Alglucerase

Abstract

Synopsis

Alglucerase is a mannose-terminated form of human placental glucocerebrosidase, developed to treat patients with Gaucher’s disease. Functional glucocerebrosidase is deficient in Gaucher’s disease, an autosomal recessive lipid storage disorder that affects people of all ethnic backgrounds, but has a higher incidence among East European Jews (Ashkenazim). Gaucher’s disease manifests with hepatosplenomegaly, bleeding disorders and bone disease, with the more rare subtypes (types 2 and 3) featuring neurological dysfunction. Prior to the development of enzyme replacement therapy, treatment for Gaucher’s disease was mainly symptomatic relief Primary treatment with glucocerebrosidase focuses on removal of the lipid metabolite that causes the pathology.

Because of the rarity of Gaucher’s disease clinical trials are small, and much of the data investigating alglucerase therapy have been obtained from studies of patients with type 1 disease, the prevalent subtype. Nonetheless, after intravenous administration of alglucerase, improvements are evident within 6 months of therapy. Patients have increased haemoglobin levels and platelet counts, and decreased incidences of epistaxis and bruising. Spleen and liver size are reduced, and skeletal parameters improve. Children gain height and most patients receiving alglucerase therapy are able to resume work and daily activities. Alglucerase is well tolerated, with few mild adverse reactions reported.

Although the pharmacokinetic and pharmacodynamic information for alglucerase is limited, its unequivocal efficacy justifies enzyme replacement therapy with this compound as first-line treatment for patients with Gaucher’s disease, for whom treatment options are limited.

Role of Glucocerebrosidase in Metabolism

Glucocerebrosidase has a role in the metabolism of glucocerebroside, an important component of all cell membranes. Deficiency of glucocerebosidase results in the inability to hydrolyse glucocerebroside to glucose and ceramide, which causes glucocerebroside to accumulate within the lysosomes of reticuloendothelial cells. This produces the characteristic Gaucher cells that are the hallmark of Gaucher’s disease: large lipid-laden macrophages that accumulate in the spleen, liver, bone marrow and perivascular spaces in the brain.

Overview of Gaucher’s Disease

Gaucher’s disease is the most prevalent lysosomal storage disorder, affecting as many as 1 in 450 births within the Ashkenazim. The incidence among the general population is approximately the same as that of haemophilia, affecting no more than 1 in 40 000, although the prevalence varies among ethnic groups.

There are 3 main subtypes of Gaucher’s disease, although 99% of cases are type 1 Gaucher’s disease. Type 1 Gaucher’s disease has a chronic time-course and manifests with hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis and bone disease. The severity and onset of symptoms vary widely, but type 1 disease is distinguished by the lack of neuropathology. Type 2 Gaucher’s disease has a very serious pathology and is usually fatal within the first two years of life. This type is characterised by severe neurological symptoms that accompany the hepatosplenomegaly common to all subtypes. Type 3 Gaucher’s disease varies in severity, and shares characteristics of both types 1 and 2.

Rationale for the Development of Alglucerase as Enzyme Replacement Therapy

Previous treatments for Gaucher’s disease have been directed towards symptomatic relief rather than addressing the glucocerebroside accumulation per se. Splenectomy and orthopaedic procedures are necessary in the majority of severe cases. Allogenic bone marrow transplantation carries a high degree of risk for patients with Gaucher’s disease and is therefore limited to patients with very severe clinical manifestations who have a matched donor. Enzyme replacement therapy is a preferable option as it removes the accumulated metabolite which causes the symptoms and has limited risk. Alglucerase was developed after studies indicated that unmodified replacement glucocerebrosidase was not reaching the principal storage site of glucocerebroside in macrophages. Glucocerebrosidase is deglycosylated to produce alglucerase, exposing mannose terminal sugars that target the enzyme to macrophages.

Pharmacokinetics of Alglucerase

Pharmacokinetic data for alglucerase in humans are limited. Elimination half-life after intravenous infusion ranged from 3 to 11 minutes in 24 patients given varying doses. In rats, 70% of exogenous native glucocerebrosidase is present in the liver 2 hours after infusion. Alglucerase activity is approximately equal in hepatocytes and nonparenchymal cells 1 hour after infusion in rats. There is no information available concerning the distribution or biotransformation of alglucerase in humans.

Use of Alglucerase in Patients with Gaucher’s disease

Clinical trials with alglucerase are predictably small due to the rarity of the disease, and initially included only patients with type 1 Gaucher’s disease. Alglucerase 60 IU/kg bodyweight administered intravenously once every 2 weeks to 12 patients for 6 months caused an increase in haemoglobin levels, improved platelet counts, and lowered plasma glucocerebroside levels to within normal limits. Most patients had reduced splenic and liver volumes after 6 months of therapy. All patients experienced enhanced lifestyle and activity level, children gained height and weight, and a few patients showed early signs of skeletal improvements. These findings were supported by a study of 4 patients who were administered a lower dose of alglucerase more frequently. These patients received a total of 30 U/kg bodyweight monthly for up to 13 months, administered in divided doses 3 or 4 times per week. Although no evidence of skeletal changes were noted, patients showed rapid haematological and subjective improvement. Two patients with pulmonary involvement showed a modest betterment of pulmonary function tests. Single case studies indicate that marked skeletal improvement is possible with high doses of alglucerase, and that red blood cell survival is enhanced with long term therapy.

Clinical Tolerability

The very few adverse effects reported during alglucerase therapy are mild, and include discomfort and swelling at the venipuncture site, slight fever, chills, abdominal discomfort, pruritus, flushing, nausea and vomiting. There appears to be a small potential for immunological reactions, with 13% of patients who receive repeated infusions developing IgG antibody to alglucerase. These patients are more likely to develop symptoms suggestive of hypersensitivity; however, there is no evidence to indicate that antibody development hinders alglucerase activity. There are no data available regarding possible mutagenic or carcinogenic effects of alglucerase, or its effects in pregnant or lactating women.

Dosage and Administration

Most regimens using alglucerase for the treatment of patients with severe manifestations commence with doses of 60 U/kg bodyweight infused intravenously over 1 to 2 hours every 2 weeks. However, dose and frequency of administration vary widely depending on the patients’ needs, and doses as low as 30 U/kg bodyweight per month in divided doses have improved organ-omegaly and haematological parameters. As the patient responds, it may be possible to reduce the dose; levels of maintenance therapy may ultimately be as low as 1 U/kg bodyweight given monthly. Further studies are ongoing to establish the optimum dosage regimen, and whether tapering dose regimens may be effective.