Summary Basis of Decision for Elaprase ™
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:
ElapraseTM
Idursulfase, 2 mg/mL, Solution, Intravenous
Shire Human Genetic Therapies, Inc.
Submission control no: 109857
Date issued: 2007-12-17
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), PrELAPRASEMD, Idursulfase, 2 mg/mL, Solution, Shire Human Genetic Therapies, Inc. No de contrôle de la présentation 109857
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):
- 02296314
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On June 13, 2007, Health Canada issued a Notice of Compliance to Shire Human Genetic Therapies, Inc. for the drug product Elaprase.
Elaprase contains the medicinal ingredient idursulfase, which is classified as an enzyme replacement therapy.
Elaprase is indicated as an enzyme replacement therapy in patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). Elaprase has been shown to improve walking capacity in these patients. Hunter syndrome is a rare, X-linked recessive lysosomal storage disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase, leading to accumulation of glycosaminoglycans (GAGs), also known as mucopolysaccharides, in nearly all body tissues. Symptoms of Hunter syndrome include growth delay, joint stiffness, and coarsening of facial features. In severe cases, patients experience respiratory and cardiac problems, enlargement of the liver and spleen, neurological deficits, and death.
Elaprase is a human iduronate-2-sulfatase manufactured by recombinant DNA technology in a human cell line. The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. One pivotal trial involving 96 patients was submitted to support the efficacy of Elaprase. Results of this study showed that the treated participants had an improved capacity to walk. At the end of the 53-week trial, patients who received weekly Elaprase infusions experienced on average, a 35-meter greater increase in the distance walked in six minutes compared to the patients on placebo. The decreases in combined liver-spleen volume and urinary GAG levels gave additional supportive benefit to weekly treatment with Elaprase. Three additional non-pivotal trials were submitted to support the safety of Elaprase, increasing the total number of patients analyzed to 108. The most commonly reported treatment-related adverse effects were infusion-related reactions; however, the Warnings and Precautions section of the Product Monograph also contains a black box warning concerning the potential for late-emergent anaphylactoid reactions and exacerbation of underlying respiratory dysfunction. The safety profile was found to be acceptable and will continue to be monitored post-marketing.
Elaprase (2 mg/mL, idursulfase) is presented as a sterile solution for infusion. Elaprase is intended for use under the supervision of a physician or other experienced health care provider. It is administered at a dose of 0.5 mg/kg body weight every week by intravenous infusion. The infusion rate may be slowed and/or temporarily stopped, based on clinical judgement, when infusion-related reactions occur. Dosing guidelines are available in the Product Monograph.
Elaprase is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Elaprase 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 Elaprase are described in the Product Monograph.
Priority Review status was granted for the evaluation of Elaprase as it demonstrated a favourable effect on a serious symptom or manifestation of Hunter syndrome, a serious, life-threatening, and severely debilitating illness for which no therapy is presently marketed in Canada.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Elaprase is favourable for enzyme replacement therapy in patients with Hunter syndrome (MPS II).
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Idursulfase, the medicinal ingredient of Elaprase is a recombinant form of the human enzyme iduronate-2-sulfatase. Iduronate-2-sulfatase is responsible for the degradation of the lysosomal glycosaminoglycans, heparan sulphate and dermatan sulfate. Patients with Hunter syndrome have insufficient levels of this enzyme. As a result, glycosaminoglycans accumulate in the cells' lysosomes in the organs and body tissues, causing significant multi-system dysfunction.
Manufacturing Process and Process Controls
Idursulfase is produced by recombinant DNA technology in a continuous human cell line. The manufacture of idursulfase is based on a two-tiered cell banking system, where a master cell bank and a working cell bank have been established. Both 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 stability has been demonstrated for cells from the master cell bank to the production at the limit of in vitro cell age.
The manufacturing process of idursulfase comprises of a series of steps which include cell culture, harvest, and purification. The purification is performed via a combination of chromatographic and viral removal steps. The consistency of the manufacturing process is ensured through defined production procedures, critical quality tests, in-process limits and idursulfase release specifications. Microbial control throughout the manufacturing process is confirmed by the results obtained for bioburden and bacterial endotoxin testing.
In-process controls performed during the manufacturing process were reviewed and are considered acceptable. Raw materials used in manufacturing process of idursulfase were either of compendial grade or of suitable quality where monographs are not available.
Characterization
Detailed characterization studies were performed to provide assurance that idursulfase is consistently exhibiting 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 idursulfase. The drug substance specifications and analytical methods used for quality control are considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life and storage conditions for idursulfase are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Elaprase is a sterile, aqueous, clear to slightly opalescent, colourless solution supplied in a 5 mL Type I glass vial. Each vial of Elaprase contains a 2.0 mg/mL solution of idursulfase drug substance (6.0 mg) in an extractable volume of 3.0 mL, and is for single-use only. The following is a list of excipients used in the Elaprase formulation: sodium chloride; sodium phosphate monobasic, monohydrate; sodium phosphate dibasic, heptahydrate; polysorbate 20; and water for injection.
All non-medicinal ingredients (excipients) found in the drug product comply with either the US Pharmacopeia, European Pharmacopeia, or National Formulary specifications. In addition, none of the raw materials were sourced from human or animal origin.
Pharmaceutical Development
The quantitative composition (i.e., concentration of medicinal and non-medicinal ingredients, and pH) of the Elaprase formulation changed during development. However, the qualitative composition (i.e., type of medicinal and non-medicinal ingredients used) remained the same. These changes were implemented in order to optimize the stability of the formulation and did not impact the quality of Elaprase.
Manufacturing Process and Process Controls
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. Idursulfase is filled into vials using proper aseptic techniques, and conventional pharmaceutical equipment and facilities.
Control of Drug Product
Elaprase is tested to verify its identity, appearance, purity, sterility, and potency, as well as the following formulation-relevant parameters: protein content, pH, and osmolality. Validation reports submitted for the analytical procedures used for in-process and release-testing of Elaprase are considered satisfactory, and are 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 real-time and accelerated stability data submitted, an expiration period of 24 months is justified for Elaprase when stored at the recommended temperature of 2°C to 8°C.
3.1.3 Facilities and Equipment
On-Site Evaluations for the facilities involved in the manufacture and testing of idursulfase and Elaprase were previously conducted by Health Canada. The design, operations and controls of the facility and equipment that 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
Harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of biological origin used in the manufacture of idursulfase are deemed suitable for their purpose, as a combination of safety measures were taken to minimize any risk of contamination by adventitious agents from these materials. 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 Elaprase 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
Hunter syndrome is caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulphate and heparan sulphate in the lysosomes of various cells. Lack of or reduced levels of this enzyme result in the accumulation of GAG in most cells in the body. This accumulation leads to cellular engorgement, organomegaly, cellular death, tissue destruction, and subsequent organ dysfunction.
Idursulfase was developed as an exogenous replacement enzyme for Hunter syndrome patients. Idursulfase hydrolyzes the 2-sulfate esters of terminal iduronate sulphate residues from the GAG dermatan sulphate and heparan sulphate in the lysosomes of various cell types. Idursulfase is internalized by M6P receptor-mediated transport, which leads to the selective lysosomal delivery of idursulfase and the subsequent catabolism of accumulated GAG.
3.2.1 Pharmacodynamics
Pharmacodynamic (PD) studies utilizing the IKO mouse model demonstrated that intravenously administered idursulfase reached the target organs and caused a dose-dependent reduction in both urinary and tissue GAG levels. Evaluation of tissues showed a marked reduction of GAG levels in the liver, kidney, heart, skin and spleen of IKO mice treated with idursulfase compared to IKO vehicle controls. The minimal effective dose was between 0.1 and 0.5 mg/kg body weight (bw), and GAG levels remained low for several weeks post-dosing.
At 1.0 mg/kg bw, long-term biweekly and weekly dosing regimens were effective in reducing tissue GAG concentrations in a variety of tissues, and caused a reduction in liver weight. The trend toward lower GAG levels following weekly dosing was considered to reflect the extra week of GAG re-accumulation with biweekly dosing.
A low weekly dose of 0.15 mg/kg bw was sufficient to reduce liver GAG levels, but monthly dosing at either 0.15 or 1.0 mg/kg bw was insufficient to maintain low GAG levels. In all other organs, weekly dosing at 1.0 mg/kg bw was required to maintain the lowest reduction in tissue GAG concentration. Monitoring of urinary GAG was predictive of relative, but not quantitative, tissue GAG concentrations.
Based on the results of the PD studies, it was concluded that idursulfase administered intravenously reaches target organs through the circulation, is taken up in an appropriate manner, most likely through the M6P receptor, and reaches the lysosomes in an active form. The site of action for idursulfase is the lysosome, and so the observed reductions in GAG levels were therefore considered to be indicative of lysosomal uptake of idursulfase.
A single-dose safety pharmacology study in monkeys at dose levels of 5, 10, and 20 mg/kg bw did not reveal any treatment-related effects on the cardiovascular, respiratory, or central nervous systems.
3.2.2 Pharmacokinetics
Idursulfase was administered as a single intravenous injection to male rats at dose levels of 0.5, 2.5 or 12.5 mg/kg bw. Mean serum idursulfase concentrations increased with dose, and had a biphasic serum elimination profile. Mean alpha half-life for the 0.5 mg/kg bw group was shorter compared to the 2.5 and 12.5 mg/kg bw groups, i.e., 0.32 hours, vs. 0.78 and 0.86 hours, respectively. Beta half-lives were 2.9, 6.2 and 4.4 hours, for the 0.5, 2.5 and 12.5 mg/kg bw groups, respectively. The maximum idursulfase concentration (Cmax) increased in an approximately dose-proportional manner. However, there was a tendency toward a larger than expected increase in drug exposure (AUC) with dose, indicating that serum clearance mechanisms had become saturated at #2.5 mg/kg bw. Idursulfase was not expected to accumulate since the residual amount of idursulfase at 24 hours was <1% of Cmax.
For male monkeys receiving a single IV dose of 0.1, 0.3, 0.5 or 1.5 mg/kg bw idursulfase, a biphasic serum elimination profile was also apparent. Elimination half-lives ranged from 45 to 320 minutes, with most of the drug being removed from the serum by 10 hours. As with rats, AUC was not dose-proportional and the data indicated that serum clearance mechanisms had become saturated at doses of ≥0.5 mg/kg bw. A repeat administration study conducted in monkeys, at doses of 0.5, 2.5, or 12.5 mg/kg bw/week, revealed that PK parameters were essentially unchanged following repeat administration. There was no accumulation of idursulfase in the monkey serum after repeat dosing.
A tissue biodistribution study was conducted in male rats at doses of 0.5 and 12.5 mg/kg bw, which indicated that the highest radioactivity concentrations for both dose groups were observed in the liver, thyroid gland, stomach, bone marrow, kidneys, spleen, and bone. Tissue half-lives for the liver, kidney, heart, spleen, and bone were estimated to be one to two days, and so weekly dosing is considered sufficient to maintain adequate amounts of idursulfase in target tissues between doses.
Development of anti-idursulfase antibodies in animals was not consistently associated with an increase in serum clearance.
3.2.3 Toxicology
The toxicity database for Elaprase was complete, and was in accordance with the ICH Guidance S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals document. All toxicology studies utilized the intravenous (IV) route of administration since this is the intended clinical route of administration. In addition, only male animals were tested, since Hunter syndrome is an X-linked recessive lysosomal disease which primarily affects male humans.
Single-Dose Toxicity
The acute non-lethal dose of idursulfase when administered by IV injection to rats or monkeys was determined to be >20 mg/kg bw (the highest dose tested). All animals survived the duration of the study period, and there were no signs of toxicity observed in either species. The safety margin compared to the proposed clinical dose was 40-fold, and is considered adequate for this product.
Repeat-Dose Toxicity
Sub-chronic testing was conducted in monkeys for six months at dose levels of 0.5, 2.5, and 12.5 mg/kg bw/week, followed by a four-week recovery period. The high dose provided a 25-fold safety margin above the proposed commercial dose of 0.5 mg/kg bw. All dose levels were well-tolerated and were not associated with any signs of treatment-related toxicity. Antibodies to idursulfase were detected in two mid-dose and four high-dose animals, but were not associated with any adverse toxicological effects nor any direct effect on serum clearance mechanisms.
Reproductive Toxicity
A male fertility study was conducted in rats at doses of 0.5, 1.5, and 5 mg/kg bw, administered twice a week for nine weeks. All dose levels were well-tolerated, with no treatment-related findings observed for any measure of male fertility.
Carcinogenicity and Mutagenicity
Carcinogenicity studies and studies to assess the mutagenic potential of idursulfase were not conducted. However, carcinogenic and mutagenic potential would not be anticipated with idursulfase since it is a naturally occurring human protein.
Genotoxicity
The mechanism of action and the site of action within the cellular lysosome do not suggest any genotoxic risk and there are no known interactions with DNA. In addition, the range and type of genotoxicity studies routinely conducted for pharmaceuticals are not applicable to biotechnology-derived pharmaceuticals and are therefore not considered appropriate.
Local Tolerance
No local irritation, inflammation or necrosis to veins or tissue related to the bolus IV injection of idursulfase were reported.
3.2.4 Summary and Conclusion
Overall, the non-clinical pharmacology and toxicology studies support the use of Elaprase for the proposed indication. In the IKO mouse model, idursulfase reached the target organs and caused a reduction in both urinary and tissue GAG levels. In the sub-chronic toxicity testing in monkeys, all dose levels were well-tolerated. The toxicity database was considered adequate to assess the safety profile of Elaprase and support its use in humans as enzyme replacement therapy for patients with Hunter syndrome.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamic (PD) studies dealt with three biomarkers as measures of the clinical activity of idursulfase: 1) GAG levels in urine as an ability to reduce urinary GAG excretion in patients; 2) reduction of liver size; and 3) reduction of spleen size. In Hunter syndrome patients, enlarged liver and spleen sizes result from accumulation of GAG within the cellular lysosomes. Therefore as PD markers, the urinary GAG reductions provided evidence of enzymatic activity in the body, while the reductions in liver and spleen size (volume) demonstrated a biological effect in these organs. The rapid and sustained reductions in both liver and spleen size observed in the Phase I/II and Phase II/III studies indicated that idursulfase reached these target organs, entered the cells in active form, degraded the accumulated GAG substrate and was capable of reversing pathological organ hypertrophy.
During the Phase II/III studies, 53/106 patients (50%) developed anti-idursulfase IgG antibodies at some point. In patients who developed anti-idursulfase antibodies, the presence of these antibodies had no effect on the typical pharmacokinetic (PK) profile, although urinary GAG clearance became impaired in some patients. The impact of the presence of antibodies extended the time to reach the GAG upper limit of normal (126.6 µg/mg creatinine) from 18 weeks to 81 weeks. However, the improvement in the 6-minute walking test and liver size reduction appeared to be not affected by the antibody status nor was there any significant correlation between the PK parameters (AUC, t1/2, CLnorm, Vssnorm,) and variables relevant to study endpoints (GAG+norm, liver vol, spleen vol, 6MWT, and FEV1) in a canonical correlation analysis.
3.3.2 Pharmacokinetics
Elaprase infusion at a dosing level of 0.5 mg/kg and a weekly dosing regimen provided a concentration sufficient for a near-maximum effect with a minimal frequency of adverse events. Preclinical biodistribution studies estimated that the half-life of idursulfase in the tissues was between 1-2 days, implying some favourable retention in the tissues before the next weekly infusion.
In the Phase I/II dose escalation studies, both Cmax and AUC were non-linear with dose, although this feature was more apparent with the AUC parameter. As well, the mean terminal half-life in the serum increased with dose level, for example, from 109 to 233 minutes. However, in a chronic dosing regimen, the initial saturation of idursulfase in the first week appeared to be mitigated somewhat over the course of 25-27 weeks. The indicators of drug absorption (AUC, and Cmax) decreased with time, while the indicators of elimination (t1/2, CL) increased in effectiveness. This pattern was not due to a change in the ratio of unbound fractions in plasma and tissue since the indicator of distribution (Vss) remained constant. This trend associated with chronic dosing appeared to be less extreme at the 0.5 mg/kg dose level.
No metabolism studies were conducted in humans. The metabolic degradation of this protein product is expected to occur in cells via normal proteolytic mechanisms.
Clinical drug interaction studies were not conducted as drug-drug interactions are not expected with enzyme replacement therapies.
3.3.3 Clinical Efficacy
One pivotal Phase II/III, multicentre, randomized, double-blind, placebo-controlled, 53-week clinical trial was submitted to support the efficacy of a 0.5 mg/kg weekly dose regimen of Elaprase in patients with Hunter syndrome. A total of 96 patients were enrolled: 32 patients were treated with placebo, 32 patients were treated with 0.5 mg/kg Elaprase every other week, and 32 patients were treated with 0.5 mg/kg Elaprase every week. All patients in this study were males 5-31 years of age.
The primary efficacy endpoint was assessed based on the composite score combining two clinical measurements: six-minute walk test and the %-predicted forced vital capacity (FVC). The results of this study demonstrate that for the intent-to-treat (ITT) population, the two-component composite score (sum of the ranked changes from baseline) for the 0.5 mg/kg Elaprase weekly group was statistically significantly greater compared to the placebo group (50.86± 8.07), with an adjusted treatment difference of 18.96 ± 6.47 (p=0.0049).
Analyzed separately, the adjusted mean difference in distance walked in six minutes between the Elaprase weekly-treatment group and the placebo group was 35.09 m (p=0.0131), favouring the Elaprase weekly-treatment group. This difference was statistically significant. However, the adjusted mean treatment difference between the Elaprase weekly dose and the placebo groups was 4.28% from baseline to Week 53 in %-predicted FVC in the ITT population, and therefore did not demonstrate a statistical significance (p=0.0650).
Supportive evidence of a favourable treatment effect with weekly doses of 0.5 mg/kg Elaprase was observed in some secondary endpoints:
- The decrease in combined liver-spleen volume was statistically significant, largely due to decreased liver volume.
- The decrease in urinary GAG levels during the study period.
Studies were not conducted with patients younger than 5 years of age, and therefore the efficacy of Elaprase treatment in these patients cannot be established.
3.3.4 Clinical Safety
The pivotal Phase II/III study (described in section 3.3.3 Clinical Efficacy) and three non-pivotal studies were evaluated to assess the safety of intravenous administration of Elaprase in Hunter syndrome patients. A total of 108 patients were included in the safety analysis. All patients were males, 5-31 years of age, diagnosed with Hunter syndrome. Due to differences in study design as well as dosing regimens and dose levels, an integrated safety analysis was not performed.
Infusion-related reactions were the most commonly reported treatment-related adverse events (AEs). The most common infusion-related AEs among all treated patients included cutaneous reactions (rash, pruritus and urticaria), pyrexia, headache, flushing, and hypertension. Infusion-related reactions were managed by slowing the infusion rate and/or interrupting the infusion, and/or administering pre-infusion medications (antihistamines, antipyretics, low-dose corticosteroids, or beta-agonist nebulization). In the clinical studies, the overall rate of infusion-related AEs was demonstrated to decline over time.
Serious adverse reactions were reported in five patients treated with 0.5 mg/kg Elaprase either weekly or every other week. Four patients reported a hypoxic episode during one or several infusions. Oxygen therapy was required in three patients with severe underlying obstructive airway disease, including two with tracheostomy. The most severe episode was associated with a brief seizure, which occurred in a patient who had a concurrent febrile respiratory exacerbation.
Respiratory-related AEs were reported in Hunter syndrome patients with underlying respiratory condition treated with Elaprase. Two of four deaths were reported in patients who experienced respiratory AEs. During the long-term extension study, the following infusion-related AEs were considered significant: three events of dyspnoea, one event of wheezing, and one event of decreased oxygen saturation.
In post-marketing experience, two patients reported symptoms and signs suggestive of late-emergent anaphylactoid reactions approximately 24 hours after treatment and recovery from an initial anaphylactoid reaction. Warnings and precautions have been included in the Product Monograph.
Across the clinical studies, 53/106 (50%) patients developed anti-idursulfase IgG antibodies. Six of the IgG positive patients were also tested positive for IgM antibodies and two patients were tested positive for IgA antibodies. No patients tested positive for IgE antibodies. Fourteen IgG positive patients had antibodies that demonstrated neutralizing activity in-vitro, however, no negative impact on efficacy and safety outcome was identified. Compared to IgG negative patients, IgG positive patients had an increased incidence rate of infusion-related reactions including hypersensitivity reactions.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The drug submission for Elaprase was reviewed under the Priority Review Policy. Elaprase has shown a favourable effect on a serious symptom or manifestation of a serious, life-threatening, or severely debilitating illness for which no therapy is presently marketed in Canada.
The efficacy and safety analysis demonstrated that benefits of weekly 0.5 mg/kg Elaprase administration outweighed the associated risks. The most significant benefits were improvements in the 6-minute walk test, reductions in urinary GAG levels, and decreases in combined liver and spleen volume. Major risks such as infusion-related reactions were demonstrated to be manageable by slowing the infusion rate, pre-medicating and/or temporarily stopping the infusion. Patients with a compromised respiratory function reported serious infusion-related reactions; however these reactions were infrequent and were demonstrated to be manageable.
Treatment with Elaprase should be supervised by a physician or other experienced health care provider and appropriate medical support measures should be readily available. The labelling information and Product Monograph have been updated in order to better inform health care professionals and patients of risks associated with idursulfase administration.
The sponsor has submitted a pharmacovigilance plan and has agreed to fulfill the following post-marketing commitments:
- Establish a registry for Hunter syndrome patients under the title Hunter Syndrome Outcome Survey.
- Complete on-going clinical studies and provide reports for evaluation.
- Submit regular Periodic Safety Update Reports.
- Conduct additional clinical studies; an immunogenicity study, and a specific sub-population study in children 5 years of age and younger.
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 Elaprase is favourable in the treatment of enzyme replacement therapy in patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). 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: ElapraseTM
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed | 2006-09-19 |
| Approval issued by BGTD. | 2006-10-03 |
| Submission filed | 2006-11-14 |
| Screening | |
| Screening Acceptance Letter issued | 2006-12-15 |
| Review 1 | |
| Quality Evaluation complete | 2007-06-11 |
| Clinical Evaluation complete | 2007-06-13 |
| Labelling Review complete | 2007-06-06 |
| NOC issued by Director General | 2007-06-13 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ELAPRASE | 02296314 | TAKEDA CANADA INC | IDURSULFASE 2 MG / ML |