Imiglucerase

Gaucher disease is a rare recessively inherited metabolic disorder that results from a deficiency of the lysosomal enzyme acid β-glucosidase. This enzyme breaks down glucosylceramide, a key component of the lipid structure of cell membranes, into glucose and ceramide. In individuals with Gaucher disease, glucosylceramide degradation is insufficient, leading to accumulation of large quantities of this substrate within the lysosomes of macrophages (termed ‘Gaucher cells’), leading to widespread secondary pathology.

Gaucher cells are typically found in liver, spleen and bone marrow and occasionally in lung, kidney and intestine. Clinically, Gaucher disease is a heterogeneous phenotypic spectrum. The most frequent disease manifestations are hepatosplenomegaly, thrombocytopenia, anaemia, and skeletal pathology, The skeletal abnormalities are frequently the most debilitating and disabling features of Gaucher disease. These skeletal manifestations include bone marrow infiltration, osteonecrosis, bone pain and bone crises, osteopenia and osteoporosis, pathological fractures, and growth impairment. Gaucher disease is associated with increased glucose production and increased resting energy expenditure rate, which may contribute to fatigue and cachexia. Patients with Gaucher disease may also have a low grade inflammatory profile. In addition, Gaucher disease has been associated with an increased risk of immunoglobulin abnormalities such as hyperimmunoglobulinemia, polyclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. The natural history of Gaucher disease usually shows progression, with the risk of irreversible complications arising in various organs over time. The clinical manifestations of Gaucher disease can adversely affect quality of life. Gaucher disease is associated with increased morbidity and early mortality. Signs and symptoms presenting in childhood typically represent more severe Gaucher disease. In children, Gaucher disease can lead to growth retardation and delayed puberty.

Pulmonary hypertension is a known complication of Gaucher disease. Patients who have undergone a splenectomy have an increased risk of pulmonary hypertension. Imiglucerase therapy reduces the requirement for splenectomy in most cases and early treatment with imiglucerase has been associated with a reduced risk of pulmonary hypertension. Routine evaluation to detect the presence of pulmonary hypertension after diagnosis of Gaucher disease and over time is recommended. Patients diagnosed with pulmonary hypertension, in particular, should receive adequate doses of imiglucerase to ensure control of underlying Gaucher disease as well as be evaluated for the need of additional pulmonary hypertension specific treatments.

Pharmacodynamic effects

Imiglucerase (recombinant macrophage targeted acid β-glucosidase) replaces the deficient enzyme activity, hydrolysing glucosylceramide, thus correcting initial pathophysiology and preventing secondary pathology. Imiglucerase reduces spleen and liver size, improves or normalises thrombocytopenia and anaemia, improves or normalises bone mineral density and bone marrow burden, and reduces or eliminates bone pain and bone crises. Imiglucerase reduces resting energy expenditure rate. Imiglucerase has been shown to improve both mental and physical aspects in the quality of life of Gaucher disease. Imiglucerase decreases chitotriosidase, a biomarker for glucosylceramide accumulation in macrophages and response to treatment. In children, imiglucerase has been shown to enable normal pubertal development, and to induce catch-up growth, leading to normal height and bone mineral density in adulthood.

During 1 hour intravenous infusions of 4 doses (7.5, 15, 30, 60 U/kg) of imiglucerase, steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 ml/min/kg, (mean ± S.D, 14.5 ± 4.0 ml/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 l/kg (mean ± S.D 0.12 ± 0.02 l/kg). These variables do not appear to be influenced by dose or duration of infusion, however, only 1 or 2 patients were studied at each dose level and infusion rate.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity.