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Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18–37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were − 0.06 (0.03) (p = 0.0010) and − 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety. • Substantial pharmacodynamic effects of venglustat in adult males with Fabry disease. • Adverse events were mostly mild (73%) and unrelated to study drug (70%). • No deaths or treatment-related life-threatening adverse events. • Nine serious and 11 severe treatment-emergent adverse events. • Exploratory efficacy justifies further clinical evaluation in patients with Fabry disease. [ABSTRACT FROM AUTHOR]

Abstract: The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6months to 76years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia. [Copyright &y& Elsevier]

Abstract: Fabry disease (α-galactosidase A deficiency) is an X-linked disorder. Women who are heterozygous for disease-causing mutations often manifest signs and symptoms of Fabry disease, but most studies of the effects of enzyme replacement therapy (ERT) have included only men. To date, no direct comparison has been made of the relative effectiveness of long-term ERT between men and women. The aim of this analysis was to report the effectiveness of agalsidase alfa in a cohort of 78 women treated for 4years and to compare outcomes with those of 172 men. All data were obtained from the Fabry Outcome Survey—an international database of patients with Fabry disease sponsored by Shire Human Genetic Therapies. Quantifiable clinical parameters were assessed at baseline and the 4-year time point. Measures of pain, health-related quality of life, cardiac structure and function, and renal function changed to a similar extent in women and men during treatment, with the exception of left ventricular mass, which only reduced significantly in women. Changes in the presence of each of 27 clinical features after 4years of ERT were evaluated in two subpopulations: patients with and patients without clinical features at baseline. It was clear for most types of clinical features that a number of women with a feature at baseline were no longer reported to have it at the 4-year time point, and that clinical features were observed in only a small percentage of women in whom they had been absent at baseline. The percentage of patients who were symptomatic at the 4-year time point was calculated for each type of clinical feature. The results showed no significant differences between men and women for most clinical features evaluated. Overall, both sexes responded to agalsidase alfa in a similar way, suggesting there should be no difference in the criteria for assessment of treatment in women and men. [Copyright &y& Elsevier]