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. Clinical Trial Registration: NCT00741338.

Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison

“…More detailed information on causes of death in the ERT group may have provided additional insights into whether certain organ systems are differentially improved or burdened in the long term. As monitoring anti-drug antibody responses is an increasingly recognized factor in ERT success 15 , 39 , 40 , this study cannot account for the degree to which it affected outcomes of the ERT group. However, a recent meta-analysis demonstrated that antibody titers generally decrease over time during treatment with ERT 40 , and while this may not be true for every patient, a more comprehensive examination of one of the patients from this group revealed that even though anti-ERT antibodies doubled in a 6-year span, there was no apparent impact on efficacy for her 13 .…”

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

“…Attempts to prevent ADA responses to ERT were seldom described. An immune tolerance induction regimen based on cyclosporin A and azathioprine was ineffective in patients with MPS IH as well as monotherapy with methotrexate [217,218]. Another immune tolerance induction regimen was used in a 4-year-old MPS II boy, with sustained high ADAs titer and limited clinical efficacy of idursulfase treatment.…”

Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery

“…Impacts on Pompe patients are often cited as the most dramatic example, where children show significant improvement in motor milestones in response to ERT only to have these effects rapidly reversed upon induction of neutralizing antibodies, leading eventually to patient death [16,18,19]. Tolerization protocols have been tested for patients where ERT efficacy is blocked by immune responses but these treatments might not be efficacious [20], are intensive for patients, and pose significant risks of infection or malignancy [16]. Gene therapy approaches are currently under development for LSDs as an alternative to ERTs.…”