Post-transplant laronidase augmentation for children with Hurler syndrome: biochemical outcomes

Abstract

Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.

Conflict of interest statement

Dr’s Lund, Polgreen and Orchard have received research funding, consulting fees, and travel expenses from Sanofi-Genzyme. Dr. Miller is an employee of Sangamo Therapeutics. Dr’s Tolar, Bigger, Liao, Shanley, Pasqali, and Ms. Sando declare no competing interests.

Figures

Figure 1

Individual patient anti-drug antibody response and urine biomarker excretion over time. (A) BL (baseline) indicates data acquisition just prior to the first dose of IV laronidase. Numbers on the x-axes indicate months on study. Left y-axes show urine heparan sulfate excretion in mg/mmol creatinine (black line). Right y-axes (logarithmic scale) show anti-laronidase antibody (ADA) titers, blue dashed line shows the titer of commercial (Com) assay, the red solid line shows independently performed titers (Ind). (B) Excretion of heparan sulfate, NRE I0S6, and NRE i0S0. Circles indicated geometric mean values; whiskers show 95% confidence intervals. Note that the geometric mean is not defined when any value is zero or negative (so is left blank). See Table 3 for statistical comparisons of baseline values to those at 24 months. The non-MPS values are shown as dashed lines in the graphs. I0S0 non-MPS is not detectable.