Myozyme (alglucosidase alfa) is a recombinant formulation of the human enzyme acid a-glucosidase (GAA), designed for intravenous infusion. The drug is designed to replace GAA deficiencies in patients with Pompe disease.
Myozyme is specifically indicated for the treatment of Pompe disease (GAA deficiency) in infants and pediatric patients.
Myozyme is supplied as a sterile, nonpyrogenic, white to off-white lyophilized cake or powder, designed for reconstitution for intravenous administration. The recommended initial dose of the drug is 20 mg/kg every 2 weeks via 4-hour IV infusion, administered by a medical professional. Infusions should be administered in a stepwise fashion; initial infusion rate should be no more than 1 mg/kg/hour with increases of up to 2 mg/kg/hour every 30 minutes thereafter, up to a maximum rate of 7 mg/kg/hr. Infusions may be slowed or temporarily halted based on severity of infusion reactions.
Approval of Myozyme was based on a pair of clinical trials, which enrolled a combined 39 patients with Pompe disease.
This international, multicenter, open-label study enrolled 18 patients, ages 7 months or less. Subjects were randomized to receive one of two doses of the drug (20 mg/kg or 40 mg/kg) every two weeks, with treatment duration of 52 to 106 weeks. The drug was shown to significantly improve survival in infants with Pompe disease, compared to historical baseline. Specifically, 12-month mortality for 61 infants born with the disease between 1982 and 2002 was 98% (n=6-/61); among subjects treated with Myozyme, no mortality was noted, and 17% (n=3/18) of subjects required invasive ventilatory support. For treatment beyond 12 months, 4 additional subjects required invasive ventilatory support, and 2 of these subjects died following 14 and 25 months of treatment, and after 11 days and 7.5 months of invasive ventilatory support. No additional mortality had occurred though median follow-up of 20 months. No differences in mortality outcome were noted between the two Myozyme dosing groups. Secondary efficacy measures included unblinded motor performance on the Alberta Infant Motor Scale (AIMS); in this measure, improvements in function occurred in 13 patients, though motor function remained substantially delayed for the majority of patients relative to healthy infants.
This ongoing, international, multicenter, non-randomized, open-label trial enrolled 21 Pompe patients, ages 3 months to 3.5 years at first treatment; 5 of these subjects were on invasive ventilatory support at treatment initiation. All subjects received 20 mg/kg Myozyme every other week for up to 104 weeks. Primary efficacy was measured by the portion of patients alive at treatment conclusion: at 52 weeks, 16 of 21 subjects were alive, 4 deaths occurred among patients free of invasive ventilator therapy at outset, with an additional 2 subjects requiring ventilation in this group. Among the 5 subjects on invasive ventilation at outset, 1 patient died and 4 remained on ventilation. These results were insufficient to determine the treatment effect of Myozyme.
Ongoing Study Commitments
b. To complete optimization and validation of CIM6 Pr binding
assay, Pompe fibroblast uptake/processing assay, and glycogen
hydrolysis kinetics test methods for drug substance and product
Final Report Submission: by March 31, 2007
c. To improve the isoaspartic acid (deamidation) content assay,
or to develop, validate, and implement an alternative more accurate
and precise assay.
Final Report Submission: by December 31, 2007
b. To revise the specification for the 5 landmark peaks in the
oligosaccharide mapping analysis.
Final Report Submission: by June 30, 2006
Adverse events associated with the use of Myozyme may include, but are not limited to, the following:
Infusion-related reactions, including serious anaphylactic reactions and anaphylactic shock, have been observed. These have included reactions considered life-threatening, which required life-support measures. Reactions included cardiovascular, respiratory and/or cutaneous symptoms. Careful monitoring of patient wellbeing and appropriate dos adjustment is essential, and appropriate support measures should be available when administering Myozyme.
Administration of Myozyme has been associated with acute respiratory failure requiring intubation and inotropic support; these reactions are possibly related to fluid overload.
Myozyme infusions should be administered through a central venous catheter, placement of which requires general anesthesia. Administration of general anesthesia in Pompe disease patients with cardiac hypertrophy has been associated with cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation. Appropriate caution and support measures should be taken when administering general anesthesia to these patients.
Myozyme is designed to act as an exogenous source of GAA, acting to correct GAA deficiency that is the hallmark of Pompe disease. Myozyme binds to mannose-6-phosphate receptors on the cell surface via carbohydrate groups on the GAA molecule, after which it is internalized and transported into Iysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in cleaving glycogen.
Zhu Y, Li X, McVie-Wylie A, Jiang C, Thurberg BL, Raben N, Mattaliano RJ, Cheng SH. Carbohydrate-remodelled acid alpha-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice. The Biochemical Journal 2005 Aug 1;389(Pt 3):619-28
Klinge L, Straub V, Neudorf U, Voit T. Enzyme replacement therapy in classical infantile pompe disease: results of a ten-month follow-up study. Neuropediatrics 2005 Feb;36(1):6-11
Klinge L, Straub V, Neudorf U, Schaper J, Bosbach T, Gorlinger K, Wallot M, Richards S, Voit T. Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial. Neuromuscular Disorders 2005 Jan;15(1):24-31. Epub 2004 Nov 26
Raben N, Fukuda T, Gilbert AL, de Jong D, Thurberg BL, Mattaliano RJ, Meikle P, Hopwood JJ, Nagashima K, Nagaraju K, Plotz PH. Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers. Molecular Therapy 2005 Jan;11(1):48-56
For additional information regarding Myozyme or Pompe disease, please visit the Myozyme web page.