Summary Basis of Decision for Myozyme ®
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:
Myozyme®
Alglucosidase alfa, 50 mg/vial, Powder for solution, Intravenou
Genzyme Canada Inc.
Submission control no: 103381
Date issued: 2007-07-30
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), PrMYOZYMEMD, alglucosidase alfa, 50 mg par flacon, poudre pour solution, Genzyme Canada Inc., Nº de contrôle de la présentation 103381
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):
- 02284863
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On August 14, 2006, Health Canada issued a Notice of Compliance to Genzyme Canada Inc. for the drug product Myozyme®.
Myozyme® contains the medicinal ingredient alglucosidase alfa which is identical in amino acid sequence to a common form of the human enzyme, acid alpha-glucosidase (GAA). Myozyme® is produced by recombinant DNA technology and is classified therapeutically as an Enzyme Replacement Therapy.
Myozyme® is indicated for use in patients with Pompe's Disease (GAA deficiency).
Pompe's Disease is a rare, inherited disorder, caused by a deficiency of GAA, an enzyme responsible for the degradation of glycogen to glucose. Lack of this enzyme causes glycogen to accumulate in cardiac, respiratory, and skeletal muscle tissues, leading to the development of cardiomyopathy and progressive muscle weakness, including impairment of respiratory function. Patients with infantile-onset Pompe's Disease experience a progressively deteriorating illness usually leading to death within 1-2 years from the time of diagnosis. Myozyme® helps treat some of the symptoms of Pompe's Disease by replacing the deficient enzyme.
Priority Review status was granted for the evaluation of Myozyme® based on its significant increase in efficacy and significant decrease in risk compared to existing therapies, for a disease that is not adequately managed by a drug marketed in Canada.
The market authorization was based on submitted data from quality control studies, pre-clinical and clinical studies. Safety and efficacy data were obtained from two clinical trials. Myozyme® has been shown to improve ventilator-free survival in patients with infantile-onset Pompe's Disease as compared to untreated historical controls, whereas use of Myozyme® in patients with other forms of Pompe's Disease has not been adequately studied to assure safety and efficacy.
Myozyme® (50 mg, alglucosidase alfa) is presented as a sterile lyophilized powder in vials, for reconstitution with 10.3 mL Sterile Water for Injection, USP. Each vial is for single use only. The recommended dosage regimen of Myozyme® is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion. Dosing guidelines are available in the Product Monograph.
Myozyme® is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Myozyme® 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 Myozyme® 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 Myozyme® is favourable for use in patients with Pompe's Disease (GAA deficiency).
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Description
Myozyme® (recombinant human acid alpha-glucosidase, [rhGAA]) is indicated for use in patients with a confirmed diagnosis of Pompe's Disease, a rare inherited disorder, caused by a deficiency of the enzyme acid alphaglucosidase (GAA). This enzyme is responsible for degrading lysosomal glycogen. Alglucosidase alfa (rhGAA), the medicinal ingredient of Myozyme®, is a recombinant human enzyme which degrades lysosomal glycogen.
Manufacturing Process and Process Controls
Alglucosidase alfa (rhGAA) is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) cell line. The manufacture of rhGAA is based on a master cell bank and a working cell bank, where 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 the absence of adventitious agents/viral contaminants. Genetic testing (DNA sequencing, restriction endonuclease mapping, and plasmid copy number analysis) also demonstrated genetic stability of the DNA encoding rhGAA in the master cell bank and working cell bank through to the End of Production (EOP) cells in the cell culture process.
The manufacture of rhGAA comprises a series of steps which include fermentation, harvest, and purification. The purification is performed via a combination of filtration, chromatography, and viral inactivation/removal steps. The consistency of the manufacturing process is ensured through defined production procedures, critical quality tests, in-process limits, and rhGAA drug substance release specifications. Microbial control is maintained throughout the manufacturing process and is demonstrated by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during the manufacture were reviewed and are considered acceptable.
The biologically sourced materials are considered suitable and meet standards for their intended use. The specifications of the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization and biochemical studies were performed to provide assurance that rhGAA consistently exhibits the characteristic structure and biological activity. Results from the process validation studies also indicate that the methods used during processing adequately control the levels of product- and process-related impurities. The impurities reported and characterized are within established limits.
The sponsor has shown that rhGAA manufactured at different scales is comparable.
Control of Drug Substance
Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of rhGAA. The drug substance specifications and the analytical methods used for quality control of rhGAA are considered acceptable. Data from lots produced at both scales were reviewed and considered to be acceptable according to the drug substance release specifications.
Stability
Based upon the real-time and accelerated stability data submitted, the proposed shelf-life and storage conditions for rhGAA are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Myozyme® (alglucosidase alfa) is a common form of the human enzyme acid
a-glucosidase and is produced by recombinant DNA technology.
Myozyme®, 50 mg/vial, is a sterile, white to off-white lyophilized cake or powder. Each single-use vial contains 50 mg of alglucosidase alfa (rhGAA) and the following non-medicinal ingredients: mannitol, polysorbate 80, sodium phosphate dibasic heptahydrate, and sodium phosphate monobasic monohydrate. The contents of each vial are reconstituted with 10.3 mL of Sterile Water for Injection (WFI) and subsequently diluted with saline prior to intravenous infusion. All excipients found in the drug product are acceptable for use in drugs by the Canadian Food and Drug Regulations. The compatibility of rhGAA with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Myozyme® is packaged in single-use glass vials with a bromobutyl or chlorobutyl stopper. No preservatives are present in the formulation.
Pharmaceutical Development
During the pharmaceutical development, changes were made to the formulation to reduce particulate formation in the reconstituted drug product. All lots used in the clinical trials submitted by the sponsor, were the proposed formulation presented in the submission. The selected formulation retains the potency and protein integrity of rhGAA during the proposed shelf-life.
There were also changes to the production scale of Myozyme®. Biochemical and functional studies demonstrated that the different scales were of comparable quality.
Manufacturing Process and Process Controls
Myozyme® is filled into vials using proper aseptic process techniques and conventional pharmaceutical equipment and facilities. The manufacturing facility is compliant with GMP (Good Manufacturing Practices) requirements. All manufacturing equipment, manufacturing steps, and in-process controls were adequately described in the submitted documentation and were found acceptable.
Control of Drug Product
Myozyme® is tested to verify its appearance, identity, purity, sterility and potency as well as the formulation-relevant parameters: concentration of rhGAA, particulate matter, osmolality and pH. The validation reports submitted for all analytical procedures used for release testing of the drug product are satisfactory and the specifications have been justified. Analytical testing results from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the results of the real-time and accelerated stability study data submitted, the proposed shelf-life of 24 months at 2-8°C for Myozyme® is considered acceptable.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of Myozyme® was not warranted since the facility was recently evaluated for another product produced by the company within the last three years. In addition, the company produces products of a similar nature to Myozyme® also abrogating the need to perform an OSE. 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 current GMP requirements.
3.1.4 Adventitious Agents Safety Evaluation
Harvest culture fluid from each lot is tested to ensure freedom of adventitious microorganisms (bacteria, mycoplasma and viral agents). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of animal origin used in the manufacturing process have been adequately tested to ensure freedom of adventitious agents. Appropriate test results were reported on material of bovine origin and the material complied with the guidance "Minimizing the Risk of Transmitting Animal Spongiform Encephalopathic Agents via Human and Veterinary Products". The excipients used in the drug product formulation were not of human or animal origin.
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Myozyme® has demonstrated that the drug substance and drug product can be consistently manufactured at both scales to meet the current 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
Non-clinical evaluation with in vivo models of Pompe's Disease has shown that Myozyme® is able to reverse biochemical and histopathological manifestations of the disease. Results of these studies show that Myozyme® removes accumulated glycogen from cardiac and skeletal muscle as measured by biochemical assay and histomorphometry.
3.2.2 Pharmacokinetics
Two findings from the pharmacokinetic (PK) studies in animals are pertinent to the clinical application of Myozyme®. Firstly, biodistribution of the drug was very low. Within one hour, an administered dose reached a maximum uptake with over 50% of the injected dose being unaccounted for in the tissues examined. The cumulative distribution was less than 1% of the injected dose within the distribution to the target organs. The percentage distribution to the heart was approximately five times greater than that to the muscles. This general pattern of distribution seems to be independent of the formulation. Secondly, the drug has a very short half-life of approximately 1-2 hours. The implications of the PK findings are that the exposure to the drug is entirely dependent on the length of time of the infusion.
3.2.3 Toxicology
The toxicity database for Myozyme® is complete and in accordance with ICH guidelines.
Single-dose Toxicity
The acute non-lethal dose of rhGAA administered by IV injection to rats or dogs was >100 mg/kg body-weight (bw) (the highest dose tested). There were no signs of toxicity observed in the rats, whereas tremors were observed in dogs 60 minutes post-dosing at dose levels of 10 and 100 mg/kg bw.
Repeat-dose Toxicity
Repeat-dose toxicity studies were conducted in rats, mice, and monkeys. High dose levels were selected as the maximum deliverable doses based on the potential for hypersensitivity reactions to treatment. Toxicokinetic evaluations performed for the individual studies indicated that sufficient exposure was achieved to permit conclusions to be made regarding safety.
Rats received dose levels of 1, 10, and 100 mg/kg bw, administered by IV injection for 4 weeks on a weekly basis. Anaphylactic responses were observed in the 100 mg/kg bw group following the third dose. As a result, all animals were then pre-treated with diphenhydramine (DPH). In spite of the pre-treatment, some animals at all dose levels exhibited hypersensitivity responses after the fourth dose. The only other findings were decreased body-weight gain for males in the 100 mg/kg bw group.
A second study was conducted in rats at dose levels ranging from 1 to 50 mg/kg bw. All animals were administered DPH prior to the third and fourth doses in an attempt to prevent the anticipated hypersensitivity response. In spite of pre-treatment with DPH, treatment-related deaths occurred at dose levels of 5 mg/kg bw and higher, and clinicalsigns consistent with a hypersensitivity response were observed at all dose levels tested. The mortalities were considered to be related to a hypersensitivity reaction. In addition, levels of aspartate aminotransferase (AST) and alanine aminotrasferase (ALT) were increased at dose levelsof 5 mg/kg bw and higher. Stomach lesions were observed at doses ≥1 mg/kg bw, in the form of dark or red areas of foci in the mucosa or diffusely red stomach mucosa. These findings were considered as a secondary effect in response to treatment.
Repeat-dose testing was conducted as well in mice for 4 weeks at dose levels of 1, 10 and 100 mg/kg bw, administered by IV injection for 4 weeks on a weekly basis. All animals were administered DPH prior to the third and fourth doses in an attempt to prevent the anticipated hypersensitivity response. There were no adverse, treatment-related effects observed at any dose level tested.
Studies were also carried out in monkeys. The animals received dose levels of 4, 20, and 100 mg/kg administered by IV injection every other week for 6 months, and 200 mg/kg administered by IV injection every other week for 3 months. The exposure at 200 mg/kg bw was determined to be 5.9 times higher than the highest clinical dose administered to humans. There were no adverse, treatment-related findings observed at any dose level tested. Measurement of rhGAA activity in the liver indicated that chronic administration of the test material may result in accumulation in the liver over time.
Carcinogenicity and Mutagenicity
Carcinogenicity studies and studies to assess the mutagenic potential of Myozyme® were not conducted. It is not anticipated that Myozyme® would be carcinogenic or mutagenic based on the structure of the drug substance (a recombinant human glycoprotein), its impurity profile, and the excipients in the final product. The biochemical properties of Myozyme® are well characterized 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 required.
Reproductive Toxicity
Fertility and embryofetal developmental studies were conducted in mice at dose levels of 10, 20, and 40 mg/kg bw. Female mice were dosed 2 weeks prior to mating through to day 8 of gestation, and were pre-treated with DPH from dosing day 7 continuing for the remainder of the dosing period. There were 2 mortalities in the 20 mg/kg bw group that were attributed to an anaphylactic-type reaction. Clinical observations indicative of a hypersensitivity reaction were observed after the 7th dose at all dose levels, which resolved after treatment with DPH. A decreased fertility index was observed in all groups. The decrease in fertility index did not indicate a dose-response pattern and was attributed to vehicle control, the intra-peritoneal (IP) administration of DPH, or stress of handling.
Epididymal sperm count was reduced in the 20 and 40 mg/kg bw groups. In addition, the percentage of abnormal sperm was increased in the 40 mg/kg bw group. A comparable reduction in sperm motility was observed in all groups and so was considered to be most likely attributed to IP administration of DPH. The impact of reduced sperm count and abnormal sperm on fertility could not be fully assessed due to the overshadowing effect of decreased sperm motility, observed at a similar incidence in the control and all treatment groups.
A follow-up study was conducted to investigate the effect of the rhGAA vehicle (20 mM sodium phosphate buffer at pH 6.2 containing 2% mannitol and 0.5% sucrose; or 2% mannitol and 0.005% polysorbate 80 in 25 mM sodium phosphate buffer), the IP administration of DPH, and the stress of handling on female fertility. In this study there was no effect on fertility index in any of the treatment groups. In addition, there were no adverse effects (AEs) on estrus cycling/fertility or caesarean section data. To conclude, treatment with rhGAA, vehicle, or DPH did not affect fertility in this study, however, based on the combined results of these two studies, it cannot be ruled out that rhGAA may affect fertility.
In a third study, pregnant mice were dosed from day 6 through to day 15 of gestation. There were no adverse, treatment-related maternal or embryofetal effects noted at all dose levels tested. The rhGAA activity analysis demonstrated that there was a dose-dependent increase in rhGAA in the adult liver and placenta, however there was very little rhGAA in the fetal liver suggesting that there was relatively little transport of rhGAA from the maternal circulation to the fetal circulation.
3.2.4 Summary and Conclusion
The non-clinical toxicity testing demonstrated that rhGAA was generally well-tolerated in mice, rats, and monkeys. However, results from the 4-week mouse and rat studies demonstrated the potential for anaphylactic-type hypersensitivity reactions. In addition, rhGAA resulted in reduced sperm count and an increase in the percent of abnormal sperm, thus potentially affecting fertility.
In conclusion, the non-clinical toxicology database was considered adequate to assess the safety profile of rhGAA. The study results support its use in humans, provided adequate safety precautions are taken.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
Pompe's Disease is a rare, autosomal recessive, progressive muscle disease, resulting from a deficiency of lysosomal GAA. This deficiency results in the accumulation of organelle-bound (lysosomal) and extra lysosomal glycogen. A build-up of glycogen occurs in various tissues, predominantly cardiac and respiratory tissue, which in turn leads to the development of cardiomyopathy and progressive muscle weakness, including respiratory dysfunction. Myozyme® is intended to act as an exogenous source of GAA for patients with Pompe's Disease.
The dose and dose regimen used in clinical studies was based on the pharmacodynamic (PD) data from the non-clinical program. No human bioequivalence or bioavailability studies have been conducted with Myozyme®, however, a number of single-dose PK and biodistribution studies were conducted throughout the non-clinical development. These included studies evaluating the PK parameters of various formulations and production scales of Myozyme®.
Safety and efficacy data obtained from two clinical trials (AGLU1602 and AGLU1702) weresubmitted to support this submission. Of note, the clinical trial AGLU1702 was ongoing at the time of the submission, and only an interim report containing the results of 15 of 21 patients was submitted.
3.3.2 Pharmacodynamics and Pharmacokinetics
PK/PD parameters were assessed in two studies, both of which included patients with infantile-onset Pompe's Disease. Pharmacodynamics were evaluated by measuring tissue GAA activity and glycogen content in quadricep muscle biopsies. GAA activity in skeletal muscle was measured at baseline and 12 weeks in both studies and at 52 weeks in the first study. In both studies, muscle GAA activity increased during treatment with Myozyme®. Glycogen content was measured both biochemically and histomorphometically in the biopsies taken from patients at the timelines listed above. Skeletal muscle glycogen content was measured as the lack of lysosomal GAA in Pompe's Disease leads to the accumulation of glycogen in muscle. The quadricep muscle was chosen because proximal muscles, particularly in the lower extremities, are involved early in the course of the disease.
Two different assays were used to measure glycogen content. Firstly, a biochemical assay was used to quantitatively measure glycogen concentration in a three-dimensional piece of muscle tissue. This method measures glycogen present in muscle as well as in non-muscle cell types included in a biopsy sample. Secondly, histomorphometric analysis of glycogen content was performed using a proprietary image analysis system which quantitatively measures glycogen in the area of a 2-dimensional histologic section of muscle tissue.
Since neither the biochemical nor histomorphometric methods distinguish lysosomal from extra-lysosomal glycogen, histological examination of the muscle biopsies was performed via electron microscopy to confirm the presence of lysosomal and cytoplasmic glycogen.
Given the relatively small size of the biopsies, the known variability in muscle architecture from fibre to fibre as observed in the same histological field, and because of the fact that only a single muscle (quadricep) was sampled, these measurements do not reflect total body glycogen content and changes do not necessarily reflect the overall clinical progress of the patient.
Continued exposure to infusions of GAA resulted in increased levels of GAA activity in the tissues of interest. Activity in skeletal muscle increased above baseline, however, this increase was not proportional to dose. Higher tissue penetration was observed in the 40 mg/kg dose group as compared to the 20 mg/kg dose. Exposure concentration (AUC∞) decreased with time in the 40 mg/kg dose group but remained stable or increased in the 20 mg/kg dose group. The AUC∞ levels indicate what is left of the infusion circulating in the blood. Less means greater tissue penetration while more means less tissue penetration. The increase in GAA activity does not always translate into reduced glycogen levels.
Continued exposure to infusions of GAA eventually produced an immune response and increased levels of anti-rhGAA IgG antibodies. This did not seem to affect the response to rhGAA infusions. This process of enzyme infusion did not reach the potential expected of this approach probably due to very low penetration into the tissue, use of the 20 mg/kg dosing regimen, and the duration of infusion.
Further work needs to be done with respect to tissue penetration and determining the best approach and a longer half-life. The half-life of Myozyme® was estimated at 2.3 h for the recommended dose (20 mg/kg).
3.3.3 Clinical Efficacy
Study AGLU01602
Study AGLU01602 was a randomized, open-label, historically-controlled clinical trial of 18 infantile-onset patients aged 6 months or less at the onset of treatment. All patients were naive to enzyme replacement therapy. Patients received either 20 mg/kg or 40 mg/kg of Myozyme® every two weeks for a period of 52 weeks. The primary endpoint was the proportion of patients alive and free of invasive ventilator support at 18 months of age as compared to survival at 18 months of age in an untreated historical cohort of patients with Pompe's Disease.
After 52 weeks, patients treated with Myozyme® demonstrated prolonged invasive ventilator-free survival (83.3% [95% CI 66.1-100]) as compared to survival in an untreated historical cohort (1.9% [95% CI 0.0-5.5]). These results provide evidence of a consistent treatment advantage (hazard ratio < 1.0) for Myozyme® treatment relative to historical control.
Study AGLU01702
Study AGLU01702 was an open-label clinical trial that assessed the safety and efficacy of Myozyme® in 21 patients with infantile-onset Pompe's Disease who ranged in age from 6 months to 3.5 years at initiation of treatment. Patients received 20 mg/kg of Myozyme® every other week for 52 weeks. Efficacy data were available for the first 15 patients who completed 52 weeks of Myozyme®. The primary efficacy outcome was the proportion of patients alive at Week 52. After 52 weeks, 11 of 15 patients treated with Myozyme® were alive. In ten patients who were free of invasive-ventilator support at baseline, five patients remained so after 52 weeks of treatment.
The clinical benefits of Myozyme® for patients on ventilator support have not been determined. Within the first 12 months of treatment, 3 of 18 Myozyme®-treated patients in study AGLU01602 required invasive ventilatory support (17%, [95% CI 4-41]) and there were no deaths. With continued treatment beyond 12 months, four additional patients required invasive ventilatory support, after receiving between 13 and 18 months of Myozyme® treatment. Two of these four patients died after receiving 14 and 25 months of treatment, and after receiving 11 days and 7.5 months of invasive ventilatory support, respectively. Survival without invasive ventilatory support was substantiallygreater in the Myozyme®-treated patients in this study than would be expected compared to the poor survival of the historical control patients. At the 52-week interim analysis of study AGLU01702, of the five patients who were receiving invasive ventilatory support at baseline, one died and four remained on invasive ventilatory support at Week 52. Other efficacy parameters including motor function, cardiac status, and growth were evaluated in both studies AGLU01602 and AGLU01702:
Motor Function: In study AGLU01602, Alberta Infant Motor Scale (AIMS)-assessed gains in motor function occurred in 13 patients. In the majority of patients, motor function was substantially delayed compared to normal infants of comparable age. Two of nine patients who had demonstrated gains in motor function after 12 months of Myozyme treatment and continued to be followed regressed despite ongoing treatment.
Given the wide range of ages at initiation of treatment in study AGLU01702 (6.3 to 43.1 months of age), two instruments were used to evaluate motor function (AIMS and PDMS-2, the Peabody Development Motor Scale). One of the three (33.3%) patients with measurable motor age-equivalent scores at baseline achieved continuous gains in motor development as indicated by increases in AIMS motor performance age-equivalent scores across subsequent assessments. In contrast, none of the six patients with non-measurable motor performance age-equivalent scores at baseline made gains in motor development with treatment. A total of 13 patients had repeat evaluations up to at least Week 12 on the PDMS-2. Of these, six patients (46.1%) made consistent gains in age-equivalent scores on the Stationary, Locomotion, and/or Object Manipulation gross motor tests, indicating the continued development of gross motor skills during treatment with Myozyme®.
The continued effect of Myozyme® treatment over time on motor function is unknown.
Cardiac Status: Improvements in cardiomyopathy were observed in patients treated with Myozyme® in study AGLU01602. Consistent with the improvements in cardiomyopathy observed in patients treated with Myozyme® in study AGLU01602, treatment with Myozyme® in study AGLU01702 resulted in decreases in Left Ventricle Mass Index (LVMI) and Left Ventricular Mass Z-scores (LVM-Z). At baseline, mean LVMI was 205.9 g/m2 (range: 63.4, 417.6; N=14), which corresponded to a mean LVM-Z score of 6.7 (range: 2.2, 10.4; N=14). After 52 weeks of treatment, mean LVMI was 89.0 g/m2 (range: 48.2, 211.6; N=9) which corresponded to a mean LVM-Z score of 2.7 (range: -1.1, 7.2; N=9). These changes represented a mean decrease from baseline in LVMI of -48.0% at Week 52 (range: -82.4%,-1.1%). Treatment effects were evident by Week 8.
Growth: Fifteen of 18 patients (83.3%) in study AGLU01602 maintained or improved their weight-for-age percentiles (≥ the third percentile) during the 52-week treatment period. The three patients who failed to maintain normal weight had weight percentiles <3% prior to Myozyme® treatment. Moreover, 15 of the 16 patients (93.8%) who had body length measured at baseline maintained normal body length-for-age percentiles during the 52-week treatment period.
Weight and length were also measured at regular intervals during study AGLU01702. Twelve of 15 patients (80%) with repeat evaluations up to at least Week 12 showed maintained or improved weight-for-age percentiles (≥ the third percentile) from baseline to Week 52 (or last available assessment). Thirteen of 14 patients (92.8%) showed maintained or improved length-for-age percentiles to Week 52 (or last available assessment).
3.3.4 Clinical Safety
In clinical trials and expanded access programs with Myozyme, 92 of 280 (33%) patients treated with Myozyme have developed infusion-associated reactions.
Fifty-nine pediatric patients received 20 or 40 mg/kg of Myozyme® administered every other week in three separate clinical trials for a period of up to 76 weeks. These three studies included a population of patients which ranged in age from 1 month to 16 years at initiation of treatment. Twenty-nine of the 59 pediatric patients (49%) experienced infusion-associated reactions. Infusion-associated reactions that occurred in ≥5% of patients included urticaria, rash, rash maculopapular, pyrexia, rigors, oxygen saturation decreased, decreased blood pressure, increased blood pressure, increased heart rate, flushing, hypertension, cough, tachypnea, tachycardia, agitation, irritability, and vomiting. The most common treatment emergent adverse events (occurring in at least 18 of the 59 patients) (regardless of relationship) included upper respiratory tract infection, otitis media, cough, pyrexia, rash, diarrhea, vomiting, and oxygen saturation decreased
Serious hypersensitivity reactions, including anaphylactic reactions, were reported during Myozyme® infusion. One patient developed anaphylactic shock during Myozyme® infusion that required life-support measures. Eight of approximately 280 patients (3%) treated in clinical trials and EAPs with Myozyme® experienced significant hypersensitivity reactions as of April 12, 2006. One of 59 pediatric patients (approximately 2%) experienced a life-threatening hypersensitivity reaction consisting of bronchospasm, a decrease in oxygen saturation, tachycardia, urticaria, and periorbital oedema.
Testing for Myozyme-specific IgE antibodies was performed in 7 of 8 patients; 5 patients tested negative, 1 tested positive, and the results are pending for the remaining patient.
Pyrexia was the most frequently reported AE in the patients with infantile-onset Pompe's Disease and was also reported in patients with late-onset Pompe's Disease. Pyrexia is often associated with the various infections experienced by this patient population and was predominantly assessed as mild and not related to Myozyme®. Pyrexia was also reported as associated with infusions and was one of the frequently reported IAR terms.
During clinical trials for the infantile-onset pooled population (N=39), 15 of 25 (60.0%) patients who had hearing test assessments at baseline had bilateral or unilateral hearing loss, while 5 of 10 (50%) patients who had normal hearing at baseline tested abnormal at Week 26. In many patients, interpretation of hearing test results was complicated by the presence of middle ear dysfunction at baseline and/or at subsequent time points. These findings suggest that the hearing loss in patients with Pompe's Disease is related to the disease itself and is not a complication of therapy.
Other frequently reported AEs that were considered unrelated to Myozyme® were cough, diarrhea, vomiting, and increased tachycardia/heart rate and, in the patients with late-onset Pompe's Disease, headache.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
In clinical trials, Myozyme® was proven to be an effective medication in improving ventilator-free survival in patients with infantile-onset Pompe's Disease. The adverse reactions related to Myozyme® were described in the sponsor's trials and the comprehensive list of them is included in the Product Monograph. The demonstrated efficacy and acceptable safety profile support market authorization for Myozyme®. The benefit risk ratio of Myozyme® for the treatment of infantile-onset Pompe's Disease is judged favourable.
The following are post-marketing commitments by the sponsor:
- Enrollment of patients treated with Myozyme® into the registry established for long-term follow-up.
- In the registry of patients treated with Myozyme®, the sponsor will select the patients who participated in pivotal studies AGLU01602 and AGLU01702 and perform a follow-up evaluation regarding the primary and secondary end points.
- The information captured in the registry is to be provided to Health Canada for future assessment of the clinical benefits of Myozyme® in ventilator-dependent patients.
- The information captured in the registry is to be provided to Health Canada for future assessment of the safety of Myozyme®. All of the serious adverse events are to be reported including deaths, cardiac and respiratory complications, hypersensitivity and infusion reactions, as well as the effects of Myozyme® on potential hearing abnormalities.
- A semi-annual report of ongoing Genzyme-sponsored studies of Myozyme®, including survival and safety data will be provided to Health Canada.
- Submission to Health Canada of the final report of study AGLU01702 as S/NDS by Q1, 2007.
- To address Health Canada's comments regarding the Risk Management Plan for Myozyme®.
Priority Review status was granted for the evaluation of Myozyme® based on its significant increase in efficacy and significant decrease in risk compared to existing therapies, for a disease that is not adequately managed by a drug marketed in 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 Myozyme® is favourable for use in patients with Pompe's Disease (GAA deficiency). 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: Myozyme®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2005-08-03 |
| Request for priority status | |
| Filed: | 2005-10-11 |
| Approval granted: | 2005-11-09 |
| Submission filed: | 2005-12-29 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2006-02-15 |
| Review 1 | |
| Quality Evaluation complete: | 2006-08-11 |
| Clinical Evaluation complete: | 2006-08-11 |
| Labelling Review complete: | 2006-07-31 |
| NOC issued by Director General: | 2006-08-14 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| MYOZYME | 02284863 | SANOFI-AVENTIS CANADA INC | ALGLUCOSIDASE ALFA 50 MG / VIAL |