Developments in the Treatment of Pompe Disease

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Disclosure:P.S.K. has received research/grant support and honoraria from Genzyme Corporation; P.S.K. is a member of the Pompe Disease Advisory Board for Genzyme Corporation. YTC has served as a consultant for Genzyme Corporation. rhGAA, in the form of Genzyme's product, Myozyme™, has now been approved by the US FDA and the EU as therapy for Pompe disease. Duke University and inventors for the method of treatment and predecessors of the cell lines used to generate the enzyme (rhGAA) used in these clinical trials may benefit financially pursuant to the University's Policy on Inventions, Patents and Technology Transfer.

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The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.


Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency, is a rare, debilitating, and often fatal lysosomal storage disease. It is caused by an autosomal recessively inherited deficiency of the enzyme acid α-glucosidase (GAA) that hydrolyzes glycogen to glucose in the lysosome; the deficiency causes the deposition of glycogen in multiple tissues, predominantly skeletal, smooth, and cardiac muscle. The age of onset and the symptoms vary considerably.1 All patients experience considerable morbidity and often early mortality, particularly in infantile onset Pompe disease. Until recently, the natural history of infantile onset Pompe disease was uniformly poor with death occurring usually by one year of age from cardiomyopathy or respiratory failure. Clinical management thereby consisted solely of palliative care.2,5

Myozyme® (alglucosidase-α, Genzyme, Cambridge MA) has recently been approved for use for the treatment of Pompe disease.3 Enzyme replacement therapy with Myozyme has been demonstrated to improve overall survival and ventilator-free survival, reverse cardiomyopathy and improve motor development in infants with Pompe disease.4 Myozyme is the first approved treatment for the to 10,000 children and adults currently affected by Pompe disease.

Description of the Compound

Myozyme consists of the human enzyme acid α-glucosidase (rhGAA) produced by recombinant DNA technology in a Chinese hamster ovary cell line. It degrades glycogen by catalyzing the hydrolysis of alpha 1, 4 and alpha 1, 6 glycosidic linkages of lysosomal glycogen. Myozyme is a glycoprotein with a calculated mass of 99,377 daltons for the polypeptide chain with a total mass of approximately 109,000 daltons. It is infused intravenously and is supplied as a sterile, nonpyrogenic, white, lyophilized powder for reconstitution with 10.3ml sterile water for injection.3

Myozyme provides an exogenous source of GAA. It binds to mannose-6-phosphate receptors on the cell surface via the carbohydrate groups on the molecule. It is subsequently internalized and transported into lysosomes where it undergoes proteolytic cleavage to its mature form resulting in increased enzymatic activity able to cleave glycogen.3Efficacy

The efficacy of Myozyme was assessed in two clinical trials in 39 patients with Pompe disease, from one month to 3.5 years of age at enrollment.


The pivotal study was an international, multicenter, open-label, clinical trial of 18 infantile-onset Pompe disease patients age 4 Efficacy was assessed by comparing the proportions of Myozyme-treated patients who died or needed invasive ventilator support, with the mortality of a historical cohort of untreated infantile-onset Pompe patients of similar age and disease severity. The historical cohort consisted of 61 untreated patients with infantile-onset Pompe disease diagnosed by age six months.5 By the age of 18 months, there was 98% mortality in the historical control group, indicating the uniformly poor outcome of patients who are untreated.

Within the first 12 months of treatment, three of 18 Myozyme-treated patients required invasive ventilatory support [17% (4-41%; 95% CI)]; there were remarkably no deaths in this same time period. With continued treatment beyond 12 months, four additional patients required invasive ventilatory support; and only two of these four patients died after receiving 14 and 25 months of treatment. No other deaths were reported through a median follow-up of 20 months. Survival without invasive ventilatory support was substantially greater in the Myozyme-treated patients than would be expected compared with the poor survival of the historical control patients. No differences in outcome were observed between patients who received 20mg/kg versus 40mg/kg.4

The second study was an international, multicenter, open-label clinical trial that enrolled 21 patients, ages three months to 3.5 years at first treatment.All patients received 20mg/kg of Myozyme every other week for up to 104 weeks.The primary outcome measure was the proportion of patients alive at the conclusion of treatment.At the 52-week analysis, 16 of 21 patients were alive.3

Factors that could influence clinical outcome are stage of disease at start of enzyme replacement treatment, genotype of the patient (whether mutations cause complete deficiency of GAA resulted in negative cross reacting immunological material),the development of inhibitory antibodies, and muscle fiber type.4,6-8

Enrollment has recently been completed in a clinical trial involving adults with late-onset Pompe disease. Ninety patients have been enrolled in this international, placebo-controlled study.3

Motor Response

Pompe disease is characterized by a progressive muscle weakness, patients with infantile presentation have profound hypotonia and flaccidity, and achievement of very few motor milestones. A subset of patients treated with rhGAA achieved motor milestones, such as the ability to sit, stand, walk, and run. Some patients have had a less robust response and in a few a motor decline was noted. Overall, more motor gains were noted in patients treated early (and therefore at an earlier stage of disease progression).4

Cardiac Changes

Substantial changes are seen in left ventricular (LV) mass with Myozyme. LV mass index (MI) was measured by echocardiography over one year of follow-up. All patients had decreases from baseline in LVMI with a mean decrease of 118g/m2, range 45-193g/m2 (see Figure 1). End-diastolic dimension also progressively decreased and systolic function remained in the normal range.4 These results are similar to previous clinical trials of enzyme replacement therapy in this disease.6-10


Substantial changes are also seen in the electrocardiogram of patients with Pompe disease treated with Myozyme. The PR interval lengthens and QT dispersion decreases with regression of LV voltage during therapy coincident with regression of LV mass (see Table 1). These results suggest that the duration of the PR interval and the degree of QT dispersion may be useful markers of the severity of cardiac disease and the response to treatment with Myozyme.11


Infusion associated reactions (IARs) occurred in approximately 50% of patients treated with Myozyme in the two infantile-onset clinical studies (52-week safety data) reported in this review. In these studies the majority of reactions were non-serious, and all were assessed as mild to moderate. Some patients were pre-treated with antihistamines, antipyretics, and/or corticosteroids.

Overall experience with Myozyme has shown that IARs occur at any time during, and mostly up to two hours after the infusion, and are more likely at the higher infusion rates IARs may occur in patients after receiving antipyretics, antihistamines, or steroids.

If an IAR occurs, regardless of pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. If severe infusion reaction occurs, immediate discontinuation of the administration of Myozyme should be considered, and appropriate medical treatment should be initiated. Due to the potential for severe hypersensitivity reactions, appropriate medical support measures should be readily available when Myozyme is administered. Patients who have experienced IARs should be treated with caution when Myozyme is re-administered. 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 when administering Myozyme.3

Overall serious hypersensitivity reactions, including anaphylactic reactions, have been reported in 3% (eight of ~280 patients treated with Myozyme in clinical trials and expanded access programs). Significant hypersensitivity reactions generally consisted of a constellation of signs and symptoms. Reactions included one or more of the following: bronchospasm, oxygen saturation decreased, hypotension, urticaria, periorbital edema, swollen tongue, angioneurotic oedema, chest discomfort, throat tightness, tachycardia, and rash.The majority of reactions occurred within the first two hours of the infusion. Reactions were primarily managed with infusion rate reduction and/or interruption of the infusion and administration of antihistamines, corticosteroids, bronchodilators, epinephrine (in two patients) and/or oxygen. All eight patients recovered without sequelae from the reactions.

While two patients have discontinued treatment due to IARs, the remaining six patients have continued to receive Myozyme (five required pre-treatment medication). Of note, the two patients who discontinued treatment were enrolled in the double blind late-onset study). Testing for Myozyme-specific immunoglobulin (Ig)E antibodies was performed in seven of the eight patients; six patients tested negative, one tested positive.

Acute cardiorespiratory failure requiring intubation and inotropic support has been observed after infusion with Myozyme in one infantile-onset patient with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of Myozyme.

With appropriate clinical precautions such as not infusing patients when ill, avoiding volume overload in patients with severe cardiac compromise, slowing the infusion rate and/or temporary interruption of the infusion where indicated and the judicious use of desensitization regimens for IgE-positive patients, the safety profile can be substantially improved.


In clinical studies, the majority of patients developed IgG antibodies to alglucosidase-α, typically within three months of treatment. Patients treated with higher doses of Myozyme tended to develop a more robust antibody response and experienced more IARs. To date, three of 39 patients in the infantile clinical trials who were IgG positive also tested positive for inhibition of enzyme effects in an in vitro assay.

Cardiac Arrhythmia and Sudden Death During General Anesthesia for Surgical Procedures

Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been associated with the use of general anesthesia in infantile-onset Pompe patients with cardiac hypertrophy. Caution should be used when administering general anesthesia for the placement of a central venous catheter or routine procedures such as gastrostomy tube placements, and tympanostomy tubes in infantile-onset Pompe patients with cardiac hypertrophy.12

Risk of Arrhythmia, Sudden Death, and Acute Cardiorespiratory Failure

Patients with Pompe disease are at risk for arrhythmia, sudden death, and acute cardiorespiratory failure due to the high risk nature of their underlying disease. Patients with infantile Pompe disease may have pre-existing ectopy and, also, arrhythmias may develop during the course of enzyme replacement therapy. The period of highest risk for arrhythmia may be early in the course of enzyme replacement therapy when these patients who have severe hypertrophic cardiomyopathy experience a substantial initial decrease in LV mass and a short initial decrease in ejection fraction. Therefore, routinely monitoring patients using 24-hour ambulatory electrocardiograms may be useful.13 Over time and with improvement in overall status including cardiac anesthesia, risks become less of an issue.


Myozyme is a novel and effective therapy for the treatment of patients with Pompe disease. In infants, Myozyme clearly prolongs ventilator-free survival and overall survival, improve cardiac disease and motor development in this devastating disease. There are ongoing studies evaluating the efficacy and safety of Myozyme in adult-onset Pompe disease.With increased survival, care in this population has changed from palliative to definitive treatment. Guidelines have recently been developed to help the treating physician in better managing these patients.14 Further efforts are warranted to assess the long-term effects of this novel therapy in terms of its effect on cardiac remodeling, variable response to therapy in individuals, quality of life, morbidity, and mortality in this once fatal disease.


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