Alglucosidase alfa

It is postulated that alglucosidase alfa will restore lysosomal GAA activity resulting in stabilisation or restoration of cardiac and skeletal muscle function (including respiratory muscles). Due to the bloodbrain barrier effect and the enzyme’s size, uptake of alglucosidase alfa in the central nervous system is unlikely.

Pompe disease

Pompe disease is a rare, progressive and fatal metabolic myopathy with an estimated global incidence of 1 in 40,000 births. Other names for Pompe disease include glycogen storage disease type II (GSDII), acid maltase deficiency (AMD) and glycogenosis type II. Pompe disease belongs to the lysosomal storage disorders as it is caused by a deficiency of a naturally-occurring lysosomal hydrolase, acid αglucosidase (GAA) that degrades lysosomal glycogen to glucose. Deficiency of this enzyme leads to glycogen accumulation in various tissues, particularly cardiac, respiratory and skeletal muscle, leading to the development of hypertrophic cardiomyopathy and progressive muscle weakness, including impairment of respiratory function.

The clinical presentation of Pompe disease can be described as a spectrum of disease which ranges from a rapidly-progressing infantile-onset form (onset of symptoms of Pompe disease typically within the first year of life and a very short expected life-span) to a less rapidly-progressing late-onset form.

The infantile-onset form of Pompe disease is characterised by massive deposition of glycogen in the heart, and skeletal muscle always resulting in rapidly progressive cardiomyopathy, generalised muscle weakness and hypotonia. Motor development is often completely arrested, or if motor milestones are achieved, they are subsequently lost. Death typically occurs due to cardiac and/or respiratory failure before the age of one year.

In a retrospective natural history study in patients with infantile-onset Pompe disease (n=168), the median age at onset of symptoms was 2.0 months and the median age of death was 9.0 months. Kaplan-Meier survival rates at 12, 24 and 36 months of age were 26%, 9% and 7%, respectively.

A non-typical, more slowly progressive form of infantile-onset Pompe disease has been described which is characterised by a less severe cardiomyopathy and consequently a more prolonged survival.

The late-onset form of Pompe disease manifests during infancy, childhood, adolescence or even adulthood and is much less rapidly progressive than the infantile-onset form. Usually, it is characterised by the presence of sufficient residual GAA activity to preclude the development of cardiomyopathy, however some cardiac involvement has been reported in up to approximately 4% of patients with late-onset Pompe disease.

Patients with late-onset Pompe disease typically present with progressive myopathy, predominantly of the proximal muscles in the pelvic and shoulder girdles, and varying degrees of respiratory involvement, ultimately progressing to profound disability and/or the need for ventilatory support. The time course of disease progression is extremely variable and not predictable, with some patients experiencing a rapid deterioration in skeletal and respiratory muscle function leading to loss of ambulation and respiratory failure, others progressing less rapidly, and yet others presenting with a dissociation in the progression of skeletal and respiratory muscle involvement.

Infantile-onset Pompe disease

In a pivotal trial including 18 patients, the pharmacokinetics of alglucosidase alfa were evaluated in 15 patients with infantile-onset Pompe disease (all less than 6 months of age at treatment-onset) who received doses of 20 mg/kg or 40 mg/kg alglucosidase alfa as an approximate 4 to 6.5-hour infusion, respectively.

Distribution and elimination

After the first and sixth infusion of alglucosidase alfa, mean maximum plasma concentrations (C_max) ranged from 178.2 to 263.7 µg/ml for the 20 mg/kg and 40 mg/kg dose groups respectively. The mean area under the plasma concentration-time curve (AUC_∞) ranged from 977.5 to 1,872.5 µg•h/ml for the 20 mg/kg and 40 mg/kg dose groups. Mean plasma clearance (CL) was 21.4 ml/h/kg and mean volume of distribution at steady state (Vss) was 66.2 ml/kg for both dose groups with small between-subject variability of 15% and 11%, respectively. Mean plasma elimination half-life (t_1/2) was 2.75 hours for the two dose groups.

Linearity/non linearity

Pharmacokinetics were dose proportional and did not change over time.

The pharmacokinetics of alglucosidase alfa were also evaluated in a separate trial in 21 patients with infantile-onset Pompe disease (all aged between 6 months and 3.5 years at treatment-onset) who received doses of 20 mg/kg of alglucosidase alfa. In 12 patients with available data the AUC_∞ and C_max were approximately equivalent to those observed for the 20 mg/kg dose group in the pivotal trial. The t½ of approximately 2-3 hours was also similar in this group of patients.

Late-onset Pompe disease

The pharmacokinetics of alglucosidase alfa were evaluated in a trial in 5 patients with late-onset Pompe disease aged 6-15 years who received 20 mg/kg alglucosidase alfa once every two weeks. There was no difference in the pharmacokinetic profile of alglucosidase alfa in these juvenile lateonset patients compared to infantile-onset patients.

The pharmacokinetics of alglucosidase alfa were studied in a population analysis of 32 late-onset Pompe disease patients from the randomized, double-blind, placebo-controlled study ranging in age from 21 to 70 years who received alglucosidase alfa 20 mg/kg once every two weeks. AUC_∞ and C_max were similar at week 0, 12 and 52 visits indicating alglucosidase alfa pharmacokinetics were not timedependent (Table).

Distribution and elimination

Alglucosidase alfa pharmacokinetics after a single dose and after 12 and 52 weeks of therapy:

There was no evidence that IgG antibodies to alglucosidase alfa affected pharmacokinetics. Higher mean clearance, lower mean AUC_∞, and lower mean C_max were observed in 5 patients who tested positive for inhibition of cellular uptake of enzyme. However, there was no apparent association between inhibition of uptake and the co-primary efficacy endpoints.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity. No significant adverse findings on embryofoetal development were observed in a mouse and a rabbit embryofoetal study and no significant adverse findings were observed in a mouse fertility and early embryonic development study. In the rabbit embryofoetal development study, following administration of alglucosidase alfa (10-40 mg/kg/day) with coadministration of diphenhydramine, a treatment-related increase in the incidence of abortions and early delivery was observed. This effect was partly attributable to maternal toxicity, as a significant decrease in feed consumption and body weight gain was observed.