Background and Objectives
Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) is a lysosomal storage disorder caused by deficiency of
N
-acetylgalactosamine-6-sulfatase, an enzyme required for ...degradation of the glycosaminoglycan keratan sulfate. Enzyme replacement therapy with elosulfase alfa provides a potential therapy for Morquio A syndrome. We analyzed the pharmacokinetics and pharmacodynamics of elosulfase alfa in Morquio A patients from a phase III clinical trial.
Methods
In a randomized double-blind study, elosulfase alfa at 2.0 mg/kg was administrated weekly or every other week for 24 weeks. Pharmacokinetic parameters of elosulfase alfa were determined at weeks 0 and 22 by non-compartmental analysis. Safety was assessed throughout the study. The relationship of pharmacokinetic parameters to patient demographics, pharmacodynamic assessments, immunogenicity, and efficacy and safety outcomes were assessed graphically by treatment group.
Results
Elosulfase alfa exposure and half-life (
t
½
) increased for both dose regimens during the study. There appeared to be no consistent trend between drug clearance (CL) and patient’s 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 prolonged
t
½
for 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.
Abstract Purpose Morquio A syndrome (mucopolysaccharidosis IVA MPS IVA) is a lysosomal storage disorder caused by deficiency of the enzyme N -acetylgalactosamine-6-sulfatase, which is required to ...degrade the glycosaminoglycan keratan sulfate. Morquio A is associated with extensive morbidity and early mortality. Elosulfase alfa is an enzyme replacement therapy that provides a treatment option for patients with Morquio A. We examined the immunogenicity profile of elosulfase alfa, assessing any correlations between antidrug antibodies and the efficacy and safety outcomes in 176 patients with Morquio A from a 24-week international Phase III trial. Methods Patients were randomized to placebo (n = 59) or elosulfase alfa 2.0 mg/kg administered weekly (n = 58) or every other week (n = 59) as an ~4-hour infusion. Blood samples were routinely tested to determine drug-specific total antibody titer and neutralizing antibody (NAb) positivity. Drug-specific immunoglobulin E positivity was tested routinely and in response to severe hypersensitivity adverse events (AEs). Antidrug antibody positivity and titer were compared with efficacy and safety metrics to assess possible correlations. Findings The 176 patients in the trial were 54% female, with a mean age of 11.9 years. In all patients treated with elosulfase alfa antidrug antibodies developed, and in the majority, antibodies capable of interfering with cation-independent mannose-6-phosphate receptor binding in vitro (NAb) developed. Less than 10% of patients tested positive for drug-specific IgE during the study. Despite the high incidence of anti–elosulfase alfa antibodies, no correlations were detected between higher total antibody titers or NAb positivity and worsened 6-minute walk test results, urine keratin sulfate levels, or hypersensitivity AEs. Drug-specific IgE pos i tivity had no apparent association with the occurrence of anaphylaxis, other hypersensitivity AEs, and/or treatment withdrawal. Implications Despite the universal development of antidrug antibodies, elosulfase alfa treatment was both safe and well tolerated and immunogenicity was not associated with reduced treatment effect. ClinicalTrials.gov identifier: NCT01275066. ( Clin Ther.
Phenylketonuria (PKU), a deficiency in the activity of the enzyme phenylalanine hydroxylase, leads to toxic levels of phenylalanine (Phe) in the blood and brain. Pegvaliase (recombinant Anabaena ...variabilis phenylalanine ammonia lyase conjugated with polyethylene glycol) is approved to manage PKU in patients aged greater than or equal to 18 years in the United States and in patients aged greater than or equal to 16 years in the European Union. Pharmacokinetic, pharmacodynamic, and immunogenicity results from five open‐label pegvaliase trials were assessed. Studies with induction/titration/maintenance (I/T/M) dosing regimens demonstrated pharmacokinetic stabilization and sustained efficacy associated with maintenance doses (20, 40, or 60 mg/day). Immune‐mediated pegvaliase clearance was high during induction/titration phases when the early immune response was peaking. The combination of low drug dosage and high drug clearance led to low drug exposure and minimal decreases in blood Phe levels during induction/titration. Higher drug exposure and substantial reductions in blood Phe levels were observed later in treatment as drug clearance was reduced due to the maturation of the immune response, which allowed for increased dosing to target levels. The incidence of hypersensitivity reactions was temporally associated with the peaking of the early antidrug immune response and decreased with time as immune response matured after the first 6 months of treatment. These results support an I/T/M dosing regimen and suggest a strategy for administration of other nonhuman biologics to achieve efficacy and improve tolerability.
Introduction
Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a progressive, debilitating, ultra-rare lysosomal storage disorder caused by the deficiency of β-glucuronidase (GUS), an enzyme ...required for breakdown of glycosaminoglycans (GAGs). Vestronidase alfa, a recombinant human GUS, is an enzyme replacement therapy approved in the US and EU for the treatment of MPS VII.
Methods
The pharmacokinetics (PK) and pharmacodynamics (PD) of vestronidase alfa were evaluated in 23 adult and pediatric subjects with MPS VII enrolled in phase I–III clinical trials to optimize the clinical dosing regimen of vestronidase alfa. The serum concentration-time profiles were adequately described by a two-compartment population PK model incorporating subjects’ body weight as the only significant covariate.
Results
Model-based simulations predicted a substantially decreased time duration of serum exposures exceeding the level of
K
uptake
(the in vitro determined vestronidase alfa concentration corresponding to 50% maximum rate of cellular uptake) for 4 or 8 mg/kg once every 4 weeks dosing, compared with 4 mg/kg once every other week (QOW) dosing by intravenous infusion, suggesting that given the same total monthly dose, the QOW dosing frequency should result in more efficient delivery to the GUS-deficient tissue cells, and therefore superior treatment efficacy. A standard inhibitory maximal effect model reasonably explained the observed pharmacological PD responses of reduction in urinary GAGs from pretreatment baseline, which appeared to have reached the plateau of maximal effect at the 4 mg/kg QOW dose.
Conclusion
The modeling results, together with the clinical evidence of safety and efficacy, supported the recommended 4 mg/kg QOW dosing regimen of vestronidase alfa for pediatric and adult patients with MPS VII.
Clinical Trial Registration
NCT01856218, NCT02418455, NCT02230566.
The purpose of this study is to examine the factors that affect the adoption of electronic invoice and in return the consequences of these factors on tax compliance process efficiency of companies in ...China. A questionnaire survey was distributed to 276 users who adopted electronic invoice and partial least squares regression was used to analyze the data. This study found that perceived benefits and trust in e-government had a positive influence on the adoption of electronic invoice. Furthermore, we also found that the adoption of electronic invoice have a positive impact on the efficiency of the tax compliance process. Moreover, the factors affecting adoption of electronic invoice can have a mediating effect between adoption and tax compliance process efficiency. This study has some limitations because it only explores these influencing factors on companies that has adopted electronic invoice. Future research will be carried out to distinguish between adopters and non-adopters. The results of this study can guide tax authorities and other electronic invoice suppliers to promote the adoption of electronic invoice. This study contributes to the electronic adoption literature by examining antecedents that have consequences on tax compliance processes efficiency.
Purpose
The purpose of this study is to examine the factors that affect the adoption of electronic invoices and in turn the impact of these factors on the tax compliance process efficiency of ...companies.
Design/methodology/approach
A questionnaire survey was distributed to 276 users who adopted electronic invoicing. Partial least squares regression was used to analyze the collected data.
Findings
This study found that perceived benefits and trust in e-government had a positive influence on the adoption of electronic invoices. At the same time, the adoption of electronic invoice was found to have a positive impact on the overall efficiency of the tax compliance process. Moreover, the factors affecting adoption of electronic invoices can have a mediating effect on that adoption and tax compliance process efficiency.
Research limitations/implications
This study only explored these influencing factors on companies that have adopted electronic invoicing. Future research should distinguish between adopters and non-adopters.
Practical implications
The results of this study can guide tax authorities and other electronic invoice suppliers when promoting the adoption of electronic invoicing.
Social implications
This research can provide guidance to tax authorities to improve their own electronic invoice system by creating a workforce that have the skills to strengthen citizen’s trust in the electronic invoice system.
Originality/value
This study contributes to the electronic adoption literature by examining those factors that impact tax compliance processes efficiency.
Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment ...outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period.
Background and Objective
Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective ...in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.
Methods
A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95−15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen.
Results
A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide’s clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population.
Conclusions
The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers.
Clinical Trial Registration
NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.
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