism for clearance, such as herpes simplex virus (HSV).
3.2.2 Pharmacokinetics
Two routes of administration, intravenous (IV) and subcutaneous (SC), were used in the evaluation of the pharmacokinetics of abatacept in studies involving the mouse and rat. In both species, the results indicated that absorption after SC administration was prolonged (Tmax values ranged from 9-48 hours), but essentially complete.
SC bioavailability in the mouse and rat ranged from 78% to 110%, and from 41% to 85%, respectively. In both species, a trend was observed towards decreasing bioavailability with increasing SC doses.
Following IV administration, the mean t1/2 of abatacept in mouse, rat, rabbit, and monkeys was approximately 3 days, 5 days, 3 days, and 6 days, respectively. In a number of studies, a shorter t1/2 value was obtained at lower doses. This may attribute to the formation of anti-abatacept antibodies when serum concentrations approached or fell below immunosuppressive levels of approximately 1 µg/mL. Values for the systemic clearance of abatacept in mice, rats, and monkeys ranged from approximately 0.5 to 1.9 mL/h/kg.
Dose-related systemic exposures (based on AUC and Cmax values) to abatacept were established. In some cases, the exposure increased in proportion with dose increment; however, in other studies, the increases were more or less than the dose increment. In general, results from the studies indicated that there were no gender differences in the species used for the toxicological evaluation of abatacept. A minimal (<3-fold) systemic accumulation of abatacept after repeated administration was observed in all species. The steady-state volume of distribution in the animal species studied indicates that abatacept is confined primarily to the vascular system and does not distribute significantly into extravascular spaces.
The toxicokinetics of abatacept during embryo-fetal development in rats and rabbits were also evaluated. These studies demonstrated that abatacept was excreted in the milk and was able to cross the placental barrier, exposing fetuses of abatacept-treated dams to the drug.
3.2.3 Toxicology
Toxicology studies were performed with two separate compounds, BMS-188667 and BMS-224818. BMS-188667 is the form of abatacept intended for commercial authorization and was the form primarily used in these studies. BMS-224818 is a second-generation molecule that differs from BMS-188667 by two amino acid residues within the CD80/86 binding domains. In primates, this difference confers a significant increase in binding avidity to CD86 relative to that of BMS-188667, which results in a greater biological activity. The 6-month repeat-dose toxicity study in monkeys was conducted with BMS-224818 to further support long-term treatment with BMS-188667.
Acute Toxicity
An acute single dose intravenous study was conducted in Cynomolgus monkeys at 100 mg/kg bw. There were no mortalities nor any adverse treatment-related findings. There were no changes in lymphocyte activation, lymphocyte phenotype, or serum immunoglobulin phenotypes. Anti-BMS-188667 antibodies were not evident by day 14.
Subchronic and Chronic Studies
Subchronic and chronic toxicity testing was conducted in CD-1 mice, Sprague-Dawley rats, and Cynomolgus monkeys.
Mice were treated with BMS-188667 by SC injection at dose levels of 20, 65, or 200 mg/kg bw/week for 6 months, followed by a 4-month recovery period. Dose levels were generally well-tolerated. Treatment resulted in a reversible increase in the incidence of renal karyomegaly at 65 and 200 mg/kg bw. This finding was also observed in the mouse chronic carcinogenicity study at dose levels ≥20 mg/kg bw/week. However, there was no evidence of adverse effects on renal function in either study, and similar renal findings were not observed in monkeys after treatment for up to one year. It was therefore concluded that renal karyomegaly was species-specific and likely represented exacerbation of a spontaneous, age-related change, and therefore was not considered to be a concern with respect to human exposure. The only other findings were reversible decreases in IgG levels at 65 and 200 mg/kg bw, consistent with the immunosuppressive activity of the drug, and decreases in splenic T- and B-cells at 65 and 200 mg/kg bw, in males only.
Rats were administered BMS-188667 as a SC or IV injection at dose levels of 80 mg/kg bw (SC only) or 200 mg/kg bw (SC and IV), every other day for 7 treatments. Dose levels were well tolerated. The only treatment-related findings were decreases in serum IgG and IgA levels in the 200 mg/kg bw group after SC and IV administration.
Subchronic and chronic IV administration of BMS-188667 in Cynomolgus monkeys was carried out every two days for one month, or on a weekly basis for one year, followed by a 3-month recovery period. Dose levels were 10, 22, or 50 mg/kg bw. A supporting IV study was conducted with BMS-224818, which was administered for 6 months at dose levels up to 50 mg/kg bw/week, followed by a 3-month recovery period. Dose levels were well-tolerated. The only findings were reversible, minimal decreases in serum IgG at all dose levels, and reversible depletion of germinal centres in the spleen and lymph nodes. Although pre-study viral screening in the one-year study demonstrated that the monkeys had previously been exposed to one or more viruses (i.e., lymphocryptovirus [LCV], Herpes B, rhesus cytomegalovirus, and simian papovavirus), there was no clinical evidence of any infections during the study period. In addition, there was no evidence of any hyperplastic, pre-neoplastic, or neoplastic changes in peripheral blood or lymphoid tissues. Given the known latency period for some malignancies, it is possible that administration of BMS-188667 for a longer period, with concomitant chronic immunosuppression, could lead to treatment-related oncogenicity. KLH immunization of recovery animals 8-9 weeks after cessation of treatment elicited a robust antibody response to KLH, indicating functional recovery of the immune system at all dose levels.
Carcinogenicity
In a chronic carcinogenicity study (84-88 weeks), CD-1 mice were administered BMS-188667 at dose levels of 20, 65, or 200 mg/kg bw/week by SC administration.Treatment induced an increased incidence of renal karyomegaly at all dose levels tested, as was noted in the 6-month mouse study at dose levels of 65 and 200 mg/kg bw/week. However, there was no evidence of adverse effects on renal function in either study, and similar renal findings were not observed in monkeys after treatment for up to one year. It was concluded that renal karyomegaly was species-specific and not a concern with respect to human exposure.
Treatment also resulted in an increased incidence of lymphomas for both sexes at all dose levels, with a concomitant increase in mortality. In addition, there was an increased incidence of mammary adenocarcinomas for females only, at dose levels of 65 and 200 mg/kg bw/week. In mice, the retroviruses MLV (murine leukemia virus) and MMTV (mouse mammary tumour virus) are known to be causative agents for lymphoma and mammary tumours, respectively. Endogenous ecotropic-specific MLV DNA was detected in the genome of CD-1 mice used in this study. In addition, results from transmission electron microscopic evaluation of mammary tumours from this study identified large numbers of virions with ultrastructural characteristics consistent with those of MMTVs. The presence of MMTV in mammary tumours from both control-and BMS-188667-treated mice was confirmed by immunohistochemistry with an anti-MMTV antibody. Long-term immunosuppression is known to be associated with an increased incidence of neoplasia in both animals and humans. In this study, significant immunosuppression was observed at every dose level tested. This was confirmed in a separate PK/PD study, which demonstrated strong suppression of the KLH antibody response and anti-drug antibody response at ≥20 mg/kg bw. These findings strongly support the conclusion that the increased malignancies in this study were secondary to long-term BMS-188667-induced immunosuppression and the resulting clinical expression of MLV and MMTV. Also in support of this conclusion, a standard battery of in vitro mutagenicity assays yielded negative results for genotoxic potential.
Reproductive and Developmental Toxicity
Fertility and early embryonic development were investigated in rats administered BMS-188667 every three days by SC administration at dose levels of 10, 45, or 200 mg/kg bw. There was no effect on reproductive parameters for males or females, nor any effect on early embryonic development noted at any dose level tested.
Embryo-fetal development testing was conducted in mice at dose levels of 10, 55, or 300 mg/kg bw/day, in rats at dose levels of 10, 45, or 200 mg/kg bw/day, and in rabbits at dose levels of 10, 45, or 200 mg/kg bw/every 3 days. BMS-188667 did not induce maternal or embryo-fetal toxicity in any species tested at all dose levels. However, BMS-188667 was detected in serum samples from fetuses of treated rats and rabbits, indicating that BMS-188667 was able to cross the placental barrier.
A 2-generation reproduction study was carried out in rats at dose levels of 10, 45, and 200 mg/kg bw/every 3 days. F1 generation rats were subjected to immunological assessment. Treatment-related findings were limited to females in the 200 mg/kg bw group, manifest as an increase (9-fold) in the T-cell-dependent antibody response in F1 generation pups on post-natal day 56, and diffuse chronic inflammation of the thyroid gland in one F1 generation female. Since these findings were minimal and no other immune parameters were affected, they were considered to represent the lower threshold limit for effects of BMS-188667 on immune parameters in the F1 generation rats. BMS-188667 was detected in maternal milk and in pup serum, indicating exposure of pups via the maternal milk.
Immunotoxicity/Immunogenicity
The following studies were conducted in order to assess the immunologic effects of abatacept. An independent immunotoxicity study was conducted in female mice administered a single IV dose of BMS-188667 at 36 mg/kg bw. In a second immunotoxicity study, 5 daily consecutive doses of BMS-188667 at 7 mg/kg bw/day was administered to female mice. In both studies, total white blood cell (WBC) count was lower due to a decrease in lymphocyte count and there was a slight decrease in the number of recoverable splenocytes. In addition, ex vivo IgG production by splenocytes was decreased, but there was no observed effect on serum IgG or IgM levels in vivo. The only other finding, observed in the 5-day study exclusively, was an increased ability of splenocytes to be activated by a T-cell mitogen ex vivo. These findings indicate that although BMS-188667 may be immunomodulatory, it does not have an overtly toxic effect on lymphocytes.
An exploratory study was also conducted in monkeys to evaluate the potential for BMS-188667 to modulate T-cell activation. BMS-188667 was administered IV to two groups of monkeys (1/sex/group) for 7 consecutive days at doses of 5.7 or 17.2 mg/kg bw. Based on clinical immunology assessment, there appeared to be no significant changes in the frequency of peripheral blood lymphocyte subpopulations (T-cells, T-helper cells, T-cytotoxic/suppressor cells, B cells). Animals treated with BMS-188667 displayed a peak BMS-188667-specific antibody response by day 58. The magnitude of the antibody response was less, and the peak response more delayed, than typically observed for an immunogenic protein. These data suggest that BMS-188667 is not very immunogenic in the monkey and/or is capable of suppressing the antibody response directed against itself.
BMS-188667 was determined to be immunogenic in mice, rats, dogs, and monkeys; however, BMS-188667-specific antibodies were only present after BMS-188667 serum levels had fallen below immunosuppressive levels, indicating that BMS-188667 suppressed the antibody response against itself. Clearance of BMS-188667 was accelerated once BMS-188667-specific antibodies were present. Hence, during treatment, the antibody response to BMS-188667 was suppressed, and developed during recovery when drug levels decreased, thus maintaining consistent exposure to BMS-188667 throughout the treatment period in the repeat-dose studies. With continuous drug exposure, the appearance of BMS-specific antibodies was not associated with any acute or target organ toxicity. However, when drug levels fell below immunomodulatory levels in mice and dogs, subsequent IV challenge with BMS-188667 resulted in clinical signs of toxicity, manifest as hypersensitivity reactions.
Immunologic effects were also examined in the pivotal studies, further detailed in section 3.3.4 Clinical Safety, below.
Local Tolerance and Irritation
Local tolerance testing was conducted in rabbits administered BMS-188667 (10 mg/mL) intravenously (5 mg), intra-arterially (5 mg) or paravenously (2 mg). Grossly, irritation was not observed at any injection site via any route of administration. However, histopathological examination revealed that paravenous administration resulted in minimally greater irritation, i.e., an increased incidence of minimal dermal hemorrhage and mononuclear cell infiltrate.
Rats were administered a single SC injection of one of 4 formulations of BMS-188667 (100 mg/mL) at a dose of 100 mg/animal. Gross and histopathological examination indicated that cutaneous irritation was similar between the control and treatment groups. Rats were treated subcutaneously with BMS-188667 (100 mg/mL) at a dose of 200 mg/kg bw, once every other day for a total of 7 treatments. Grossly, there was no treatment-related irritation observed at any injection site. However, histopathological examination revealed that there was a treatment-related increase in the incidence and severity of subcutaneous inflammation when compared to the vehicle control, which was considered acceptable.
There was no evidence of any irritation at the injection site of monkeys in the repeat-dose studies of up to one year duration.
3.2.4 Summary and Conclusion
Pharmacokinetic assessment of BMS-188667 in mice, rats, rabbits, and monkeys demonstrated that systemic exposure was dose-related, there were no apparent gender differences, and accumulation was minimal after repeat dosing. The terminal t½ ranged from 3 to 6 days in rats and mice, 1 to 3 days in rabbits, and 5 to 7 days in monkeys.
Abatacept was well tolerated, and produced minimal irritation and treatment-related clinical effects. There were no effects on reproductive parameters in either sex, nor on embryonic development. However, abatacept was able to cross the placental barrier, and exposure was also observed via the maternal milk.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
An interim study was conducted over 4 months to examine synovial immune responses in subjects with active RA who had inadequate responses to TNF-blocking agents. The data presented in this preliminary report suggest that abatacept treatment reduces expression of inflammatory factors in synovial tissue as measured by quantitative RT-PCR, and reduces the numbers of CD11b-positive macrophages in synovial tissue as measured by immunohistochemical techniques. Both of these changes are consistent with the proposed mechanism of action for abatacept in the treatment of patients with RA. This study was limited by a small sample size, however evaluation of a larger population (n=18) should help to confirm the preliminary results.
3.3.2 Pharmacokinetics
The sponsor conducted a population pharmacokinetic (PPK) analysis by pooling data from six Phase II and III clinical studies.
A two-compartment model was selected and was supported by previous data. Estimates of abatacept apparent clearance (CL/F), apparent volume of distribution (V/F), and half-life (t1/2) were determined from the PPK analysis.
Abatacept demonstrated a positive correlation between clearance and weight, where increased patient weight resulted in increased clearance. Based on the values reported, a subject weighing 40 kg would be expected to have a 19% lower expected clearance than the reference subject, while a subject weighing 160 kg would have a 35% increase. Therefore, the effect of weight is substantial and clinically relevant, making a weight-based dose regimen important to control the inter-individual variability of exposure to abatacept. The proposed weight-adjusted dose regimen, i.e. 500 mg for subjects weighing <60 kg, 750 mg for subjects weighing between 60 and 100 kg, and 1000 mg for subjects weighing >100 kg, is considered appropriate.
Renal function, as measured by serum creatinine, was not identified as a covariate. The liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also not found to affect the pharmacokinetics of abatacept. This is not surprising considering that abatacept is not metabolized by liver enzymes and is not excreted by the kidney because of its high molecular weight. Large proteins like abatacept are primarily limited to clearance by cellular mechanisms such as Kupffer and sinus endothelial cells in the liver (other general routes of clearance of large proteins are via uptake by splenic macrophages and some limited proteolytic clearance in the lung and intestines).
Neither age nor gender were found to have an effect on the clearance or volume of distribution of the central compartment of abatacept after accounting for the effect of weight on clearance. Several commonly co-administered medications (methotrexate, corticosteroids, NSAIDs, and TNF-blocking agents) were also investigated, and were not found to influence the PK of abatacept. Baseline disease status (tender joint counts and swollen joint counts) and the duration of RA were not associated with significant changes in the PK of abatacept.
3.3.3 Clinical Efficacy
Clnical efficacy and safety of abatacept were examined in four pivotal Phase II/III studies (three pivotal Phase III studies, and one Phase II study to evaluate the safety and immunogenicity of multiple doses of abatacept), as well as several non-pivotal studies. All pivotal studies were homogeneous for the level of RA clinical activity and assessed the same validated outcome measures. In the two main efficacy studies, abatacept was administered as an IV infusion at a dose approximating 10 mg/kg on days 1, 15, 29 and then every 28 days for 6 months or 1 year. Patients were randomized in a 2:1 ratio of abatacept treatment vs. placebo. In the one-year study, abatacept-treated patients received a combination of methotrexate (MTX) and abatacept (vs. MTX monotherapy).
6-month Study
In the 6-month study, 391 patients were randomized. This study examined patients with long-term RA; the average duration of disease was 12 years and more than half had experienced the disease for more than 10 years. Patients were required to have previously failed an anti-TNF drug for efficacy reasons.
Of those who started, 223 patients on abatacept (86.4%) completed the study compared to 99 (74.4%) administered the placebo. Approximately 90% of patients on abatacept received all doses of the drug. Discontinuation rates due to AEs were identical in both groups (3.6%). Discontinuation for lack of efficacy occurred in 20% of placebo patients compared to 5.4% of abatacept patients. There were no deaths during the 6-month study, although one death occurred in an abatacept patient who discontinued for an AE at a later date.
The ACR20 (≥20% improvement in RA signs and symptoms) response is a relative change from baseline. The ACR20 response rate after six months of abatacept treatment was 50.4% compared to 19.5% for patients on placebo. It must be kept in mind that the patients in this study were very active and relatively resistant to treatment. Thus an ACR20 response of 50% is meaningful.
Differences in response rate were equivalent in patients who were past users of an anti-TNF compared to concurrent users at screening. Response rates were equal regardless of the prior anti-TNF agent used.
Significantly more patients on abatacept met ACR50 and ACR70 response rates than on placebo; 20% and 10% vs. 4% and 2% respectively. A statistically significant difference between placebo and abatacept in the ACR20 response rates was apparent as early as Day 15 and was maintained throughout the 169 day study. The ACR50 response rate became statistically significant at day 85 and the ACR70 response rate at day 57.
Each component of the ACR response was statistically better with abatacept treatment compared to placebo at six months, with most being evident as early as Day 15. Swollen joint counts were statistically better at Day 29 and pain was statistically improved at Day 113.
The DAS (Disease Activity Score) is a composite score providing an absolute measure of disease activity. Significant improvements were seen in the DAS at Day 169 compared to placebo (a drop of 1.98 points vs. a drop of 0.71 points). Clinically meaningful improvement was seen in 71% of abatacept patients compared to 32% of placebo patients. After treatment only 17% of abatacept patients met the definition of low disease activity and only 10% met criterion for DAS remission. This does not reflect poorly on abatacept. Rather it attests to the difficult-to-treat nature of the patient and speaks well for abatacept.
The proportion of patients meeting a decrease in the Health Assessment Questionnaire (HAQ) score of 0.3 units was 47.3% on abatacept vs. 23.3% on placebo.
Consistent efficacy for the ACR20 and HAQ responses were seen for clinical sub-groups of sex, weight, geographic region, duration of RA, history of anti-TNF use, and baseline measures of disease activity.
Patients on abatacept demonstrated statistically significant greater improvements in the Physical and Mental component scores of the SF-36 questionnaire compared to placebo at Day 169. This data supports the claim for improvement in physical function. Patients on abatacept also experienced greater reductions in the Sleep Problems Index, duration of morning stiffness, fatigue, and limitation of activity.
One-year Study
In the one-year study, 656 patients were randomized, though four were not treated. Ninety-three percent (93%) of patients treated with abatacept reached the first 6-month efficacy assessment vs. 79% on placebo. Discontinuation for lack of efficacy was 15% in the placebo group vs. only 3% in the abatacept group. Eighty-nine percent (89%) of patients treated with abatacept completed the full year vs. 74% of the placebo group.
At six months, the ACR20 response rate was 68% for those administered abatacept vs. 40% on placebo. The difference between abatacept and placebo was apparent as early as day 15, and maintained throughout the study. After six months of stable therapy, additional treatments were permitted to be added to the drug regimen as required. A new treatment was added for 14.4% of patients on placebo and to 3.7% of patients on abatacept.
The ACR20 response rate was analyzed according to demographic and clinical sub-groups. Abatacept was equally superior to placebo regardless of gender, body weight, duration of RA, rheumatoid factor (RF) status, or age (older and younger than 65).
The 6-month ACR20 in the placebo group of 40% is high, but could reflect the ongoing background treatment with MTX. The equal response to abatacept regardless of baseline clinical or demographic variable is important, however the study was not designed to explore these differences. For example, only 75 patients on abatacept were RF-negative compared to 520 who were RF-positive (though the CI for the response in RF-negative individuals was well matched with the RF-positive group). This is an important observation and compares with observations that RF-negative patients do not respond well to rituximab (a comparator drug) and respond less well to anti-TNF drugs. An intriguing effect of abatacept is the diminution of RF levels during treatment and a change in RF status from positive to negative in ~8% of patients on abatacept.
Baseline HAQ scores were quite high for abatacept at 1.7. At 12 months, the proportion of patients demonstrating a fall in the HAQ of at least 0.3 points was 61.1% for abatacept and 45.3% for placebo. The mean improvement in HAQ was 0.66 units for abatacept and 0.37 units for placebo.
Abatacept therapy was also associated with statistically significant improvements in the Physical and Mental components of the SF-36 health questionnaire.
At 12 months, abatacept patients also exhibited smaller increases in the scores of joint space narrowing and erosions upon x-ray examination.
3.3.4 Clinical Safety
The overall clinical safety database is based on the sponsor's clinical studies, including open-phase extension studies. There is some bias associated with such a safety database because of its relatively small sample size, limited duration of observation, and the deliberate exclusion of "sicker" patients from the studies. However, based on the available safety database, there are no safety issues of sufficient magnitude to tilt the risk to benefit ratio against abatacept.
Nevertheless, several safety issues are apparent. Patients on abatacept had a higher rate of non-serious and serious infections, particularly bacterial infections of all types and HSV. This was most apparent in, but not limited to, patients on concurrent anti-TNF therapy. Fortunately the higher rate of infection in these studies was not accompanied by a higher rate of fatal infections. Patients responded to therapy. Patients older than 65 and patients with pre-existing chronic obstructive pulmonary disease (COPD) were at higher risk of bacterial infections. Tuberculosis (TB) did not appear to be a particular problem because of mandated pre-treatment screening for TB. The frequency of opportunistic infections was not increased unduly compared to placebo, but the sample size in the studies to date might be too small to detect a significant difference.
Older patients were also noted to have an increased number of malignancies. No one specific type of malignancy predominated. Lymphomas were not frequent and were within the rate expected for individuals with RA. Lung cancer occurred in 8 patients on abatacept, an unexpected finding of uncertain significance. The rate seen in RA patients on abatacept exceeded the expected rate in an age matched population, however it is unclear if this rate exceeds the expected rate in RA patients. Data was provided on lung cancer prevalence in three large RA databases. In two databases the expected rate is the same as the general population, raising concerns about abatacept, however in the third database the rate of lung cancer in patients taking DMARDs is the same as the rate seen with abatacept. An analysis of the lung cancer cases on abatacept finds that 3/8 cases may have existed at screening. If these cases are excluded the rate of lung cancer falls to a rate similar to the general population. The sponsor acknowledges concern over the issue and, as a post-marketing commitment to the United States Food and Drug Administration (FDA), has proposed to conduct a pharmacovigilance study to explore this further.
Patients on abatacept may develop autoimmune complications such as psoriasis, vasculitis and keratoconjunctivitis sicca (KCS). The development of additional autoimmune phenomena has been seen with anti-TNF drugs and suggests modulation of immune responses.
No cases of systemic lupus erythematosus (SLE) or multiple sclerosis (MS) were seen. Immediate peri-infusional reactions such as headaches and dizziness were observed, however peri-infusional hypersensitivity reactions and/or anaphylaxis were uncommon.
The non-pivotal trials were supportive of the pivotal trials. A similar rate of AEs was noted. No new AEs were reported.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Based on the studies outlined above, abatacept clearly demonstrates efficacy in treating RA, including decreasing clinical manifestations, improving physical function and retarding x-ray progression. Improvement in clinical outcomes is consistent from study to study. Abatacept is effective when added to inadequate MTX or other DMARD therapy.
The concurrent use of abatacept and an anti-TNF is not recommended as this combination is associated with a higher rate of infections and it is not clear if the higher risk is associated with better disease control.
The efficacy of abatacept appears equal in RF positive and negative patients, and no demographic is associated with a poorer response. A limited number of subjects older than 65 were treated, however the limited data does not identify a poorer response in older versus younger patients.
Overall, the studies support the clinical indications for abatacept outlined in the Product Monograph and it is concluded that the benefit to risk ratio for abatacept in the treatment of patients with RA is positive. It is suggested however, that pharamacovigilance studies of "real-world" patients be conducted to provide additional information on the safety risks such as opportunistic infections, lung cancer, and other malignancies.
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 Orencia is favourable for reducing signs and symptoms, inducing clinical responses, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs) and/or to tumour necrosis factor (TNF) antagonists. 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 pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Orencia
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2005-01-21 |
| Request for priority status | |
| Filed | 2005-03-10 |
| Approval issued by Director, CERB | 2005-03-30 |
| Submission filed | 2005-05-06 |
| Screening | |
| Screening Acceptance Letter issued | 2005-06-06 |
| Review | |
| On-Site Evaluation | 2006-03-31 |
| Quality Evaluation complete | 2006-06-12 |
| Clinical Evaluation complete | 2006-05-26 |
| Labelling Review complete | 2006-06-14 |
| NOC issued by Director General | 2006-06-29 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ORENCIA | 02282097 | BRISTOL-MYERS SQUIBB CANADA | ABATACEPT 250 MG / VIAL |