The first 5 years of clinical experience with laroniclase enzyme replacement therapy for mucopolysacchariclosis I

Mucopolysaccharidosis I (IVIPS I, McKusick 25280) is caused by the deficiency or absence of the lysosomal enzyme, alpha-L-iduronidase (EC 3.2.1.76). This inherited disease causes progressive cellular, tissue and organ damage across the entire phenotypic spectrum. Disabling, multi-organ disease is the rule, and generally results in death between the first and fourth decades of life. Recently, laronidase (Aldurazyme((R)) [Genzyme], a specific recombinant human a-L-iduronidase) became commercially available as long-term enzyme replacement therapy. Results from the Phase I/II and III extended clinical studies have shown that laronidase safely and effectively alleviates many systemic signs and symptoms of this progressive multisystemic disease. Clinically meaningful and sustained improvements in pulmonary function and functional capacity have been observed in Phase III study patients. Significant and sustained reductions in urinary glysosaminoglycan (GAG) excretion and hepatomegaly have also been observed. Improvements in sleep apnoea and joint range of motion occurred in patients with the most severe symptoms at baseline. Improvements in Disability Index scores as measured using the CHAQ and HAQ questionnaires were modest, which may have been related to the fact that these disability measuring tools are not disease-specific. Anecdotal reports of improvements in the performance of daily activities further add to the therapeutic benefits, as do case histories pointing at stabilisation or improvement of symptomatology in various organs, such as the eyes, heart, and muscles. With the availability of specific treatment, the importance of early recognition of the disease and appropriate therapeutic intervention has increased. The variability in clinical symptomatology is reviewed in detail and may allow for a better understanding of the diagnostic and therapeutic challenges. Results of the clinical trials and their initial extension periods, as well as the anecdotal experiences of physicians with laronidase in non-study settings, are discussed.