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Myozyme (alglucosidase alfa)

Company: Genzyme
Approval Status: Approved April 2006
Treatment for: Pompe disease
Areas: Pediatrics

| General Information | Clinical Results | Side Effects | Mechanism of Action | Literature References | Additional Information |


General Information

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.


Clinical Results

FDA Approval
Approval of Myozyme was based on a pair of clinical trials, which enrolled a combined 39 patients with Pompe disease.

Study 1
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.

Study 2
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

  • Genzyme commits to completing the juvenile- and adult-onset Pompe disease study AGLU02704, entitled "A randomized, double-blind, multi-center, multinational, placebo-controlled study of the safety, efficacy and pharmacokinetics of Myozyme, recombinant human acid alpha-glucosidase (rhGAA), treatment in patients with late-onset Pompe disease."
    Protocol Submission: Completed
    Study Start: Completed
    Patient Enrollment: Completed
    Study Completion: September 30, 2007
    Final Report Submission: by May 31, 2008
  • Genzyme commits to conducting the extension to the juvenile- and adult-onset Pompe disease study AGLU02704 through 24 months (AGLU03206), entitled "An open-label extension study of patients with late-onset Pompe disease who were previously enrolled in protocol AGLU02704".
    Protocol Submission: Completed
    Study Start: Completed
    Patient Enrollment: by December 31, 2007
    Study Completion: by June 30, 2008
    Final Report Submission: by November 30, 2008
  • Genzyme commits to completing study AGLUOI702, entitled "An open-label, multi-center, multinational study of the safety, efficacy, pharmacokinetics, and pharmacodynamics of recombinant human acid alpha-glucosidase (rhGAA) treatment in patients 6 months and ~36 months old with infantile-onset Pompe disease (Glycogen Storage Disease Type II)."
    Protocol Submission: Completed
    Study Start: Completed
    Study Completion: by June 12, 2006
    Final Report Submission: by February 28, 2007
  • Genzyme commits to designing and implementing a registry of patients with Pompe disease being treated with alglucosidase alfa that will be established to obtain long-term clinical status information. Information will be collected on patient demographics, specifics of treatment with alglucosidase alfa, clinical status, ventilatory status, motor assessments, adverse events, assessment of immunogenicity, and potential effects of antibody formation. In patients who are less than one year of age at the start of treatment, information is to be collected on cognitive status, and auditory and visual screening assessments. This registry will be designed so that detailed clinical status information is collected at registry entry and on a 6- to 12-month basis for at least 15 years. Genzyme commits to conducting two sub-studies within the registry: one sub-study that will evaluate the effect of alglucosidase alfa on pregnancy and lactation, and one sub-study that will collect information on the clinical status of patients on ventilatory support at the time of entry into the registry. The registry data will be analyzed at yearly intervals and the results will be submitted in your annual reports for BB-IND 10780.
    Protocol Submission: September 29, 2006
    Study Start: March 31, 2007
    Final Report Submission: by September 30, 2022
  • Genzyme commits to designing and implementing an infantile-onset Pompe disease study to assess growth and development with treatment with alglucosidase alfa, in patients who are less than one year of age at study entry. This study is to include blinded assessments of growth (including standardized measurements of recumbent length, height, weight, and head circumference), developmental testing (the scales used need to be prospectively agreed upon), auditory and visual screening, neuro-imaging, and antibody assessments at 6- to 12- month intervals over a 10-year period.
    Protocol Submission: September 29, 2006
    Study Start: January 31, 2007
    Final Report Submission: by September 30, 2017
  • Genzyme commits to designing and implementing an immune tolerance protocol in Pompe disease patients who have significant antibody titers, or the presence of neutralizing antibody, and are failing treatment. Genzyme commits to designing and implementing a preventive immune tolerance protocol in Pompe disease patients at high risk for the development of significant immune responses to the product. This would involve 1) establishing the correlation among genotype, the level of a-glucosidase protein (non-enzymatic assay), and the presence and levels of binding, IgE, and neutralizing antibodies over time, using validated assays; and 2) developing an immune tolerance regimen that would be implemented before or concomitant with onset of therapy for those at high risk. Additionally, Genzyme commits to monitoring antibody positive patients, whose immune responses are not associated with loss of efficacy or severe hypersensitivity responses, at regular intervals over an extended period of time (i.e., 18-24 months) to specifically assess if a sub-population of patients become tolerant with routine treatment. Reports from preclinical studies to assess potential tolerance regimens and a commitment for timelines for a subsequent clinical study will be submitted to CDER by December 29, 2006.
    Protocol Submission: October 31, 2006
  • Genzyme commits to designing and implementing a dose- and dose-interval exploration study in patients with poor responses to treatment, regardless of antibody status. This study is to include patients in the infantile-, juvenile-, and adult-onset patient populations.
    Protocol Submission: September 29, 2006
    Study Start: January 31, 2007
    Final Report Submission: by September 30, 2009
  • Genzyme commits to initiate a 6-month intravenous chronic toxicity study of Myozyme in neonatal/juvenile mice.
    Study Start: September 29, 2006
    Final Report Submission: by September 30, 2007
  • Genzyme commits to submit the final report of Study 6354-163 titled "Intravenous Injection Study of Recombinant Human Acid-alfa-Glucosidase (rhGAA) on Female Fertility and Early Embryonic Development to Implantation in Mice".
    Final Report Submission: by June 30, 2006
  • Genzyme commits to conduct a Segment II. teratology study of Myozyme in rabbits. In the interest of clarity and precision for the data obtained, pretreatment of the animals with diphenhydramine should be avoided in the study.
    Final Report Submission: by June 30, 2007
  • Genzyme commits to conduct histopathology examination of the testes of male mice in 6354-155 titled "Intravenous Injection Study of Recombinant Human Acid alfa-Glucosidase (rhGAA) on Fertility and Early Embryonic Development to Implantation in Mice".
    Final Report Submission: by October 30, 2006
  • Genzyme commits to submit the data from the third Segment I. reproductive/toxicology study in mice. If necessary, Genzyme commits to submit an additional protocol for the study of the effects of Myozyme on spermatocytogenesis and spermiogenesis in male rabbits. In any future protocols, animals should be treated for a minimum of 90 days.
    Final Report Submission: by December 31, 2006
  • Genzyme commits to conduct a Segment III. prenatal and postnatal study in rats or mice.
    Study Start: Q3 2006
    Final Report Submission: by September 30, 2007
  • Regarding method validations:
    a. To complete validation of bis-mannose-6-phosphate (M6P) content and quantitative isoform distribution (cIEF) test methods for drug substance and/or product release.
    Final Report Submission: by December 31, 2006

    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 release.
    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

  • To provide a revised protocol for requalification and confirmation of stability of the primary and working reference standards that incorporates the new panel of validated methods.
    Protocol Submission: by July 31, 2006
  • Regarding the drug substance specifications:
    a. To re-evaluate the specification for NANA, and establish a limit for NGNA in the specification, following assay re-validation.
    Final Report Submission: by December 31, 2006

    b. To revise the specification for the 5 landmark peaks in the oligosaccharide mapping analysis.
    Final Report Submission: by June 30, 2006

  • To characterize the composition of the flocculent material observed after reconstitution of drug product and to investigate the nature of particle formation.
    Final Report Submission: by November 30, 2007
  • Validated stability indicating assays will be incorporated into the stability program (including accelerated stability on drug product, and after reconstitution and dilution).
    Final Report Submission: by June 30, 2007
  • To perform a study on formulated bulk drug product to confirm its hold time using the bis-M6P content assay and other stability-indicating assays.
    Final Report Submission: by November 30, 2007
  • To conduct bracketed, in use photostability studies on product diluted for infusion using current methods.
    Final Report Submission: by December 31, 2006
  • To provide interim summary reports regarding progress of CMC post marketing commitments every 6 months after licensure.
  • To provide information from a validated cell-based neutralizing antibody assay to evaluate the potential effect of GAA antibody on mannose-6-phosphate receptor dependent enzyme uptake using human fibroblast cells.
    Final Report Submission: by June 30, 2006
  • To provide results using the validated inhibition of enzyme uptake into human fibroblast assay from all patients in Studies AGLU01602 and AGLUOI 702, as well as all patients in clinical studies or the expanded access program for Myozyme who have become invasively ventilated since February 2, 2006.
    Final Report Submission: by October 31, 2006.

Side Effects

Adverse events associated with the use of Myozyme may include, but are not limited to, the following:

  • Pyrexia
  • Diarrhea
  • Rash
  • Vomiting
  • Cough
  • Pneumonia
  • Otitis Media
  • Upper Respiratory Tract Infection
  • Gastroenteritis
  • Decreased Oxygen Saturation
  • Diaper Dermatitis
  • Pharyngitis

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.


Mechanism of Action

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.


Literature References

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


Additional Information

For additional information regarding Myozyme or Pompe disease, please visit the Myozyme web page.




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Myozyme Drug Information

The Myozyme drug information shown above is licensed from Thomson CenterWatch. The information provided here is for general educational purposes only and does not constitute medical or pharmaceutical advice which should be sought from qualified medical and pharmaceutical advisers.





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