Summary Basis of Decision for Tysabri ™
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:
TysabriTM
Natalizumab, 300 mg/15 mL, Solution, Intravenous infusion
Biogen Idec Canada Inc.
Submission control no: 093001
Date issued: 2007-10-05
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), TYSABRIMD, natalizumab, 300 mg/15 mL, solution, Biogen Idec Canada Inc. Nº de contrôle de la présentation 093001
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):
- 02286386
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
TYSABRI™ is a trademark of Elan Pharma International Ltd.
2 Notice of decision
On September 28, 2006 , Health Canada issued a Notice of Compliance to Biogen Idec Canada Inc. for the drug product Tysabri.
Tysabri, a recombinant humanized monoclonal antibody, contains the medicinal ingredient natalizumab which is a selective adhesion molecule inhibitor.
Tysabri is indicated as monotherapy (i.e. single disease-modifying agent) for the treatment of patients with the relapsing-remitting form of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations, to decrease the number and volume of active brain lesions identified on magnetic resonance imaging (MRI) scans, and to delay the progression of physical disability. Tysabri is generally recommended in MS patients who have had an inadequate response to, or are unable to tolerate, other therapies for MS.
In MS, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and endothelial cells of the vessel wall. Natalizumab binds to the α4-subunit of human integrin (specifically α4β1) which is highly expressed on the surface of all leukocytes, with the exception of neutrophils. Blocking the molecular interactions of α4β1 with its targets reduces inflammatory activity present in the brain in MS and inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation or enlargement of MS lesions.
Priority Review status was granted for Tysabri due to MS being a serious life-threatening or severely debilitating disease that is not adequately managed by a drug marketed in Canada.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. In the randomized, double-blinded, placebo-controlled, Phase III Study 1801 (AFFIRM) (n=942), MS patients treated with Tysabri (n=627) demonstrated a 68% decrease in the annualized relapse rate compared to those treated with placebo. Tysabri effects were also evident on the MS lesions, as well as quality of life. The efficacy and safety of Tysabri in patients with chronic progressive multiple sclerosis, and in geriatric and pediatric patients, have not been established. The efficacy and safety of Tysabri for a treatment duration beyond 2 years has not been determined.
Tysabri (300 mg/15 mL, natalizumab) is presented as a solution for single-use only. One vial of Tysabri should be diluted with 0.9% sodium chloride injection, USP before intravenous (IV) infusion. The recommended dose of Tysabri is 300 mg by IV infusion every 4 weeks. Tysabri should not be administered as an IV push or bolus injection. Dosing guidelines are available in the Product Monograph.
Tysabri is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container; patients who have or have had progressive multifocal leukoencephalopathy; and patients who are immunocompromised, including those immunocompromised due to immunosuppressant or antineoplastic therapies, or immunodeficiencies (HIV, leukemias, lymphomas, etc.). Tysabri 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 Tysabri are described in the Product Monograph.
Treatment with Tysabri has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML). PML can cause disability or death. Healthcare professionals should monitor patients on Tysabri for any new sign or symptom that may be suggestive of PML. Tysabri dosing should be withheld immediately at the first sign or symptom suggestive of PML.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Tysabri is favourable as monotherapy for the treatment of patients with the relapsing-remitting form of MS to reduce the frequency of clinical exacerbations, to decrease the number and volume of active brain lesions identified on MRI scans, and to delay the progression of physical disability.
3 Scientific and Regulatory Basis for Decision
A Priority Review Status request for Tysabri (natalizumab) was filed with Health Canada in June 2004. In July 2004, Priority Review Status was granted and a New Drug Submission for Tysabri (natalizumab) was filed. The submission was accepted for review in August 2004. Over the course of evaluation three cases of progressive multifocal leucoencephalopathy (PML) were reported for patients treated with natalizumab. This led to discussion with the sponsor and issuance of a Notice of Deficiency (NOD) in May 2005, to request from the sponsor a complete safety evaluation for natalizumab, supporting data and an updated risk-benefit analysis. A response from the sponsor was received and accepted for review in November 2005. The response and the original submission were evaluated. Discussion related to the evaluation of safety data is within subsection 3.3.4 Clinical Safety. A Notice of Compliance was issued by Health Canada for the submission for Tysabri (natalizumab) in September 2006, indicated as monotherapy (i.e. single disease modifying agent) for the treatment of patients with the relapsing-remitting form of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations, to decrease the number and volume of active brain lesions identified on magnetic resonance imaging (MRI) scans, and to delay the progression of physical disability. Tysabri was indicated to be generally recommended in MS patients who have had an inadequate response to, or are unable to tolerate, other therapies for multiple sclerosis.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Description
Natalizumab, the medicinal ingredient of Tysabri, is a recombinant humanized IgG 4 monoclonal antibody that binds to the α4-subunit of human integrin, which is highly expressed on the surface of peripheral blood mononuclear leukocytes. The binding of natalizumab to the α4-subunit of human integrin prevents transmigration of mononuclear leukocytes across the endothelium into inflamed parenchymal tissue. Therefore, natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit further recruitment of immune cells into inflamed tissues.
Manufacturing Process and Process Controls
Natalizumab is produced by recombinant DNA technology in NS/0 cells. The manufacture of natalizumab is based on a NS/0 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 the International Conference on Harmonization (ICH) guidelines. Results of these tests confirmed cell line identity and the absence of adventitious agents/viral contaminants. Genetic characterization also demonstrated stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of natalizumab comprises of 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 the natalizumab 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 of the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that natalizumab consistently exhibits the desired characteristic structure. Results from the process validation studies also indicate that the methods used during the 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 were satisfactorily submitted for the analytical procedures used for in-process and release testing of natalizumab. The drug substance specifications, and analytical methods used for quality control of natalizumab are considered acceptable.
Stability
Based upon real-time and accelerated stability studies, the suggested shelf-life and storage conditions for natalizumab are supported and considered to be appropriate.
3.1.2 Drug Product
Description and Composition
Tysabri is a colourless, clear to slightly opalescent, sterile, concentrate solution packaged in a single-dose 15 mL Type I glass bottle with a grey rubber stopper, an aluminum closure and a plastic flip-off cap. Each vial of product contains 300 mg of natalizumab along with sodium phosphate monobasic, sodium phosphate dibasic, sodium chloride, polysorbate 80, and water for injection.
All excipients found in the drug product are acceptable for use in drugs by the Canadian Food and Drug Regulations. The compatibility of natalizumab with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
The composition of the Tysabri formulation changed during development. These changes were implemented in order to optimize the stability of the formulation and did not impact the quality of Tysabri.
Changes were also made to the Tysabri 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. The formulated solution is filled into vials using proper aseptic process techniques, and conventional pharmaceutical equipment and facilities.
Control of Drug Product
Tysabri is tested to verify its appearance, identity, purity, sterility, and potency, as well as the formulation-relevant parameters: protein content, pH, and osmolality. The validation reports submitted for the analytical procedures used for in-process and release testing of Tysabri 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 on the results of real-time and accelerated stability studies, an expiration period of 24 months is justified for Tysabri when stored at the recommended temperature of 2 °C to 8 °C.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of facilities involved in the manufacture and testing of natalizumab 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.
Except for the components which are a part of the cell bank culture and cryopreservation media, no raw materials of animal or human origin are used in the manufacture of natalizumab. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Tysabri 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
Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord characterized by focal areas of inflammation that lead to destruction of the myelin sheath and to varying degrees of axonal injury. The adhesion molecule α4β1 integrin found on lymphocytes is required for circulating lymphocytes and monocytes to interact with inflamed endothelium, with subsequent infiltration into the central nervous system (CNS).
All relevant assays were shown to be sensitive, specific, reproducible and accurate enough for the assessment of the pharmacodynamic (PD) and pharmacokinetic (PK) studies, and to support the toxicology studies of natalizumab in the relevant species.
3.2.1 Pharmacodynamics
The non-clinical PD studies have demonstrated that natalizumab binds specifically to the α4 subunit of the α4β1 integrin, blocking lymphocyte adherence to the underlying vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cells. Hence, the primary PD effect of natalizumab in all species tested was an increase in the circulating lymphocyte count resulting from the blockade of α4 integrins. Natalizumab reacted with lymphocytes from rhesus and cynomolgus monkeys, dogs, pigs, guinea pigs and ferrets. The binding affinity of natalizumab for α4 on lymphocytes was similar between the animal species and human lymphocytes.
A battery of cellular immune function assays indicated that natalizumab did not significantly alter immune regulatory and effector cell functions in normal human lymphocytes or monocytes (e.g., proliferation, cytokine production, T cell cytolytic function and natural killer cell activity).
Safety testing in Beagle dogs at dose levels of 3.0 mg/kg body weight (bw) and higher resulted in transient hypotension in some of the dogs, but this finding was not reproduced when administered to non-human primates.
Guinea pig studies revealed that there was a correlation between plasma levels of antibody and physiologic efficacy. The effective circulating antibody level in guinea pigs was 10-20 μg/mL. When natalizumab was administered to guinea pigs with experimental allergic encephalomyelitis (EAE) during active disease, the dose level of 3.0 mg/kg bw resulted in clearance of leukocytes from the CNS accompanied by a reversal of clinical findings, a marked decrease in abnormal pathologic findings, and a reversal of the blood-brain barrier permeability changes seen with EAE (MR imaging). These results indicate that natalizumab may be useful in the treatment of autoimmune diseases such as MS.
3.2.2 Pharmacokinetics
Single-dose animal studies were conducted to compare the formulation and manufacturing scale changes that took place during product development. There were no statistically significant differences in PK parameters and there were no changes in efficacy at the minimal efficacious dose in guinea pigs with EAE. These data supported the conclusion that the formulation and manufacturing changes did not result in changes to the PK behaviour of natalizumab.
Absorption, Distribution, Metabolism, and Elimination
All studies used intravenous (IV) infusion administration of natalizumab; therefore absorption studies were not performed.
The PK evaluation of natalizumab demonstrated a typical monoclonal antibody PK profile, with dose-dependent but not dose-proportional increases in the drug exposure parameters Cmax and AUC. In addition, there were increases in elimination half-lives with dose increases that were also accompanied by decreases in clearance rates. Development of anti-natalizumab antibodies limited either the extent and/or the duration of exposure in some animals, particularly in the lower dose groups.
The volume of distribution values indicated limited redistribution into the extravascular space. Transfer of natalizumab across the placenta to the fetus was demonstrated in both guinea pigs and cynomolgus monkeys. Levels of natalizumab were also found in the off-spring of dams treated with doses of 30 mg/kg bw. Little to no natalizumab was transferred into breast milk.
No studies were conducted to evaluate the metabolism or excretion of natalizumab.
3.2.3 Toxicology
Acute Toxicity
An acute single-dose intracardiac study was conducted in guinea pigs at the dose level of 126.9 mg/kg bw. Results from this study reported that there were no treatment-related findings, therefore the LD50 was >126.9 mg/kg bw.
Sub-Chronic Toxicity
Sub-chronic toxicity testing was conducted in monkeys for one month at dose levels of 0.3, 3, 10 and 30 mg/kg bw, and for six months at dose levels of 3, 10, 30, and 60 mg/kg bw. Dose levels were generally well-tolerated. However, infusion-related hypersensitivity reactions were observed in the six-month studies at dose levels of 3, 10 and 60 mg/kg bw. A total of 4 of the 74 animals treated were affected (5.4%). Hypersensitivity reactions were not observed in monkeys after treatment for one month. Anti-natalizumab antibodies were present in the serum of two of the affected monkeys, and changes in complement parameters were consistent with reactions resulting from immune complex formation and subsequent complement activation.
Increased white blood cell (WBC) counts, due primarily to increased lymphocyte counts, were seen in the one-month and six-month studies at doses ≥ 0.3 mg/kg bw. In addition, increases in nucleated red blood cells (NRBC) and reticulocyte counts were observed in the six-month studies. These findings were considered to be the result of the pharmacologic action of the test material and were associated with serum natalizumab levels in excess of 1-5 μg/mL. Hematologic parameters returned to normal baseline levels after treatment-free periods, when serum natalizumab levels fell below 1-5 μg/mL.
Additional findings (seen inconsistently with the various doses) included increased spleen weights, lymphoplasmacytic inflammation of the intestinal mucosa of the large intestine, glomerulonephritis, glomerulonephrosis, follicular hyperplasia of the spleen and lymph nodes, red cell leukocytosis in the spleen, and focal leukocyte infiltrates in the liver. All animals with glomerulonephritis had high levels of anti-natalizumab antibodies and evidence of immune complex formation and complement activation. However, not all animals with these factors exhibited glomerulonephritis, i.e., 80% of animals just prior to necropsy had detectable antibody levels, most of which were immune complex and complement activation positive, whereas only 10% exhibited glomerulonephritis. For the most part, the noted findings had reversed after a recovery period of up to 17 weeks.
Mutagenicity
A standard battery of mutagenicity assays yielded negative results for genotoxic potential. Natalizumab treatment did not elicit increased proliferation or cytotoxicity in the in vitro proliferation studies using α4+ tumour cell lines. There was no increase in tumour take, growth or metastasis as a result of natalizumab treatment in the in vivo tumour graft studies.
Carcinogenicity
Carcinogenicity testing in animals was not conducted. Natalizumab and the murine parent and anti-human α4 antibody do not cross-react with the murine integrins α4β1 or α4β7, nor do they cross-react with rat or hamster α4 integrins. In addition, administration of natalizumab to non-human species results in the formation of anti-natalizumab antibodies resulting in the rapid clearance and loss of the pharmacological activity of natalizumab in these animals. Hence, standard 2-year carcinogenicity studies in rats, mice or hamsters could not be conducted with natalizumab nor with the murine form of the antibody.
Reproductive and Developmental Toxicity
Fertility studies were conducted in male and female guinea pigs at dose levels of 3, 10 and 30 mg/kg bw. For males, all dose levels were well-tolerated. There were no effects on male fertility, sperm function, reproductive organ weights or histopathology. In females, fertility was affected at 30 mg/kg bw, manifest as a significant reduction in pregnancy rates when dosed for a minimum of 28 days prior to mating with dosing continuing through organogenesis. There were no adverse, treatment-related maternal effects nor effects on embryo/fetal development at any dose level tested.
Rats that were administered natalizumab during the last half of pregnancy showed a dose-related trend towards more dead pups and fewer live pups on post-natal day 1.
Embryo/fetal developmental and reproduction toxicity testing was conducted in monkeys. In one of the three studies and in only one of the two study cohorts, treatment with 30 mg/kg bw resulted in an increased incidence of abortion. An increased incidence of abortion was not observed in any of the other embryo/fetal developmental studies in monkeys nor in guinea pigs tested at similar dose levels. However, the observed incidence of abortions was above concurrent and historical control values, and therefore could not be ruled out as unrelated to treatment.
Treatment-related findings in fetuses born to females receiving ≥ 10 mg/kg bw were manifest as increased WBC counts, increased NRBC counts, altered RBC parameters indicative of mild anemia, decreased platelet counts, trends toward low liver and thymus weights with decreased extramedullary hematopoiesis, decreases in CD3+ and CD20+ cells in some lymphoid organs and an increase in background proliferation in response to phytohemagglutinin (PHA) stimulation. The reversibility and potential functional consequences of these findings were evaluated in a post-natal development study, which followed post-natal infants for 18 months. In this study, lymphocyte counts were increased in the circulation of infants from dams treated with 30 mg/kg bw natalizumab until parturition, which is consistent with the measurement of natalizumab in the sera of these infants. There were no changes in RBC parameters, indicating that the anemia noted in the embryo/fetal study was reversible by one month of age. Serum levels of IgG, IgM, and IgA were unaffected. Infant responses to a T cell-dependent antigen, KLH, were unaffected by natalizumab treatment of dams. Immunohistochemistry evaluation of the spleen, thymus, liver, axillary lymph node, mesenteric lymph node, Peyer's patches, and tonsils for lymphocyte subsets demonstrated no differences in numbers, distribution, or intensity of staining of B and T cell types between infants born to control and natalizumab-treated dams. Spleen weights were increased at the day 372 necropsy. However, this effect was reversible since it was not observed in infants from this group at the day 546 necropsy. There were no treatment-related findings at gross necropsy or at histopathological examination.
Immunotoxicity
Immunotoxicity testing was conducted in monkeys with dose levels of 3 and 30 mg/kg bw. Treatment was well-tolerated with the expected pharmacologic-related increase in lymphocyte count. Natalizumab treatment did not appear to significantly impair the ability to mount a primary or secondary humoral response to a T cell-dependent antigen that was administered during the course of natalizumab treatment, although some slight reductions were noted in the primary immune responses at early time points.
Tissue Cross Reactivity
Tissue cross reactivity studies of natalizumab with normal adult human, monkey and guinea pig tissues were consistent with staining patterns reported in the literature and did not result in the identification of any unexpected target tissues.
3.2.4 Summary and Conclusion
The non-clinical studies provide support for the mechanism of action of natalizumab, such that natalizumab may be useful in the treatment of MS. Natalizumab was shown to have a typical monoclonal antibody PK profile, adequate to support its use clinically.
The non-clinical toxicity testing demonstrated that natalizumab was generally well-tolerated in guinea pigs and monkeys. However, results from the 6-month studies in cynomolgus monkeys demonstrated the potential for immune-mediated hypersensitivity reactions. In addition, natalizumab may potentially affect the immune system and hematopoietic system of the developing fetus, and could cause abortions. The Product Monograph addresses these concerns. Women who are trying to become pregnant should be informed prior to treatment that natalizumab may result in decreased fertility, and adequate safety precautions/risk-benefit analysis should be taken for women who are pregnant or are lactating. In conclusion, the non-clinical toxicology database was considered adequate to assess the safety profile of natalizumab and support its use in humans, provided adequate safety precautions are taken.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The PD studies provided evidence to support the mechanism of action of natalizumab, the binding of the recombinant humanized monoclonal antibody to the α4 -subunit ( α4β1) of human integrin which is highly expressed on the surface of mononuclear leukocytes. The consequence of integrin saturation is a decrease in adhesion to the vascular endothelium which would lead to an increase in all circulating WBCs expressing the integrin.
The administration of 300 mg natalizumab resulted in a mean α4-integrin saturation of >90% immediately post-infusion with maintenance levels of approximately 70% or greater during the entire 28-day dosing interval. Similar α4-integrin binding was observed after the first dose and after the sixth dose. Elevations in WBC counts were reported in all circulating WBCs expressing the integrin such as monocytes and lymphocytes but not polymorphonucleated leukocytes (PMNs). Leukocyte counts in patients receiving natalizumab reached approximately two-fold the normal values.
Some patients developed anti-natalizumab antibodies which had significant consequences on the PD of natalizumab. Patients with these antibodies had a reduction in drug concentration and activity. The level of natalizumab exposure was correlated with a consistent reduction in α4-integrin saturation on leukocytes.
3.3.2 Pharmacokinetics
The PK parameters were evaluated after a single 300 mg dose of natalizumab in healthy subjects. The half-life was estimated to be 224 hours in one study and 249 hours in another. Similar values were observed in MS patients after a single dose and after 6 months of dosing as monotherapy. Increases in the PK drug exposure parameters indicate that some drug accumulation occurred over the 6-month dosing period.
Altered PK parameters were reported in patients that developed anti-natalizumab antibodies. Patients with persistent antibodies had trough natalizumab concentrations that were consistently below the limit of quantitation. Patients that had transient anti-natalizumab antibodies had delays reaching normal natalizumab trough concentrations and had less clinical efficacy.
3.3.3 Clinical Efficacy
The efficacy of natalizumab was demonstrated in three studies. The 6-month Phase II randomized, multicentre, double-blind, placebo-controlled Study MS 231 (n=231) in relapsing-remitting or secondary-progressive MS patients demonstrated the clinical and MRI efficacy of natalizumab compared to placebo and established that the 3 mg/kg dose was as effective as the 6 mg/kg dose. Stopping therapy at 6 months was associated with a return, but not rebound, of disease activity. Studies C-1801 (n=942) and C-1802 (n=1171) were the two pivotal Phase III randomized, double-blind, placebo-controlled studies of efficacy in relapsing-remitting MS. Patients treated with natalizumab were administered IV doses of 300 mg natalizumab every 4 weeks for up to 30 infusions.
The pivotal studies compared natalizumab mono-therapy to placebo (Study C-1801) or add-on natalizumab therapy to baseline Avonex vs. Avonex alone (Study C-1802). Study C-1802 was designed to evaluate natalizumab as combination therapy with Avonex, however the study did not address the true efficacy of combination therapy versus natalizumab monotherapy, as this would have required a natalizumab monotherapy arm. Patients in Study C-1802 were treated with Avonex for at least one year prior to randomization and continued a intramuscularly weekly dosage of 30 µg Avonex throughout the study. These patients were then randomized to natalizumab or placebo.
Both studies involved approximately 2000 patients, more than 1000 patients were administered natalizumab and the results were statistically vigorous. All patients completed the 104-week visit (26 of the 30 weekly infusions) and all patients in Study C-1801 and approximately 90% of the patients in Study C-1802 completed the 120-week study duration (30 infusions). The high rate of study completion attests to the quality of the outcome data and to the safety database in which controlled safety observations on about 1000 patients were available over 120 weeks of continuous therapy.
The two pivotal studies, Study C-1801 and Study C-1802, had two primary endpoints: the Expanded Disability Status Scale (EDSS) progression at two years and the annualized relapse rate. Progression of disability measured by the EDSS scores at two years was inhibited by natalizumab in both studies. The effect was more evident in Study C-1801; a 42% reduction compared to a 24% reduction in C-1802. The difference may be explained by somewhat more advanced MS in Study C-1802 where patients were slightly older, had a slightly longer duration of MS and a slightly higher median EDSS (2.5 vs. 2). The annualized relapse rates at one and two years were significantly reduced by natalizumab. Again the effect in Study C-1801 was higher; a 68% reduction compared to a 53% reduction in Study C-1802. The relapse rates in the placebo groups were equal. The clinical efficacy was strongly supported by significant decreases in the numbers of MRI-detected new active lesions and chronic lesions, and functional measures such as those measured by the Functional Composite Score (MSFC) and the generic quality of life questionnaire (SF-36). Inferences that combination therapy might not be better than monotherapy were provided by the diminished reductions in annualized relapses and EDSS progression in Study C-1802 compared to Study C-1801, and the same rates of annualized relapses in patients administered placebo in Study C-1801 and those that received only Avonex in Study C-1802.
The development of anti-natalizumab antibodies had a significant negative impact on efficacy by altering the PK and PD of natalizumab. In each pivotal study, approximately 12% of the patients that were administered natalizumab developed anti-natalizumab antibodies. These antibodies were usually evident by week 12. Six percent of these patients had transient antibodies; the other 6% had antibodies that were persistent. Patients with transient antibodies had less clinical efficacy and the efficacy was severely diminished in patients with persistent antibodies. Development of these persistent antibodies would be an indication for cessation of natalizumab therapy. The Product Monograph includes information on the effect of anti-natalizumab antibodies on the efficacy of Tysabri and provides instructions on discontinuing the treatment should those antibodies persist.
In both pivotal studies, the clinical benefit of natalizumab was significantly diminished or not observed in patients with <9 T2-hyperintense lesions at baseline. There was also an inference that patients with MS classified by McDonald criteria 2-4 may also be less responsive. While patients with these baseline characteristics constitute a small subset of all patients rendering any interpretation as problematic, these observations were consistent in both studies.
Overall, continuous natalizumab therapy over 120 weeks was highly effective at controlling relapsing-remitting MS. It is possible that some patients can be identified at baseline who might not benefit from treatment and that some patients can be identified during the first 6 months of treatment who should be withdrawn.
3.3.4 Clinical Safety
The clinical safety of natalizumab was evaluated in the two pivotal studies, Study C-1801 and Study C-1802 (described in section 3.3.3 Clinical Efficacy). A total of 1617 patients with MS were treated with natalizumab in the placebo-controlled studies. Of these, 1271 patients received 300 mg IV monthly and 1062 patients were observed over 2 years, exceeding the existing regulatory safety database requirements. Twenty non-pivotal studies of natalizumab in patients with MS and Crohn's disease (CD) were also reviewed from a safety perspective. Additional safety experiences were obtained from the treatment of patients with Crohn's disease.
The overall safety profile of two years of natalizumab therapy was favourable. The incidence of common adverse events (AEs) was balanced between the patients that were treated with natalizumab and those that received placebo. Rates of AEs in the various organ systems were almost identical, except for MS relapses which occurred more often in the placebo group.
Approximately 6% of the patients treated with natalizumab developed persistent anti-natalizumab antibodies and the presence of such antibodies correlated strongly with the development of hypersensitivity-like reactions and symptoms suggestive of such reactions such as pyrexia, rigors, headaches, flushing and dizziness.
The most striking safety issue was the development of three cases of progressive multifocal leucoencephalopathy (PML) in patients treated with natalizumab. Two cases were in MS patients from Study C-1802 who had received multiple doses of natalizumab on a background of Avonex therapy, and the third case was in a patient with CD who had also received long-term natalizumab therapy. This led to the issuance of a Notice of Deficiency (NOD) to request from the sponsor a complete safety evaluation for natalizumab, supporting data and an updated risk-benefit analysis. The response to the NOD was evaluated in addition to the original submission. Independent of industry, a rigorous comprehensive reassessment of patients with MS that received natalizumab did not identify any additional patients with PML. While the two cases of PML were seen in patients on concurrent Avonex, the role of combination therapy vs. natalizumab monotherapy in promoting the infection is inconclusive.
The safety of natalizumab in combination with other MS treatments, except for corticosteroids, has not been analyzed in this review.
Serious adverse events (SAEs) occurred in 15% of the patients treated with natalizumab compared to 19% in patients that received placebo. Relapse of MS was the most common SAE. Serious infections were low with a slight increase in appendicitis and urinary tract infections occurring in the natalizumab group. There was no apparent increase in pneumonia. An increased rate of H. Zoster was noted in Study C-1802. Aside from PML, other opportunistic infections were rare. No cases of tuberculosis were encountered.
No cases of lymphoma or lymphoproliferative disorders were noted. The rate of other malignancies such as breast cancer and malignant melanoma did not exceed expected rates in age and sex matched populations. However, most of the safety database included observations up to 18 months of therapy. Ongoing observations are required to substantiate the safety of natalizumab in the long term, especially for the development of malignancies and infections including all severe and serious infections, TB, and opportunistic infections.
There were only 17 treatment-emergent deaths in patients in the MS studies, two being cases of PML. In the placebo-controlled studies, deaths in both groups occurred at similar rates. Aside from PML, death was usually not attributed to natalizumab.
The consensus of Canadian MS experts, based on the review of the clinical and safety data, concluded that despite the 3 cases of PML, the risk to benefit ratio of natalizumab remains positive. In addition, because both cases occurred in patients on concomitant Avonex therapy and because natalizumab therapy appears much more effective than Avonex monotherapy, the combination of natalizumab and Avonex should not be used.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The evaluation of the submission for Tysabri (natalizumab) was granted Priority Review Status. Tysabri was shown to provide a significant increase in efficacy such that the overall benefit/risk profile was improved over existing therapies for the treatment of relapsing-remitting MS, a serious, life-threatening, or severely debilitating disease that was not adequately managed by a drug marketed in Canada.
The benefits of natalizumab appear to outweigh the risks in patients with relapsing-remitting MS. Both pivotal studies provided significant data that Tysabri was effective at decreasing clinical, functional, and structural damage in patients with relapsing-remitting MS. In terms of safety, the rate of AEs and SAEs was acceptable in the contexts of the indication for this drug and of the underlying medical conditions. The incidence of PML derived from the three cases reported was approximately 1/1000. A pharmacovigilance program of adequate size and duration of exposure is required to obtain long-term safety data. Neurologist education and the Product Monograph will provide the necessary information on the pros and cons of natalizumab therapy and the methods for monitoring for the possible development of PML.
To better anticipate and prevent potential post-marketing safety issues, the sponsor has submitted a Risk Management Plan (RMP) for Tysabri. This RMP includes a Risk Minimization Plan and a Pharmacovigilance Plan.
The goal set out in the Risk Minimization Plan of the RMP is to increase awareness of the risks associated with Tysabri and thereby reduce the risk of opportunistic infections (i.e., caused by agents that cause significant disease in people with impaired immunity), particularly PML. The Risk Minimization Plan relies on a patient registry (Tysabri Care Program) and an educational approach targeting both patients receiving Tysabri and healthcare providers in Canada.
The Pharmacovigilance Plan relies on the monitoring of safety information in accordance with Good Pharmacovigilance Practices, including regular review and evaluation of safety data from both clinical trials and post-marketing sources. Pharmacovigilance activities related to Tysabri in Canada will be the responsibility of the sponsor. Formal review of safety information will be undertaken periodically in the form of Periodic Safety Update Reports which will be submitted to Health Canada.
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 Tysabri is favourable as monotherapy (i.e. single disease-modifying agent) for the treatment of patients with the relapsing-remitting form of MS to reduce the frequency of clinical exacerbations, to decrease the number and volume of active brain lesions identified on MRI scans, and to delay the progression of physical disability. Tysabri is generally recommended in MS patients who have had an inadequate response to, or are unable to tolerate, other therapies for MS. 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: TysabriTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2004-06-18 |
| Request for priority status | |
| Filed | 2004-06-23 |
| Priority Review Granted | 2004-07-13 |
| Submission filed | 2004-07-29 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2004-08-24 |
| Review 1 | |
| NOD issued by Director General (a complete safety evaluation and an updated risk-benefit analysis was required) | 2005-05-20 |
| Response received | 2005-11-02 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2005-11-18 |
| Review 1 | |
| On-Site Evaluation | 2006-06-19 - 2006-06-23 |
| Quality Evaluation complete | 2006-08-31 |
| Clinical Evaluation complete | 2006-09-26 |
| Labelling Review complete | 2006-08-23 |
| NOC issued by Director General | 2006-09-28 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TYSABRI | 02286386 | BIOGEN CANADA INC | NATALIZUMAB 300 MG / 15 ML |