Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease

Purpose: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. Methods: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. Results: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. Conclusion: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD

Gaucher Disease in Bone: From Pathophysiology to Practice

Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years' of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X-ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow-up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc

Presenting signs and patient co-variables in Gaucher disease : outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative

© 2018 The Authors. Internal Medicine Journal by Wiley Publishing Asia Pty Ltd on behalf of Royal Australasian College of Physicians.Background: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. Aim: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify ‘at-risk’ patients who may benefit from diagnostic testing. Methods: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. Results: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. Conclusion: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.Peer reviewedFinal Published versio

Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy

In the phase 3 trial of eliglustat in patients with Gaucher disease type 1 already stabilized with enzyme therapy (ENCORE), at one year, eliglustat was non-inferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all four measures remained collectively stable (composite endpoint relative to baseline values) in ≥85% of patients, as well as individually in ≥92%. Mean bone mineral density Z-scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well-tolerated over 4 years; 4 (2.5%) patients withdrew due to adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years.The ENCORE trial was funded and conducted by Sanofi Genzyme

Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study

Background Late-onset Pompe disease is characterized by progressive skeletal myopathy followed by respiratory muscle weakness, typically leading to loss of ambulation and respiratory failure. In this population, enzyme replacement therapy (ERT) with alglucosidase alfa has been shown to stabilize respiratory function and improve mobility and muscle strength. Muscle pathology and glycogen clearance from skeletal muscle in treatment-naïve adults after ERT have not been extensively examined. Methods This exploratory, open-label, multicenter study evaluated glycogen clearance in muscle tissue samples collected pre- and post- alglucosidase alfa treatment in treatment-naïve adults with late-onset Pompe disease. The primary endpoint was the quantitative reduction in percent tissue area occupied by glycogen in muscle biopsies from baseline to 6 months. Secondary endpoints included qualitative histologic assessment of tissue glycogen distribution, secondary pathology changes, assessment of magnetic resonance images (MRIs) for intact muscle and fatty replacement, and functional assessments. Results Sixteen patients completed the study. After 6 months of ERT, the percent tissue area occupied by glycogen in quadriceps and deltoid muscles decreased in 10 and 8 patients, respectively. No changes were detected on MRI from baseline to 6 months. A majority of patients showed improvements on functional assessments after 6 months of treatment. All treatment-related adverse events were mild or moderate. Conclusions This exploratory study provides novel insights into the histopathologic effects of ERT in late-onset Pompe disease patients. Ultrastructural examination of muscle biopsies demonstrated reduced lysosomal glycogen after ERT. Findings are consistent with stabilization of disease by ERT in treatment-naïve patients with late-onset Pompe disease

Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial

Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α-galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half-life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open-label, 3-month dose-ranging study, followed by a 9-month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment-emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half-life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m 2 at baseline, remaining stable throughout treatment. Three patients developed treatment-induced IgG ADAs; following 1 year's treatment, all became ADA-negative. Nearly all treatment-emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity