1. Name Of The Medicinal Product
Myozyme 50 mg powder for concentrate for solution for infusion
2. Qualitative And Quantitative Composition
One vial contains 50 mg of alglucosidase alfa.
After reconstitution, the solution contains 5 mg of alglucosidase* alfa per ml and after dilution, the concentration varies from 0.5 mg to 4 mg/ml.
*Human acid α-glucosidase is produced in Chinese hamster ovary cells (CHO) by recombinant DNA technology.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for concentrate for solution for infusion.
White to off-white powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Myozyme is indicated for long-term enzyme replacement therapy (ERT) in patients with a confirmed diagnosis of Pompe disease (acid α-glucosidase deficiency).
Myozyme is indicated in adults and paediatric patients of all ages.
In patients with late-onset Pompe disease the evidence of efficacy is limited (see section 5.1).
4.2 Posology And Method Of Administration
Myozyme treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases.
Posology
The recommended dose regimen of alglucosidase alfa is 20 mg/kg of body weight administered once every 2 weeks.
Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease.
Paediatric and elderly population
There is no evidence for special considerations when Myozyme is administered to paediatric patients of all ages or elderly patients.
Renal and hepatic impairment
The safety and efficacy of Myozyme in patients with renal or hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.
Method of administration
Myozyme should be administered as an intravenous infusion.
Infusions should be administered incrementally. It is recommended that the infusion begin at an initial rate of 1 mg/kg/h and be gradually increased by 2 mg/kg/h every 30 minutes if there are no signs of infusion associated reactions (IARs) until a maximum rate of 7 mg/kg/h is reached. IARs are described in section 4.8.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Life threatening hypersensitivity (anaphylactic reaction) to the active substance or to any of the excipients, when rechallenge was unsuccessful (see sections 4.4 and 4.8).
4.4 Special Warnings And Precautions For Use
Hypersensitivity/Anaphylactic reactions
Serious and life-threatening anaphylactic reactions, including anaphylactic shock, have been reported in infantile- and late-onset patients during Myozyme infusions (see section 4.8). Because of the potential for severe infusion associated reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered. If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of Myozyme infusion should be considered and appropriate medical treatment should be initiated. The current medical standards for emergency treatment of anaphylactic reactions are to be observed.
Infusion Associated Reactions
Approximately half of the patients treated with Myozyme in infantile-onset clinical studies and 28% of the patients treated with Myozyme in a late-onset clinical study developed infusion associated reactions (IARs). IARs are defined as any related adverse event occurring during the infusion or during the hours following infusion. Some reactions were severe (see section 4.8). A tendency was observed in infantile patients treated with a higher dose (40 mg/kg) to experience more symptoms when developing IARs. Infantile onset patients who develop high antibody titres appear to be at higher risk for developing more frequent IARs. Patients with an acute illness (e.g. pneumonia, sepsis) at the time of Myozyme infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient's clinical status prior to administration of Myozyme. Patients should be closely monitored and all cases of IARs, delayed reactions and possible immunological reactions should be reported to the marketing authorisation holder.
Patients who have experienced IARs (and in particular anaphylactic reactions) should be treated with caution when re-administering Myozyme (see sections 4.3 and 4.8). Mild and transient effects may not require medical treatment or discontinuation of the infusion. Reduction of the infusion rate, temporary interruption of the infusion, or pre-treatment, generally with oral antihistamine and/or antipyretics and/or corticosteroids, has effectively managed most reactions. IARs may occur at any time during the infusion of Myozyme or generally up to 2 hours after, and are more likely with higher infusion rates.
Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from infusion associated reactions. Therefore, these patients should be monitored more closely during administration of Myozyme.
Immunogenicity
In clinical studies, the majority of patients developed IgG antibodies to rhGAA typically within 3 months of treatment. Thus seroconversion is expected to occur in most patients treated with Myozyme. A tendency was observed for infantile-onset patients treated with a higher dose (40 mg/kg) to develop higher titers of antibodies. There does not appear to be a correlation between the onset of IARs and the time of IgG antibody formation. A limited number of the IgG positive patients evaluated tested positive for inhibitory effects on in vitro testing. Due to the rarity of the condition and the limited experience to date, the effect of antibody formation on safety and efficacy is currently not fully established. The probability of a poor outcome and of developing high and sustained antibody titers appears higher among CRIM-negative patients (Cross Reactive Immunologic Material; patients in whom no endogenous GAA protein was detected by Western blot analysis) than among CRIM-positive patients (patients in whom endogenous GAA protein was detected by Western blot analysis). However, high and sustained antibody titers also occur in some CRIM-positive patients. The cause of a poor clinical outcome and of developing high and sustained antibody titers is thought to be multi-factorial. IgG antibody titers should be regularly monitored.
Patients who experience hypersensitivity reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis. Patients who develop IgE antibodies to Myozyme appear to be at a higher risk for the occurrence of IARs when Myozyme is re-administered (see section 4.8). Therefore, these patients should be monitored more closely during administration of Myozyme. Some IgE positive patients were successfully rechallenged with Myozyme using a slower infusion rate at lower initial doses and have continued to receive Myozyme under close clinical supervision.
Transient nephrotic syndrome
Transient nephrotic syndrome which resolved following temporary interruption of ERT was observed in one patient with infantile-onset Pompe disease who received very frequent dosing of rhGAA (10 mg/kg 5 times weekly) over an extended period.
Immune complex-mediated reactions
Severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa, including ulcerative and necrotizing skin lesions (see section 4.8). Patients should be monitored for signs and symptoms of systemic immune complex-mediated reactions involving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactions occur, discontinuation of the administration of alglucosidase alfa should be considered and appropriate medical treatment initiated. The risks and benefits of re-administering alglucosidase alfa following an immune-mediated reaction should be considered. Some patients have been successfully rechallenged and continued to receive alglucosidase alfa under close clinical supervision.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interactions studies have been performed. Because it is a recombinant human protein, alglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.
4.6 Pregnancy And Lactation
Pregnancy
There are no data from the use of alglucosidase alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Myozyme should not be used during pregnancy unless clearly necessary.
Breast-feeding
Alglucosidase alfa may be excreted in breast milk. Because there are no data available on effects in neonates exposed to alglucosidase alfa via breast milk, it is recommended to stop breast-feeding when Myozyme is used.
Fertility
There are no clinical data on the effects of alglucosidase alfa on fertility. Preclinical data did not reveal any significant adverse findings (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. Because dizziness has been reported as an infusion associated reaction, this may affect the ability to drive and use machines on the day of the infusion.
4.8 Undesirable Effects
Infantile-onset Pompe disease
In clinical trials, 39 infantile-onset patients were treated with Myozyme for more than three years (168 weeks with a median of 121 weeks; see section 5.1). Adverse reactions reported in at least 2 patients are listed in Table 1 by System Organ Class. Adverse reactions were mostly mild to moderate in intensity and almost all occurred during the infusion or during the 2 hours following the infusion (infusion associated reactions, IARs). Serious infusion reactions including urticaria, rales, tachycardia, decreased oxygen saturation, bronchospasm, tachypnea, periorbital edema and hypertension have been reported.
Late-onset Pompe disease
In a placebo-controlled study lasting 78 weeks, 90 patients with late-onset Pompe disease, aged 10 to 70 years, were treated with Myozyme or placebo randomized in a 2:1 ratio (see section 5.1). Overall, the numbers of patients experiencing adverse reactions and serious adverse reactions were comparable between the two groups. The most common adverse reactions observed were IARs. Slightly more patients in the Myozyme group than in the placebo group experienced IARs (28% versus 23%). The majority of these reactions were non-serious, mild to moderate in intensity and resolved spontaneously. Adverse reactions reported in at least 2 patients are listed in Table 1. Serious adverse reactions reported in 4 patients treated with Myozyme were: angioedema, chest discomfort, throat tightness, non-cardiac chest pain and supraventricular tachycardia. Reactions in 2 of these patients were IgE-mediated hypersensitivity reactions.
Table 1: Adverse reactions (reported in at least 2 patients) and adverse reactions reported in post-marketing setting, expanded access programs and non-controlled clinical trials, per System Organ Class, presented by frequency categories: very common (
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1 Reactions reported in 39 infantile-onset patients in 2 clinical trials
2 Reactions reported in 60 late-onset patients in a placebo-controlled clinical trial
3 Reactions reported more frequently in the placebo group than in the Myozyme group in late-onset patients
4 Additional adverse reactions from post-marketing, expanded access programs and non-controlled clinical trials.
A small number of patients (<1%) in clinical trials and in the commercial setting developed anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life-support measures. Reactions generally occurred shortly after initiation of the infusion. Patients presented with a constellation of signs and symptoms, primarily respiratory, cardiovascular, edematous and/or cutaneous in nature (see section 4.4).
Patients with moderate to severe or recurrent IARs have been evaluated for Myozyme specific IgE antibodies; some patients tested positive including some who experienced an anaphylactic reaction.
Severe cutaneous reactions, possibly immune-mediated, have been reported with alglucosidase alfa including ulcerative and necrotizing skin lesions (see section 4.4).
4.9 Overdose
There is no experience with overdose of alglucosidase alfa. In clinical studies doses up to 40 mg/kg body weight were used.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes.
ATC code: A16AB07.
Pompe disease
Pompe disease is a rare, progressive and fatal metabolic myopathy with an estimated global incidence of 1 in 40,000 births. Other names for Pompe disease include glycogen storage disease type II (GSD-II), acid maltase deficiency (AMD) and glycogenosis type II. Pompe disease belongs to the lysosomal storage disorders as it is caused by a deficiency of a naturally-occurring lysosomal hydrolase, acid α-glucosidase (GAA) that degrades lysosomal glycogen to glucose. Deficiency of this enzyme leads to glycogen accumulation in various tissues, particularly cardiac, respiratory and skeletal muscle, leading to the development of hypertrophic cardiomyopathy and progressive muscle weakness, including impairment of respiratory function.
The clinical presentation of Pompe disease can be described as a spectrum of disease which ranges from a rapidly-progressing infantile-onset form (onset of symptoms of Pompe disease typically within the first year of life and a very short expected life-span) to a less rapidly-progressing late-onset form.
The infantile-onset form of Pompe disease is characterised by massive deposition of glycogen in the heart, and skeletal muscle always resulting in rapidly progressive cardiomyopathy, generalised muscle weakness and hypotonia. Motor development is often completely arrested, or if motor milestones are achieved, they are subsequently lost. Death typically occurs due to cardiac and/or respiratory failure before the age of one year.
In a retrospective natural history study in patients with infantile-onset Pompe disease (n=168), the median age at onset of symptoms was 2.0 months and the median age of death was 9.0 months. Kaplan-Meier survival rates at 12, 24 and 36 months of age were 26%, 9% and 7%, respectively.
A non-typical, more slowly progressive form of infantile-onset Pompe disease has been described which is characterised by a less severe cardiomyopathy and consequently a more prolonged survival.
The late-onset form of Pompe disease manifests during infancy, childhood, adolescence or even adulthood and is much less rapidly progressive than the infantile-onset form. Usually, it is characterised by the presence of sufficient residual GAA activity to preclude the development of cardiomyopathy, however some cardiac involvement has been reported in up to approximately 4% of patients with late-onset Pompe disease.
Patients with late-onset Pompe disease typically present with progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and varying degrees of respiratory involvement, ultimately progressing to profound disability and/or the need for ventilatory support. The time course of disease progression is extremely variable and not predictable, with some patients experiencing a rapid deterioration in skeletal and respiratory muscle function leading to loss of ambulation and respiratory failure, others progressing less rapidly, and yet others presenting with a dissociation in the progression of skeletal and respiratory muscle involvement.
It is postulated that Myozyme will restore lysosomal GAA activity resulting in stabilisation or restoration of cardiac and skeletal muscle function (including respiratory muscles). Due to the blood-brain barrier effect and the enzyme's size, uptake of alglucosidase alfa in the central nervous system is unlikely.
Infantile-onset Pompe disease; clinical trial in patients aged 6 months or less
The safety and efficacy of Myozyme was assessed in a pivotal, randomised, open-label, historically-controlled clinical trial of 18 non-ventilated infantile-onset patients aged 6 months or less at the onset of treatment. The untreated historical cohort was matched to the pivotal study population and was derived from a retrospective natural history study (n=42) in patients with infantile-onset Pompe disease. Patients were randomized to receive either 20 mg/kg or 40 mg/kg once every two weeks for a period of 52 weeks. After a minimum of 52 weeks, 16 of these 18 patients were enrolled in an extension study to receive continued treatment at the same dose for a total duration of up to three years (150 weeks).
The primary endpoint was the proportion of patients who were alive and free of invasive ventilator support. However, the invasive ventilator-free survival was not recorded in the untreated historical cohort and a comparison of this endpoint is not possible. After 52 weeks of treatment, all 18 patients treated with Myozyme were alive and 15 of these 18 patients were alive and free of invasive ventilatory support whereas 1 of 42 patients in the untreated historical cohort was alive at 18 months of age. Two patients died and did not enter into the extension study. After 104 weeks of treatment, all 16 patients who enrolled in the extension study were alive and 10 of these 16 patients were free of invasive ventilatory support. At the end of the study (with individual patient treatment durations ranging from 60 to 150 weeks; mean follow-up period of 119 weeks) 14 of 16 patients were alive and 9 of 16 patients were alive and free of invasive ventilatory support. One additional patient died after study end and another one after withdrawal from the study.
Comparison of survival curves from time of diagnosis versus the untreated historical cohort was made using a Cox proportional hazards regression analysis. Patients treated with Myozyme demonstrated prolonged survival as compared to survival in an untreated historical cohort (see Table 2).
Table 2: Results for endpoint survival using the Cox regression model
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Echocardiographic indices of cardiomyopathy improved as measured by a decrease in left ventricular mass (LVM). After 52 weeks of treatment, LVM decreased from baseline in all 14 patients with available data and was within normal limits in 3 of 14 patients. After the first year (64 up to 130 weeks) of treatment LVM further decreased in 8 patients. At 104 weeks of treatment LVM assessments were available for 8 patients, of which 5 decreased to within normal limits.
As measured by motor performance age-equivalent scores of the Alberta Infant Motor Scale (AIMS), seven of the 18 patients made motor development gains during the study and were walking independently by the last study assessment (with individual patient treatment durations ranging from 52 to 130 weeks; mean follow-up period of 94 weeks). An additional 4 patients made motor development gains during the study and were sitting independently by the last study assessment (with individual patient treatment durations ranging from 78 to 130 weeks; mean follow-up period of 110 weeks), although they did not have functional use of the legs. The remaining 7 patients made no clinically significant motor gains or were unable to sustain the motor gains made and had very limited motor movement by the last study assessment (with individual patient treatment durations ranging from 52 to 142 weeks; mean follow-up period of 103 weeks).
After 52 weeks of treatment 14 of 18 patients (77.8%) had maintained or improved weight-for-age percentiles (above the 3rd percentile), 14 of 15 patients (93.3%) were above the 3rd percentile for length and 12 of 15 patients (80.0%) were above the 3rd percentile for head circumference. In the second year of treatment, 15 out of 17 patients had further improved weight-for-age percentiles (with individual patient treatment durations ranging from 78 to 142 weeks; mean follow-up period of 111 weeks), 10 out of 16 patients had further improved length-for-age percentiles (with individual patient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 113 weeks) and 11 out of 15 patients had further improved head circumference-for-age percentiles (with individual patient treatment durations ranging from 90 to 130 weeks; mean follow-up period of 110 weeks). At 104 weeks of treatment, all 13 patients with available data had maintained or improved weight-for-age percentiles (above the 3rd percentile), all 12 patients with available data were above the 3rd percentile for length and all 12 patients with available data were above the 3rd percentile for head circumference.
Analyses of efficacy did not reveal meaningful differences between the 2 dose groups with respect to survival, invasive ventilator-free survival, any ventilator-free survival, decrease in LVM, gains in growth parameters and acquisition of motor milestones. Based on these results the 20 mg/kg qow dose is recommended.
Infantile-onset Pompe disease; clinical trial in patients aged 6 months to 3.5 years
A second open-label clinical trial also assessed the safety and efficacy of Myozyme in 21 patients with predominantly a non-typical form of infantile-onset Pompe disease who ranged in age from 6 months to 3.5 years at initiation of treatment. Patients received 20 mg/kg Myozyme once every two weeks for 52 weeks except for 8 patients who received 40 mg/kg after at least 26 weeks of treatment. After 52 weeks all patients continued treatment for a total duration of more than 3 years (168 weeks with a median of 121 weeks).
The primary endpoint of the pivotal trial was the proportion of patients who were alive. After 52 weeks of treatment, 16 of 21 patients (76.2%) treated with Myozyme were alive. After 104 weeks of treatment, 14 of 21 patients (66.7%) were alive and 1 patient was alive but had discontinued from the study. These proportions were maintained up to the end of the study (with individual patient treatment durations ranging from 1 to 168 weeks; mean follow-up period of 109 weeks). In the untreated historical cohort 5 of 47 patients (10.6%) for whom data were available, were alive at age 30 months (2.5 years).
Survival in the treated patients was compared to survival in a similar historical cohort of untreated subjects using a Cox proportional hazards regression analysis (See Table 3).
Table 3: Results for endpoint survival using the Cox regression model
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Additional efficacy data showed that of 16 patients who were free of invasive-ventilator support at baseline, 7 remained so after 104 weeks of treatment. The 9 remaining patients either died (5 patients) or became invasive-ventilator dependent (4 patients). All 5 patients who were receiving invasive ventilation at baseline continued to require ventilation throughout the study (4 patients survived beyond week 104 and one patient died).
After 52 weeks of treatment, LVM decreased from baseline in all 12 patients with available data and was within normal limits in 6 of 12 patients. After the first year (58 up to 168 weeks) of treatment LVM further decreased in 9 out of 12 patients with available data. At 104 weeks of treatment LVM assessments were available for 10 patients, of which 9 decreased to within normal limits.
After 52 weeks of treatment, 3 out of 8 patients with available data made gains in motor function over baseline as measured by raw scores and age-equivalent scores from baseline in the AIMS. Six of the 11 patients with available data continued to make motor development gains beyond Week 52 (with individual patient treatment durations ranging from 58 to 168 weeks; mean follow-up period of 121 weeks), including 3 patients ambulatory and 3 patients with only functional sitting skills by the last study visit. The remaining 5 patients showed no significant change in motor development beyond Week 52 (with individual patient treatment durations ranging from 104 to 168 weeks; mean follow-up period of 140 weeks), including 4 patients with no significant motor skills in any of the positions evaluated and 1 patient with only functional sitting skills by the last study visit.
The vast majority of patients with infantile-onset Pompe disease treated with Myozyme demonstrate improvement in cardiac function as well as stabilisation or improvements in growth parameters. However, motor and respiratory responses to treatment have been more variable.
Patients with infantile-onset Pompe disease who demonstrated motor gains, had greater preservation of motor function and lower glycogen content in the quadriceps muscle at baseline. It is noteworthy that a higher proportion of patients with better motor outcomes show stability or improvement in growth parameters (weight), while the large majority of patients, regardless of their motor outcomes or baseline features, show reversal of cardiomyopathy as measured by changes in LVM Z-score.
The totality of the data suggests that early diagnosis and treatment at an early stage of disease may be critical to achieve the best outcomes in these infantile onset patients.
Late-onset Pompe disease
The safety and efficacy of Myozyme was assessed in a randomized, double-blind, placebo-controlled study in 90 patients with late-onset Pompe disease who ranged in age from 10 to 70 years at initiation of treatment and were all naive to enzyme replacement therapy. Patients were randomized in a 2:1 ratio and received 20 mg/kg Myozyme (n=60) or placebo (n=30) once every two weeks for 78 weeks (18 months).
The co-primary efficacy outcome assessments were distance walked (meters) in 6 minutes (6-Minute Walk Test, 6MWT) and FVC (Forced Vital Capacity) % predicted in the sitting position. After 78 weeks, patients treated with Myozyme showed improvement in distance walked as measured by 6MWT and stabilization of pulmonary function as measured by FVC % predicted as compared to placebo-treated patients. The distance walked in 6 minutes increased by a median of 15.0 meters for Myozyme-treated patients and decreased by a median of 7.5 meters for placebo-treated patients, indicating a statistically significant Myozyme treatment effect compared to placebo (p=0.0283). The % predicted FVC changed by a median of 0.0 for Myozyme-treated patients and decreased by a median of 3% for placebo-treated patients, indicating a statistically significant treatment effect (p=0.0026). The results are shown in Table 4.
Table 4: Change from baseline: efficacy outcomes in the placebo-controlled study
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