title: Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I.
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.
  
  
  BACKGROUND
  NCT00741338.
authors.affiliation: Hospital de Clinicas de Porto Alegre, Medical Genetics Service, Porto Alegre, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Hospital de Clinicas de Porto Alegre, Medical Genetics Service, Porto Alegre, Brazil.
authors.forename: Taiane Alves
authors.initials: TA
authors.lastname: Vieira
authors.affiliation: Hospital de Clinicas de Porto Alegre, Medical Genetics Service, Porto Alegre, Brazil.
authors.forename: Clarissa Gutierrez
authors.initials: CG
authors.lastname: Carvalho
authors.affiliation: Hospital de Clinicas de Porto Alegre, Medical Genetics Service, Porto Alegre, Brazil.
authors.forename: Maria-Veronica
authors.initials: MV
authors.lastname: Muñoz-Rojas
authors.affiliation: Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia.
authors.forename: Alla N
authors.initials: AN
authors.lastname: Semyachkina
authors.affiliation: Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, Moscow, Russia.
authors.forename: Victoria Y
authors.initials: VY
authors.lastname: Voinova
authors.affiliation: Sanofi Genzyme, Cambridge, MA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Richards
authors.affiliation: Sanofi Genzyme, Cambridge, MA, USA.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Cox
authors.affiliation: Sanofi Genzyme, Cambridge, MA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xue
keywords: Anti-drug antibodies; Enzyme replacement therapy; Hurler syndrome; Immune tolerance; Laronidase; Mucopolysaccharidosis type I