The safety and efficacy of Myozyme® were assessed in two separate clinical trials involving a total of 39 patients with Pompe disease who ranged in age from 1 month to 3.5 years at the time of their first infusion.1, 2, 4
A placebo group was not included in the infantile trials because it was deemed unethical in these critically ill infants. Instead, a historical comparator of Pompe patients of similar age and disease severity was derived from a retrospective infantile-onset natural history study.3
Study 1: Improved ventilator-free survival in infants with rapidly progressive disease1,2
Study design and patient characteristics
Study 1 was an open-label, international multicenter trial of 18 infantile-onset patients aged 7 months or less at the onset of treatment. 1,2
- All patients had cardiomyopathy (left ventricular mass index [LVMI] ≥ 65 g/m2 determined by echocardiography), minimal GAA activity, and did not require ventilator use at study entry.
- Patients were randomized into two equal groups to receive either 20 mg/kg or 40 mg/kg of Myozyme every two weeks, with length of treatment ranging from 52 to 106 weeks.
For the historical cohort, 61of 168 untreated patients born between 1982 and 2002 and diagnosed with infantile-onset Pompe disease by 6 months of age were identified by a retrospective review of medical charts.3
- Efficacy was assessed by comparing the proportion of Myozyme-treated patients alive and free of invasive ventilator support at 18 months of age to the proportion of patients alive in the historical cohort of patients of similar age and disease severity.
- After 52 weeks of treatment 15 of 18 (83%) patients achieved the clinical outcome measure of ventilator-free survival (95% confidence interval: 66-100%), thus 3 of 18 (17%) patients required invasive ventilator support (95% confidence interval 4-41%) – See Chart 1 below.
- Only 1 of 61 historical control patients survived to 18 months of age (98% mortality).
- Clinical responses were similar between patients who received 20 mg/kg versus 40 mg/kg of Myozyme.
- After 13 to 18 months of treatment, four additional patients required invasive ventilatory support. Two of these four patients died, one after 14 months of treatment and 11 days of ventilatory support, and one after 25 months of treatment and 7.5 months of invasive ventilatory support.
- The remaining 16 patients (two on ventilatory support) have survived through a median follow-up of 20 months.
- Survival without invasive ventilatory support was substantially greater in the Myozyme-treated patients in this study than would be expected compared to the poor survival of the historical control patients.
Improved ventilator-free survival
Improvement in cardiac measurements
- By Week 52, mean LVMI had decreased from
193.4 g/m2 (range 59.3, 301.8 g/m2; N = 15) at Baseline to 86.8 g/m2 (range 44.9, 157.3 g/m2; N = 15) at Week 52, which corresponded to a mean LVM Z-score of 3.3 (range 0.7, 6.3) (see figure below).
- The mean decrease in LVMI in the 14 patients with data at both Baseline and Week 52 was 118 g/m2, range 45-193 g/m2, corresponding to a decrease from Baseline of approximately 60%.
- The magnitude of the decrease in LVMI did not correlate with the clinical outcome measure of ventilator-free survival.
Gains in motor function
- 13 of 18 (72%) patients treated with Myozyme demonstrated gains in motor function as assessed by the Alberta Infant Motor Scale (AIMS). In the majority of patients, motor function remained substantially delayed compared to normal infants of comparable age.
- The continued effect of Myozyme treatment on motor function over time is not known.
- 2 of 9 patients who demonstrated gains in motor function after 12 months of treatment later regressed despite ongoing treatment.
Study 2: Results in patients with rapidly progressive, more advanced disease1,4
Study design and patient characteristics
Study 2 was an international, multicenter, non-randomized, open-label clinical trial. Unlike Study 1, patients on ventilatory support were not excluded and the population included patients who began treatment later, with the age at first Myozyme infusion ranging from 3 months to 3.5 years.
- 21 patients were treated.
- At baseline, all patients had cardiomyopathy and minimal GAA activity and 5 patients were on invasive ventilatory support.
- Patients initially received 20 mg/kg of Myozyme every other week for 26 weeks. Dose could be increased to 40 mg/kg after 26 weeks of treatment, if certain clinical criteria were met.
- The primary outcome measure was the proportion of patients alive at the conclusion of treatment.
- After 52 weeks of treatment, 16 of 21 patients were alive (76% survival).
- 16 patients were free of invasive ventilatory support at the time of first infusion: of these, 4 died, 2 required invasive ventilatory support, and 10 were free of invasive ventilatory support after 52 weeks of treatment.
- For the 5 patients who were receiving invasive ventilatory support at baseline, 1 died, and 4 remained on invasive ventilatory support at Week 52.
- The status of patients at Week 52 overlapped with that of an untreated group of patients, and no effect of Myozyme treatment could be determined. Study 1 and 2:
Safety Results: Study 1 and 2 1
The most common adverse reactions requiring intervention were infusion reactions. Twenty of 39 patients (51%) treated with Myozyme in the studies above developed infusion reactions.
|Summary of Outcomes for Infants Treated with Myozyme
||Study 1 (n=18)2
||Study 1 Extension (n=16)5
||Study 2 (n=21)4
|Initiation of ERT
||< 6 months of age at start of treatment
||< 7 months of age at the start of treatment
||6-36 months of age at the start of treatment
||100% at 18 months of age
||94% at 24 months of age
72% at 36 months of age
|71% at study end
|Survival without invasive ventilator support
||83% at 18 months of age
||67% at 24 months of age
49% at 36 months of age
|44% remained free of invasive ventilation at the study end
|Cardiac response / Decrease in LVM
||100% showed reduction in LVM
||94% showed reduction in LVM
||81% showed reduction in LVM
|Measurable motor gains
||72% demonstrated motor development gains
||61% demonstrated motor developement gains
||62% demonstrated motor development gains
For more information related to adverse reactions to Myozyme, see Table 2. Summary of Adverse reactions by System organ Class and Preferred Term Occuring in at least 20% of patients Treated with Myozyme in Clinical Trials in the Full Prescribing Information for Myozyme.
MYOZYME (alglucosidase alfa) is a lysosomal glycogen-specific enzyme indicated for use in patients with Pompe disease (GAA deficiency). MYOZYME has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of MYOZYME in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy.
Important Safety Information
WARNING: ANAPHYLAXIS, SEVERE ALLERGIC AND IMMUNE MEDIATED REACTIONS AND RISK OF CARDIORESPIRATORY FAILURE
Life-threatening anaphylactic reactions, severe allergic reactions and immune mediated reactions have been observed in some patients during MYOZYME infusions. Therefore, appropriate medical support should be readily available when MYOZYME is administered.
Risk of Cardiorespiratory Failure:
Patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation of their cardiac or respiratory compromise due to infusion reactions, and require additional monitoring.
Anaphylaxis and Allergic Reactions: Anaphylaxis and severe allergic reactions have been reported in some patients during and up to three hours after MYOZYME infusion, some of which were IgE-mediated. Some of the reactions were life-threatening and included: anaphylactic shock, cardiac arrest, respiratory distress, hypotension, bradycardia, hypoxia, bronchospasm, throat tightness, dyspnea, angioedema, and urticaria. Interventions have included: cardiopulmonary resuscitation, mechanical ventilatory support, oxygen supplementation, intravenous (IV) fluids, hospitalization, treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids.
In clinical trials and postmarketing safety experience with MYOZYME, approximately 1% of patients developed anaphylactic shock and/or cardiac arrest during MYOZYME infusion that required life-support measures. In clinical trials and expanded access programs with MYOZYME, approximately 14% of patients treated with MYOZYME have developed allergic reactions that involved at least 2 of 3 body systems, cutaneous, respiratory or cardiovascular systems. These events included: Cardiovascular: hypotension, cyanosis, hypertension, tachycardia, ventricular extrasystoles, bradycardia, pallor, flushing, nodal rhythm, peripheral coldness; Respiratory: tachypnea, wheezing/bronchospasm, rales, throat tightness, hypoxia, dyspnea, cough, respiratory tract irritation, decreased oxygen saturation; Cutaneous: angioedema, urticaria, rash, erythema, periorbital edema, pruritus, hyperhidrosis, cold sweat, livedo reticularis.
If anaphylactic or other severe allergic reactions occur, immediate discontinuation of the administration of MYOZYME should be considered, and appropriate medical treatment should be initiated. Because of the potential for severe allergic reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when MYOZYME is administered. The risks and benefits of re-administering MYOZYME following an anaphylactic or severe allergic reaction should be considered. Some patients have been rechallenged and have continued to receive MYOZYME under close clinical supervision. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product
Immune Mediated Reactions: Severe cutaneous and systemic immune mediated reactions have been reported in postmarketing safety experience with MYOZYME in at least 2 patients, including ulcerative and necrotizing skin lesions, and possible type III immune mediated reactions. These reactions occurred several weeks to 3 years after initiation of MYOZYME infusions. Skin biopsy in one patient demonstrated deposition of anti-rh-GAA antibodies in the lesion. Another patient developed severe inflammatory arthropathy in association with fever and elevated erythrocyte sedimentation rate. Nephrotic syndrome secondary to membranous glomerulonephritis was observed in a few Pompe patients treated with alglucosidase alfa and who had persistently positive anti-rhGAA IgG antibody titers. In these patients renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis. Patients should be monitored for the development of systemic immune mediated reactions involving skin and other organs while receiving MYOZYME. If immune mediated reactions occur, discontinuation of the administration of MYOZYME 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 successfully been rechallenged and have continued to receive alglucosidase alfa under close clinical supervision.
Risk of Acute Cardiorespiratory Failure: Acute cardiorespiratory failure requiring intubation and inotropic support has been observed up to 72 hours after infusion with MYOZYME in infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of MYOZYME. Patients with acute underlying respiratory illness, compromised cardiac function and/or sepsis may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during MYOZYME infusion, and infants with cardiac dysfunction may require prolonged observation times that should be individualized based on the needs of the patient.
Risk of Cardiac Arrhythmia and Sudden Cardiac Death During General Anesthesia for Central Venous Catheter Placement: Administration of general anesthesia can be complicated by the presence of severe cardiac and skeletal (including respiratory) muscle weakness. Therefore, caution should be used when administering general anesthesia for the placement of a central venous catheter intended for MYOZYME infusion. Ventricular arrhythmias and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in infantile-onset Pompe disease patients with cardiac hypertrophy during general anesthesia for central venous catheter placement.
Infusion Reactions: Infusion reactions occurred in 20 of 39 (51%) of patients treated with MYOZYME in clinical studies. Severe infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: fever, decreased oxygen saturation, tachycardia, cyanosis and hypotension. Other infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturation, vomiting, tachypnea, agitation, increased blood pressure/hypertension, cyanosis, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness and wheezing. Some patients were pre-treated with antihistamines, antipyretics and/or steroids. Infusion reactions occurred in some patients after receiving antipyretics, antihistamines, or steroids. Infusion reactions may occur at any time during, or up to 2 hours after, the infusion of MYOZYME, and are more likely with higher infusion rates. The risks and benefits of re-administering MYOZYME following an anaphylactic or severe allergic reaction should be considered. Some patients have been rechallenged and have continued to receive MYOZYME under close clinical supervision. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.
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 reactions. Therefore, these patients should be monitored more closely during administration of MYOZYME. Patients with an acute illness at the time of MYOZYME infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient’s clinical status prior to administration of MYOZYME. If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. If severe infusion or allergic reactions occur, immediate discontinuation of the administration of MYOZYME should be considered, and appropriate medical treatment should be initiated.
Monitoring: Laboratory Tests: Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. Testing for IgG titers may also be considered if patients develop allergic or other immune mediated reactions. Patients who experience anaphylactic or allergic reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis.
The most serious adverse reactions reported with MYOZYME were anaphylactic reactions, acute cardiorespiratory failure, and cardiac arrest. Anaphylactic reactions have been reported during and within 3 hours after MYOZYME infusion. Acute cardiorespiratory failure has been observed in a few infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa. Infusion reactions, defined as an adverse reaction occurring during the infusion or within 2 hours after completion of the infusion, that occurred in more than 1 patient in clinical studies and the expanded access program include rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturations, vomiting, tachypnea, agitation, increased blood pressure/hypertension, cyanosis, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness, and wheezing. In addition to the infusion reactions reported in clinical trials and expanded access programs, the following infusion reactions have been reported in patients during postmarketing use of MYOZYME: cardiac arrest, respiratory arrest, apnea, stridor, pharyngeal edema, peripheral edema, chest pain, chest discomfort, muscle spasm, fatigue and conjunctivitis. Additional adverse drug reactions included proteinuria and nephrotic syndrome.
Immunogenicity: The majority of patients (34 of 38; 89%) in the two clinical trials tested positive for IgG antibodies to alglucosidase alfa. Most patients who develop antibodies do so within the first 3 months of exposure. There is evidence to suggest that patients developing sustained titers =12,800 of anti-alglucosidase alfa antibodies may have a poorer clinical response to treatment, or may lose motor function as antibody titers increase. Five patients with antibody titers = 12,800 at Week 12 had an average increase in clearance of 50% from Week 1 to Week 12. The effect of antibody development on the long-term efficacy of MYOZYME is not fully understood. However, CRIM-negative infants have shown poorer clinical response in the presence of high sustained IgG antibody titers and inhibitory and positive inhibitory antibodies. Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions. Therefore, these patients should be monitored more closely during administration of MYOZYME.
To report suspected adverse reactions contact Genzyme Medical Information at 800-745-4447, option 2.
Please see full prescribing information for complete details, including boxed warning.
Myozyme Prescribing Information (June 2010)
Kishnani P, Corzo D, Nicolino M, et al. Recombinant human acid a-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007; 68:99-109.
Kishnani PS, Hwu-W-L, Mandel H, et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 2006;148:671-676.
Nicolino M, Byrne B, Wraith JE, et al. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med. 2009;11(3):210-219.
Kishnani P, Corzo D, Leslie N, Gruskin D, van der Ploeg A, Clancy J, et al. Early treatment with alglucosidase alfa prolongs long term survival of infants with Pompe disease. Pediatr Res 2009;66:329-35