To evaluate whether the variability in patient pharmacodynamics was related to elosulfase alfa exposure (as measured either by AUClastorCmaxin plasma), levels of uKS from patients with Morquio A syndrome were assessed over time and compared with elosulfase alfa exposure (Fig.4). == Elosulfase alfa exposure and half-life (t) increased for both dose regimens during the study. There appeared to be no consistent trend between drug clearance (CL) and patients sex, race, body weight, or age. All patients developed anti-drug antibodies, but no association was noted between total antibody titer and CL. In contrast, positive neutralizing antibody (NAb) status appeared to associate with decreased CL and prolongedtfor patients in the cohort dosed weekly. NAb may interfere with receptor-mediated cellular uptake and lead to increased circulation time of elosulfase alfa. == Conclusion == Despite the association between NAb and decreased drug clearance, neither dosing cohort showed associations between drug exposure and change in urinary keratan sulfate, 6-min walk test distances, or the occurrence of adverse events. == Electronic supplementary material == The online version of this article (doi:10.1007/s40262-014-0173-y) contains supplementary material, which is available to authorized users. == Key Points == == Introduction == Morquio A syndrome (mucopolysaccharidosis Dimebon 2HCl IV A; MPS IVA; OMIM Dimebon 2HCl 253000) is an autosomal, recessive, lysosomal storage disease caused by a deficiency ofN-acetylgalactosamine-6-sulfatase (GALNS; EC 3.1.6.4), an enzyme required for degradation of the glycosaminoglycans (GAGs) chondroitin-6-sulfate Dimebon 2HCl and keratan sulfate (KS). Morquio A syndrome is rare, with an incidence estimated to range from 1 in 76,000 to 1 1 in 640,000 live births in different populations [13]. Patients with Morquio A syndrome appear healthy at birth but develop multiple clinical signs owing to the accumulation of GAGs causing cellular disruptions in multiple cells, tissues, and organs. The progress of the disease and the severity of individual clinical manifestations can vary considerably between patients. Prominent skeletal and connective tissue abnormalities are common, with patients often manifesting dwarfism with short trunk and neck, spinal abnormalities, Dimebon 2HCl genu valgum, pectus carinatum, hip dysplasia, and joint instability and hypermobility as a result of ligamentous laxity and joint bone deformities [4]. Pulmonary and cardiac manifestations are also common, which can result in reduced endurance and impact both quality of life and mortality; death often results from cardiorespiratory or neurological complications [4]. Patients with slowly progressing disease rarely survive their sixth decade, and patients with rapidly progressing disease often die in their second or third decade [4]. Enzyme replacement therapy (ERT) by intravenous infusion of recombinant human GALNS (elosulfase alfa; Vimizim, BioMarin Pharmaceutical Inc., Novato, CA, USA) is approved by the US Food and Drug Administration for treatment of patients with Morquio A syndrome. Elosulfase alfa is expected to increase the degradation of accumulated KS and chondroitin-6-sulfate that cause the Morquio A clinical manifestations. The MOR-004 phase III study was designed to assess the safety and efficacy of two different elosulfase alfa dosing regimens, 2.0 mg/kg every other week (QOW) and 2.0 mg/kg weekly (QW), in comparison with placebo [5]. The elosulfase alfa dose level of 2.0 mg/kg was chosen based on prior in vitro analysis in a human cell culture model of Morquio A syndrome [6] and a prior phase 1/2 dose-escalation study in patients with Morquio A syndrome [7]. Results from the phase III study indicated that elosulfase alfa had a short plasma elimination half-life of about 40 min following repeat intravenous infusion and that increases in the area under the plasma concentration-time curve from time zero to the time of last measurable concentration (AUClast) and the maximum concentration in plasma Dimebon 2HCl (Cmax) were greater than dose proportional when the dose was increased from 1.0 to 2.0 mg/kg/week [8]. Here, we report the pharmacokinetic and pharmacodynamic results of elosulfase alfa in patients with Morquio A syndrome from the pivotal phase III trial. == Methods == == Study Design and Patients == RGS20 Data from the MOR-004 study served as the basis for this analysis [5]. In brief, MOR-004 was a phase III, randomized, double-blind, placebo-controlled study of elosulfase alfa in patients with Morquio A syndrome over 24 weeks, conducted at 33 study centers in 17 countries. The study protocol was approved by an Institutional Review Board, Independent Ethics committee, or.