Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study

Objective

To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).

Methods

Patients with Morquio A aged ≥5 years (N?=?176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.

Results

At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P?=?0.017) for weekly and 0.5 m (95 % CI ?17.8, 18.9; P?=?0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI ?2.1, 4.4; P?=?0.494) for weekly and ?0.5 stairs/min (95 % CI ?3.7, 2.8; P?=?0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.

Conclusions

Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.     

Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation

Allergy is the result of a complex immune cascade leading to the dysregulated production of Th2 cytokines, the generation of allergen-specific IgE-producing B cells and the subsequent activation and degranulation of mast cells upon allergen challenge. Dendritic cells (DCs) play an important role in several models of allergy, but factors instructing DCs to induce a dysregulated Th2 response are currently unknown. In this review, we present recent evidence that human thymic stromal lymphopoietin (TSLP), a novel IL-7-like cytokine, might represent an early trigger of the allergic immune cascade. TSLP-activated human DCs produce Th2-attracting chemokines but no IL-12, and induce naive CD4⁺ and CD8⁺ T cell differentiation into effector cells with a typical pro-allergic phenotype. TSLP is produced by human epithelial, stromal, and mast cells. It is highly expressed by the keratinocytes of atopic dermatitis but not in other types of skin inflammation. Thus, epithelial- and stromal-cell-derived TSLP might represent one of the factors initiating the allergic responses, and could be a target for a curative therapeutic approach to allergy.     

Tumor cell proliferation in early gastric cancer: biological and clinical behavior

BACKGROUND/AIMS: Recently, early gastric cancers without lymph node metastasis have successfully been removed through a simple endoscopic resection. Tumor cell proliferation may be related to the malignant potential of early gastric cancer. The purpose of this study is to prospectively investigate the relationship between the incorporation rate of bromodeoxyuridine (BrdU) into the DNA of dividing cells, and the main biological and clinical early gastric cancer characteristics. METHODOLOGY: Multiple tumor specimens were taken from 27 early gastric cancers and analyzed through anti-BrdU monoclonal antibody. Tumor BrdU labeling index (LI=% positive cells over 2,000 tumor cells) was determined. Early gastric cancers were evaluated in tumor size, mucosal and submucosal involvement, histologic type and grading, lymphatic and venous invasion, and nodal metastasis. RESULTS: BrdU LI was significantly higher in patients with submucosal neoplastic invasion, Pen A Kodama type, tumor vessel invasion and lymph node involvement. Early gastric cancer patients with over 22% BrdU LI showed a significantly higher incidence of submucosal invasion, lymphatic-venous involvement and a reduced survival when compared to patients with medium (12-22%) or low BrdU LI (<12%). CONCLUSIONS: Our results suggest that BrdU LI may be considered a useful indicator of early gastric cancer aggressiveness.     

Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPSIII) is a lysosomal storage disease with predominant neurological manifestations in affected children. It is considered heterogeneous with respect to prevalence, clinical presentation, biochemistry (four biochemical forms of the disease referred to as MPSIIIA, B, C, and D are known), and causative mutations. The perspective of therapeutic options emphasizes the need for better knowledge of MPSIII incidence and natural history. We performed parallel retrospective epidemiological studies of patients diagnosed with MSPIII in France (n = 128), UK (n = 126), and Greece (n = 20) from 1990 to 2006. Incidences ranged from 0.68 per 100,000 live‐births in France to 1.21 per 100,000 live‐births in UK. MPSIIIA, which predominates in France and UK, was absent in Greece, where most patients have MPSIIIB. The study confirmed the large allelic heterogeneity of MPSIIIA and MPSIIIB and detected several yet undescribed mutations. Analysis of clinical manifestations at diagnosis and over a 6–7 years follow‐up indicated that almost all patients, whatever the disease subtype, expressed neurological manifestations before the age of 5 years, including language acquisition delay, cognitive delay, and/or abnormal behavior. In contrast to relatively homogeneous early onset manifestations, disease progression showed significant variation depending on subtype and age at diagnosis. Different severities of disease progressions and different allele distribution between France and UK suggested that mutations are not equally deleterious, although genotype–phenotype correlation could not be established. Notwithstanding the rapidity of further clinical deterioration, all MPSIII patients suffer early onset devastating neurological manifestations that deserve early treatment when available. © 2010 Wiley‐Liss, Inc.     

Allogeneic bone marrow transplantation in mevalonic aciduria

Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.     

Functional analysis of a novel POLγA mutation associated with a severe perinatal mitochondrial encephalomyopathy

Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POLγA) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POLγA often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POLγA mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death. Muscle biopsy identified scattered COX-deficient muscle fibers, respiratory chain dysfunction and mtDNA depletion. We identified a novel POLγA mutation (p.His1134Tyr) in trans with the previously identified p.Thr251Ile/Pro587Leu double mutant. Biochemical characterization of the purified recombinant POLγA variants showed that the p.His1134Tyr mutation caused severe polymerase dysfunction. The p.Thr251Ile/Pro587Leu mutation caused reduced polymerase function in conditions of low dNTP concentration that mimic postmitotic tissues. Critically, when p.His1134Tyr and p.Thr251Ile/Pro587Leu were combined under these conditions, mtDNA replication was severely diminished and featured prominent stalling. Our data provide a molecular explanation for the patient´s mtDNA depletion and clinical features, particularly in tissues such as brain and muscle that have low dNTP concentration.     

A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states

Objective:  Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania.
Methods:  After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5–20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values.
Results:  Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean ± SE changes in YMRS scores were observed on day 2 with asenapine (−3.0 ± 0.4) and olanzapine (−3.4 ± 0.4) versus placebo (−1.5 ± 0.5, both p < 0.01) and were maintained until day 21 (−10.8 ± 0.8 with asenapine, −12.6 ± 0.8 with olanzapine; both p ≤ 0.0001 versus placebo, −5.5 ± 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures.
Conclusions:  These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.     

Near strongly resonant periodic orbits in a Hamiltonian system

We study an analytic Hamiltonian system near a strongly resonant periodic orbit. We introduce a modulus of local analytic classification. We provide asymptotic formulae for the exponentially small splitting of separatrices for bifurcating hyperbolic periodic orbits. These formulae confirm a conjecture formulated by V. I. Arnold in the early 1970s.