ABSTRACT
Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose laronidase infusions (0.058-0.29 mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment. CLINICAL TRIAL REGISTRATION: NCT00741338.
ABSTRACT
OBJECTIVE: To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease. STUDY DESIGN: We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echocardiograms, growth, and motor and cognitive function. RESULT: After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related. CONCLUSION: rhGAA improved ventilator-free survival, cardiomyopathy, growth, and motor function in patients with infantile-onset Pompe disease compared with outcomes expected for patients without treatment.