Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)--10-year follow-up of patients who previously participated in an MPS VI Survey Study.

Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4-7-year-old baseline age group and by 16.8 cm in the 8-12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those ≥13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the ≥13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10-0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival.

Quantifying preferences for urea cycle disorder treatments using a discrete choice experiment.

AIMS: Urea cycle disorders (UCDs) can cause ammonia accumulation and central nervous system toxicity. Nitrogen-binding medications can be efficacious, but certain attributes may negatively impact adherence. This study sought to quantify the administration-related attributes influencing overall prescription selection and patient adherence. METHODS: A web-based, quantitative survey including discrete choice experiment (DCE) methodology captured responses from health care providers for patients with UCDs. A series of hypothetical treatment profile sets with attributes such as route of administration, taste/odor, preparation instructions, packaging, dose measurement, and weight use restrictions were presented. From 16 sets of 3 hypothetical product profiles, respondents evaluated attributes most preferred for prescription selection or patient adherence. Attributes assumed a higher overall preference if relative importance (RI) scores were >16.67% (the value if all attributes were of equal importance). Preference weight scores were assessed. A nine-point Likert scale assessed respondent attitudes, such as satisfaction. RESULTS: A total of 51 respondents completed the survey. Respondents reported dissatisfaction with current treatments (mean [SD] = 5.4 [1.7]). For prescription selection, four attributes achieved RI >16.67%: taste/odor (24%), weight restrictions (21%), preparation instructions (18%), and route of administration (17%). For adherence, three attributes related to administration achieved RI >16.67%: taste/odor (28%), preparation instructions (21%), and route of administration (17%). Preference weights for "taste/odor masked" were higher than "not taste/odor masked" for prescription selection (mean [SD]; 1.52 [1.10] vs -1.52 [1.10]) and treatment adherence (73.8 [55.2] vs -73.8 [55.2]). LIMITATIONS: This study contained a relatively small sample size. Survey respondent selection, the use of hypothetical product profiles, and exclusion of non-pharmacologic treatment options could have contributed to potential biases. CONCLUSIONS: Among attributes tested, taste/odor was the most important attribute influencing overall preference for both prescribing and patient adherence, with taste/odor masking preferred. Optimizing nitrogen-binding medications through masking taste/odor may support improved patient adherence and outcomes in UCDs.

Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies.

BACKGROUND: Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing. OBJECTIVE: Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID. METHODS: PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale. RESULTS: Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were -5.5 [-9.8, -1.2], p = 0.012 and -5.2 [-9.5, -0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively). CONCLUSIONS: IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

A benefit-risk analysis of pegvaliase for the treatment of phenylketonuria: A study of patients' preferences.

BACKGROUND: Phenylketonuria (PKU) leads to an accumulation of phenylalanine (Phe) in the blood and subsequent neurologic, cognitive, psychiatric, and behavioral dysfunction. Many patients report social isolation and decreased quality of life. Pegvaliase is an enzyme substitution therapy that reduces blood Phe levels in patients with PKU and is associated with a risk of hypersensitivity reactions. OBJECTIVE: To define the minimum acceptable benefit (MAB) of pegvaliase, i.e., the minimum probability of achieving a blood Phe level <360 µmol/L, which patients require to tolerate the risks of hypersensitivity associated with pegvaliase. METHODS: Adult, pegvaliase-naïve patients with blood Phe levels >600 µmol/L participated in a patient-preference web survey using two surveys: adapted swing-weighting and thresholding. Participants were asked to make ordinal choices between varying clinical benefit and severity levels for hypersensitivity. Disease effects and treatment satisfaction were also assessed. RESULTS: Among 45 participants, the mean (standard deviation) self-reported blood Phe level was 976.9 (429.9) µmol/L; only 28.8% reported satisfaction with their current treatment. Most (84.4%) indicated difficulty in following a PKU diet; 60% reported that the PKU diet was burdensome, and 58% reported feeling socially isolated. Most (≥69%) reported their MAB to be less than the expected clinical benefit provided by pegvaliase; the mean MAB was 22.7% and 34.4% in the swing-weighting and thresholding surveys, respectively. CONCLUSION: Most participants felt the burden of PKU on their daily lives, were dissatisfied with current treatments, and were willing to accept the risks of hypersensitivity reactions to achieve recommended blood Phe levels with pegvaliase treatment.

Pulmonary function tests (maximum inspiratory pressure, maximum expiratory pressure, vital capacity, forced vital capacity) predict ventilator use in late-onset Pompe disease.

In patients with Late-Onset Pompe Disease (LOPD), progressive respiratory muscle involvement leads to reduced pulmonary function, with respiratory failure the most common cause of mortality. Early disease manifestations include sleep-disordered breathing, which can be treated with non-invasive ventilation; however, progressive diurnal deficits can require invasive ventilation. To determine if pulmonary function tests (PFTs) predict the thresholds for ventilation and wheelchair use, a systematic literature review identified cross-sectional clinical patient data (N = 174) that was classified into ventilation and wheelchair cohorts. PFTs included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and vital capacity (VC), with vital capacities measured in the upright (-U) and supine (-S) positions. Receiver operating characteristic (ROC) curves were used to calculate cut-points (CP) and area under the curve (AUC). For all ventilation and mobility thresholds tested, ROC analyses demonstrated AUC values from 86-89% for MIP, 72-96% for MEP, and 74-96% for all vital capacity metrics. Thus, PFTs are useful in predicting the thresholds for nighttime ventilation, daytime ventilation, and wheelchair use, with MIP and VC-U having both high AUC values and consistency. The PFT mobility CPs were low (MIP CP = 0.9 kPa, MEP, CP = 2.6 kPa, VC-U CP = 19% predicted), suggesting an endurance component associated with wheelchair use.

Growth Charts for Individuals with Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome).

BACKGROUND: The skeletal phenotype of mucopolysaccharidosis VI (MPS VI) is characterized by short stature and growth failure. OBJECTIVE: The purpose of this study was to construct reference growth curves for MPS VI patients with rapidly and slowly progressive disease. METHODS: We pooled cross-sectional and longitudinal height for age data from galsulfase (Naglazyme(®), BioMarin Pharmaceutical Inc.), treatment naïve patients (n = 269) who participated in various MPS VI studies, including galsulfase clinical trials and their extension programs, the MPS VI clinical surveillance program (CSP), and the MPS VI survey and resurvey studies, to construct growth charts for the MPS VI population. There were 229 patients included in this study, of which data from 207 patients ≤25 years of age with 513 height measurements were used for constructing reference growth curves. RESULTS: Height for age growth curves for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles were constructed for patients with rapidly and slowly progressing disease defined by the pre-enzyme replacement therapy (ERT) uGAG levels of > or ≤200 µg/mg creatinine. The mean (SD) pre-ERT uGAG levels were 481.0 (218.6) and 97.8 (56.3) µg/mg creatinine for the patients ≤25 years of age with rapidly (n = 131) and slowly (n = 76) progressing MPS VI disease, respectively. The median growth curves for patients with ≤ and >200 µg/mg creatinine were above and below the median (50th percentile) growth curve for the entire MPS VI population. CONCLUSION: MPS VI growth charts have been developed to assist in the clinical management of MPS VI patients.

Effects of Food Intake on the Relative Bioavailability of Amifampridine Phosphate Salt in Healthy Adults.

PURPOSE: Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow therapeutic index, and supratherapeutic exposure has been associated with dose-dependent adverse events, including an increased risk for seizure. This study assessed the effect of food on the relative bioavailability of amifampridine in healthy subjects and informed on conditions that can alter exposure. METHODS: This randomized, open-labeled, 2-treatment, 2-period crossover study enrolled 47 healthy male and female subjects. Subjects were randomly assigned to receive 2 single oral doses of amifampridine phosphate salt (20 mg base equivalents per dose) under fed or fasted conditions separated by a washout period. Blood and urine samples for pharmacokinetic analyses were taken before and after dosing. Plasma concentrations of amifampridine and an inactive 3-N-acetyl metabolite were determined. The relative bioavailability values of amifampridine and metabolite were assessed based on the plasma PK parameters AUC0-∞, AUC0-t, and Cmax in the fed and fasted states using noncompartmental pharmacokinetic analysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect on bioavailability would be established if the 90% CI of the ratio of population geometric mean value of AUC0-∞, AUC0-t, or Cmax between fed and fasted administration was not within the bioequivalence range of 80% to 125%. Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use. FINDINGS: Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (Cmax, 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean Tmax was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean Cmax. Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed. IMPLICATIONS: At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13.

Inhibition of graft coronary arteriosclerosis after heart transplantation.

Graft coronary arteriosclerosis (GCA) is the leading cause of long-term mortality after heart transplantation (HTx). The goal of this study was to demonstrate that inhibition of immunemediated injury by cyclosporine (CsA) protects the allograft from GCA. ACI-to-Lewis rat allografts were disparate in major and nonmajor histocompatibility loci. Isografts (Lewis-Lewis) were controls. Treatment groups received either olive oil or CsA at 2.5, 5, 10, or 20 mg/kg/day for 3 months. Histology (elastin) and immunohistochemistry using monoclonal antibodies to CD4, CD8, CD45R, RT1B, CD11b/c, CD25, and alpha-actin was performed to examine the epicardial and intramyocardial coronary arteries. Computerized image morphometry was utilized to measure intimal and medial thickness and area. Rats receiving olive oil or CsA at 2.5 mg/kg/day had severe rejection and no graft survival. CsA at 5 mg/kg/day resulted in less severe rejection with significant intimal and medial proliferation (P < 0.001). CsA at 10-20 mg/kg/day paralleled Lewis-Lewis isograft outcomes and inhibited arteriosclerotic vascular changes in the allograft (P < 0.001). Perivascular T-helper cells and macrophages were a characteristic finding with low-dose CsA but rare with higher CsA doses. In this new model of accelerated GCA in rats, immune-mediated antigen-dependent vasculopathy as a result of inadequate immunosuppresion is fundamental in the development of GCA, which appeared equally in epicardial arteries and intramyocardial arterioles. CsA prevents GCA in a dose-dependent fashion in the rat allograft.

Long-Term Galsulfase Treatment Associated With Improved Survival of Patients With Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): 15-Year Follow-Up From the Survey Study

Abstract Mucopolysaccharidosis VI (MPS VI) is a progressive lysosomal storage disorder with multiorgan and multisystemic pathology. Currently, galsulfase enzyme replacement therapy (ERT) is the only approved treatment for MPS VI. A crosssectional survey study of 121 patients with MPS VI conducted in 2001 to 2002 and a 10-year follow-up study of the same patients (resurvey study; ClinicalTrials.gov NCT01387854) found that those receiving galsulfase at any time showed physical improvements and a lower mortality rate (16.5%) versus treatment-naive patients (50%). After *15 years, galsulfasetreated patients (n » 104) continue to have a survival advantage over treatment-naive patients (n » 14), as demonstrated by a 24% versus 57% mortality rate. This survival advantage is further supported by data from the commercial use of galsulfase (2005-2016), which show a 5-year mortality rate for galsulfase-treated patients of 12.5%. Together, these findings suggest that galsulfase ERT can increase life expectancies for patients with MPS VI over a period of at least 15 years.

Eosinophilic myocarditis in patients awaiting heart transplantation.

OBJECTIVE: To determine the possible causative agents of eosinophilic or hypersensitivity myocarditis in patients awaiting heart transplantation. DESIGN: Consecutive patient series. SETTING: Large university-affiliated hospital. PATIENTS: A total of 190 consecutive patients who had heart transplantation at our center. INTERVENTIONS: The myocardium of the explanted heart was examined for a mixed inflammatory cell infiltrate containing an identifiable component of eosinophils. The relative quantity of each cell type was evaluated by a semiquantitative grading system (scored 0 to 3). The clinical findings and medications were reviewed, and patients were followed after heart transplantation. MEASUREMENTS AND MAIN RESULTS: Eosinophilic myocarditis (EM) was found in the explanted heart in 14 patients (7.4%). Myocardial infiltration by eosinophils ranged from mild (n = 6), often focal involvement to marked (n = 8), usually multifocal or widespread involvement. Twelve patients (86%) had peripheral blood eosinophilia before transplant, and in ten (71%), the eosinophil count at least doubled. Loop or thiazide diuretics were used in all 14 patients, and angiotensin-converting enzyme inhibitors were used in 12. Preoperative characteristics were similar in patients with and without EM, except for a higher frequency of inotropic support and assist devices in EM patients. Dobutamine was used in 12 (86%) and dopamine in seven (50%; one with dopamine alone), and one patient (7%) received neither dopamine nor dobutamine. In two patients receiving dobutamine and one receiving dopamine, tapering or discontinuation of the inotropic infusion resulted in a significant diminution of the peripheral eosinophilia and the EM before transplantation. Postoperative survival in patients with and without EM was similar at 8 yrs (50% +/- 13% and 54% +/- 4%, p =.34). No patient in this study has had EM on biopsy after transplant. CONCLUSIONS: EM is a complication of multiple drug therapy in patients awaiting heart transplantation, and should be suspected when peripheral blood eosinophilia is present or the eosinophil count increases by at least two-fold. EM may be related to intravenous inotropic therapy, and this is the first study to document improvement in myocardial pathology after inotropic drug withdrawal. Hypersensitivity to thiazide and loop diuretics, angiotensin-converting enzyme inhibitors, and antibiotics must also be considered. Survival after heart transplantation is not impaired, and postoperative steroid therapy may prevent EM.