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Mechanism of Action

Pompe disease (glycogen storage disease type II, GSD II, glycogenosis type II, acid maltase deficiency) is an inherited disorder of glycogen metabolism caused by the absence or marked deficiency of the lysosomal enzyme GAA.

In the infantile-onset form, Pompe disease results in intralysosomal accumulation of glycogen in various tissues, particularly cardiac and skeletal muscles, and hepatic tissues, leading to the development of cardiomyopathy, progressive muscle weakness, and impairment of respiratory function.

In the juvenile- and adult-onset forms, intralysosomal accumulation of glycogen is limited primarily to skeletal muscle, resulting in progressive muscle weakness. Death in all forms is usually related to respiratory failure.

MYOZYME (alglucosidase alfa) provides an exogenous source of GAA. Binding to mannose-6-phosphate receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in cleaving glycogen.

Pharmacokinetics

The pharmacokinetics of alglucosidase alfa were evaluated in 13 patients of age ranging from 1 month to 7 months with infantile-onset Pompe disease who received 20 mg/kg (as an approximate 4-hour infusion) or 40 mg/kg (as an approximate 6.5-hour infusion) of MYOZYME (alglucosidase alfa) every 2 weeks. The measurement of alglucosidase alfa plasma concentration was based on an activity assay using an artificial substrate. Systemic exposure was approximately dose proportional between the 20 and 40 mg/kg doses (see Table 1).

Table 1. Pharmacokinetic Parameters (Mean ± SD)

The pharmacokinetics of alglucosidase alfa were also evaluated in a separate trial in 14 patients of age ranging from 6 months to 3.5 years with Pompe disease who received 20 mg/kg of MYOZYME (alglucosidase alfa) as an approximate 4-hour infusion every 2 weeks. The pharmacokinetic parameters were similar to those observed for the 20 mg/kg dose group in the trial of patients of age ranging from 1 month to 7 months.

Nineteen of 21 patients who received treatment with MYOZYME (alglucosidase alfa) and had pharmacokinetics and antibody titer data available at Week 12 developed antibodies to alglucosidase alfa. Five patients with antibody titers ≥ 12,800 at Week 12 had an average increase in clearance of 50% (range 5% to 90%) from Week 1 to Week 12. The other 14 patients with antibody titers < 12,800 at Week 12 had similar average clearance values at Week 1 and Week 12.

Clinical Studies

The safety and efficacy of MYOZYME (alglucosidase alfa) were assessed in 2 separate clinical trials in 39 Pompe disease patients, who ranged in age from 1 month to 3.5 years at the time of first infusion.

Study 1 was an international, multicenter, open-label, clinical trial of 18 infantile-onset Pompe disease patients. This study was conducted between 2003 and 2005. Patients were randomized equally to either 20 mg/kg or 40 mg/kg MYOZYME (alglucosidase alfa) every two weeks, with length of treatment ranging from 52 to 106 weeks. Enrollment was restricted to patients ages 7 months or less at first infusion with clinical signs of Pompe disease, with cardiac hypertrophy, and who did not require ventilatory support at study entry.

Efficacy was assessed by comparing the proportions of MYOZYME (alglucosidase alfa) -treated patients who died or needed invasive ventilator support with the mortality experience of an historical cohort of untreated infantile-onset Pompe patients with similar age and disease severity. In the historical cohort, 61 untreated patients with infantile-onset Pompe disease diagnosed by age 6 months, born between 1982 and 2002, were identified by a retrospective review of medical charts. By the age of 18 months, only one of the 61 historical control patients was alive (98% mortality), indicating the poor outcome of patients who are left untreated.

Within the first 12 months of treatment, 3 of 18 MYOZYME (alglucosidase alfa) -treated patients required invasive ventilatory support (17%, with 95% confidence interval 4% to 41%); there were no deaths. With continued treatment beyond 12 months, 4 additional patients required invasive ventilatory support, after receiving between 13 and 18 months of MYOZYME (alglucosidase alfa) treatment; 2 of these 4 patients died after receiving 14 and 25 months of treatment, and after receiving 11 days and 7.5 months of invasive ventilatory support, respectively. No other deaths have been reported through a median follow-up of 20 months, and all 16 surviving patients continue to be followed. Survival without invasive ventilatory support was substantially greater in the MYOZYME (alglucosidase alfa) -treated patients in this study than would be expected compared to the poor survival of the historical control patients. No differences in outcome were observed between patients who received 20 mg/kg versus 40 mg/kg.

Other outcome measures in this study included unblinded assessments of motor function by the Alberta Infant Motor Scale (AIMS). The AIMS is a measure of infant motor performance that assesses motor maturation of the infant through age 18 months and is validated for comparison to normal, healthy infants. AIMS-assessed gains in motor function occurred in 13 patients. In the majority of patients, motor function was substantially delayed compared to normal infants of comparable age. The continued effect of MYOZYME (alglucosidase alfa) treatment over time on motor function is unknown. Two of 9 patients who had demonstrated gains in motor function after 12 months of MYOZYME (alglucosidase alfa) treatment and continued to be followed regressed despite ongoing treatment.

Changes from baseline to Month 12 in left ventricular mass index (LVMI), an evaluation of bioactivity, were measured by echocardiography. For the 15 patients with both baseline and Month 12 echocardiograms, all had decreases from baseline in LVMI (mean decrease 118 g/m², range 45 to 193 g/m²). The magnitude of the decrease in LVMI did not correlate with the clinical outcome measure of ventilator-free survival.

Study 2 is an ongoing, international, multicenter, non-randomized, open-label clinical trial that enrolled 21 patients who were ages 3 months to 3.5 years at first treatment. All patients received 20 mg/kg MYOZYME (alglucosidase alfa) every other week for up to 104weeks. Five of 21 patients were receiving invasive ventilatory support at the time of first infusion.

The primary outcome measure was the proportion of patients alive at the conclusion of treatment. At the 52-week interim analysis, 16 of 21 patients were alive. Sixteen 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 historical group of patients, and no effect of MYOZYME (alglucosidase alfa) treatment could be determined.

Last reviewed on RxList: 2/2/2009
This monograph has been modified to include the generic and brand name in many instances.