Aim: Late-onset Pompe disease (LOPD) is a rare lysosomal disease primarily impacting muscle strength and respiratory function. LOPD has a substantial burden despite the availability of alglucosidase alfa (alg). Patients often require mobility and respiratory support over time. Cipaglucosidase alfa in combination with miglustat (cipa + mig) is one of two more recently approved treatments for adults with LOPD. Given limited data on the lifetime trajectory to mobility and respiratory support in LOPD, a patient-level simulation model was developed to compare the long-term impact of cipa + mig with alg on these outcomes. Materials & methods: The patient-level simulation predicts lifetime mobility and respiratory disease progression outcomes based on the 6-min walk distance and %predicted forced vital capacity for alg and cipa + mig for the overall LOPD population using available data and assumptions from experienced clinicians. PROPEL/PROPEL open-label extension ( NCT03729362 ) and ATB200-02 ( NCT02675465 ) studies informed outcomes for four years with cipa + mig and one year with alg. French Pompe disease registry data were used thereafter. Results: Based on the available data and clinical assumptions, the model predicts cipa + mig slows the overall progression of LOPD, allowing patients an additional 2.72 years without mobility or respiratory support compared with alg. People receiving alg may be wheelchair dependent and require invasive respiratory support for an additional 2.57 and 1.55 years, respectively. Conclusion: Cipa + mig may delay disease progression compared with alg over the lifetime of a patient with LOPD, which would increase the amount of time spent without mobility and respiratory support dependency.

Enzyme replacement therapies (ERTs) approved for Fabry disease require infusions every 2 weeks (E2W). Pegunigalsidase alfa, a PEGylated ERT with a prolonged half-life vs. other ERTs, may allow extension of the dosing interval to every 4 weeks (E4W). BRIGHT F51 (NCT03614234) is an ongoing phase III, open-label extension study evaluating long-term efficacy and safety of pegunigalsidase alfa 2 mg/kg E4W in adults with Fabry disease previously treated with agalsidase alfa or beta E2W for ≥ 3 years who completed one year of pegunigalsidase alfa treatment in the BRIGHT study. This interim analysis reports results following 3–5 years of treatment (cutoff date December 31, 2022). Twenty-nine patients were enrolled. Median (interquartile range [IQR]) annualized eGFR slope during treatment was ‒2.2 (‒2.9; ‒1.1) mL/min/1.73 m2/year (males: ‒2.4 [‒2.9; ‒1.0, n = 23]; females: ‒1.8 [‒2.4; ‒1.3, n = 6]; anti-drug antibody [ADA]-positive: ‒2.6 [‒4.0; ‒1.7, n = 9 all male]; ADA-negative: ‒1.8 [‒2.7; ‒0.6, n = 20]). Median (IQR) change in plasma lyso-Gb3 from baseline to Week 208 was 3.2 (‒3.9; 8.5, n = 17) nM in males; concentrations remained low and stable in females. Overall, 51/477 treatment-emergent adverse events in 13 patients (45

Untreated women with Gaucher disease (GD) are at an increased risk of GD-related complications during pregnancy. Enzyme replacement therapy with imiglucerase is effective at improving hematologic, visceral, and bone manifestations of GD, and the Food & Drug Administration prescribing information supports that imiglucerase is not associated with adverse maternal or fetal outcomes when used during pregnancy. This study population included women with GD enrolled in the International Collaborative Gaucher Group Gaucher Registry (NCT00358943) Pregnancy Sub-Registry who were treated with imiglucerase during at least one pregnancy as of October 2023. We describe frequency of pregnancy outcomes, birth outcomes, and maternal and neonatal complications. Imiglucerase exposure was reported in 110 pregnancies in 68 women with GD type 1; 68% of pregnancies were exposed during all three trimesters. Of 104 fetuses with reported data, 92 were live births (88.5%), eight were spontaneous abortions (7.7%), and four were elective/therapeutic terminations (3.8%); no stillbirths (> 20 weeks gestation) were reported. The majority of infants (80 of 85 [94.1%]) were born at term. Among 108 pregnancies with data, maternal pregnancy, labor and delivery, and post-partum complications were reported for 33 (30.6%), 26 (24.1%), and 24 (22.2%) pregnancies, respectively, with anemia, thrombocytopenia, and vaginal bleeding among the most prevalent complications. Among 74 infants with data, neonatal complications were reported for seven infants (9.5%). Most pregnancies to women with GD treated with imiglucerase resulted in live births and healthy infants, with risk of spontaneous abortions similar to that of the general population (12%-18%).

Abstract Background Fabry disease (FD) is a rare lysosomal storage disorder with cardiac involvement. The efficacy of cardiac assessments in predicting disease progression is uncertain and few long-term studies have evaluated a clinically comprehensive approach in tracking cardiac outcomes. We developed a multi-modal framework integrating sex, genetics, clinical assessments, electrocardiography (ECG), imaging, and biomarkers to characterize the progression of cardiac involvement in FD and assess the predictive value of each modality for adverse cardiovascular outcomes. Results Our cohort encompassed 525 “visit years” across 98 participants (60 females; 60 with classic mutations; mean age at presentation: 42.5 ± 17). We defined four cardiac phenotypic clusters (CPC): abnormal ECG, elevated cardiac biomarkers, left ventricular hypertrophy (LVH) (by echocardiography or cardiac magnetic resonance [CMR]), and late gadolinium enhancement (LGE) (by CMR). The primary outcome was a composite of cardiac hospitalization, device implantation, or cardiovascular/cerebrovascular death. A CPC progression map was plotted, outlining the course of events in FD cardiomyopathy, where changes in ECG and the occurrence of hypertrophy precede increase in cardiac biomarkers and the formation of LGE. Mutation type (classic vs. late-onset) and sex (female vs. male) showed a significant link with a composite outcome of cardiac-related hospitalizations, device implantations (defibrillator/pacemaker), and cardiovascular or cerebrovascular mortality [Hazard ratio, HR (95% confidence interval, CI, p-value): 12.8 (3.5,46.7), p = 0.0001 and 0.09 (0.03,0.33), p = 0.0002, respectively]. The presence of LGE CPC was associated with an increased likelihood of encountering the composite outcome. Conclusions We propose a readily-applied “4 domain CPC” model, that can be routinely used in clinical practice, as a prospective “guide-map” for FD cardiomyopathy progression. Its utility is demonstrated in showing the expected role of sex, mutation and CMR findings in the cardiac trajectory of FD.

Fabry disease is an X-linked lysosomal storage disorder that causes accumulation of glycosphingolipids in body tissues and fluids, leading to progressive organ damage and life-threatening complications. It can affect both males and females and can be classified into classic or later-onset phenotypes. The disease severity in females ranges from asymptomatic to the more severe, classic phenotype. Most females are hemizygous and the X-linked inheritance is associated with variable X-activation pattern and residual enzymatic activity. The heterogeneity of clinical presentation in females requires different approaches to diagnosis and management than males. A European group of 7 physicians, experienced in the management of Fabry disease, convened to discuss patient perspectives and published guidelines. The experts discussed the need to focus on psychological treatment in relation to individual coping styles when monitoring targets, and the lack of data supporting the use of plasma globotriaosylsphingosine over enzyme activity in the diagnosis of these patients. It was suggested that the high phenotypic variability in female patients may be related to the dynamic nature of the X-chromosome inactivation process and further understanding of this process could help predict the progression of Fabry disease in females and facilitate timely intervention. Due to the range of disease severity they exhibit, female patients with Fabry disease may require a more individualized treatment approach than males. Despite current recommendations, the experts agreed that early disease-specific treatment initiation in high-risk females could improve clinical outcome.

PURPOSE:To evaluate the disease biomarker response of venglustat in patients with Fabry disease (FD), utilizing data from a single-arm phase 2 study of venglustat and a placebo-controlled phase 3 study of agalsidase beta through historical control and case-matched analyses. METHODS:Eleven venglustat-treated male patients with classic FD in the phase 2 study were matched with placebo- or agalsidase beta-treated patients from the phase 3 study based on propensity scores at baseline. Changes from baseline in plasma globotriaosylceramide (GL-3 or Gb3) concentrations were analyzed at approximately 6-36 months. RESULTS:Venglustat treatment resulted in greater significant reductions in plasma GL-3 concentrations at 6 months from baseline vs. placebo (mean difference -2.56 μg/mL, p < 0.001), and at 24 and 36 months from baseline vs. agalsidase beta (mean difference -1.8 μg/mL, p < 0.05 and -2.35 μg/mL, p < 0.01, respectively). GL-3 concentrations continued to decline with venglustat for up to 3 years without plateauing. CONCLUSIONS:Venglustat showed significantly greater reductions in plasma GL-3 concentrations than placebo after 6 months and agalsidase beta after 24 and 36 months. These findings support the potential of long-term venglustat treatment to reduce GL-3 accumulation in patients with classic FD. Further studies are needed to confirm clinical benefit.

Abstract Background Patients with Gaucher disease (GD) require continual monitoring; however, lack of specific disease biomarkers was a significant challenge in the past. Glucosylsphingosine (lyso-Gb1) has been shown to be a reliable, key, specific, and sensitive biomarker for diagnosis, prognosis, and treatment response in clinical studies of patients with GD. We evaluated the change in lyso-Gb1 concentration over time following enzyme replacement therapy in patients with confirmed GD using real-world data from the Gaucher Outcome Survey disease registry. Methods Data for patients aged ≥ 18 years with a confirmed diagnosis of GD and at least two lyso-Gb1 assessments were analyzed retrospectively. Patients were stratified by treatment status at baseline (time of first lyso-Gb1 assessment). Lyso-Gb1 concentrations were measured from dried blood spot (DBS) samples by Centogene AG. Assessments included change in lyso-Gb1 concentration, hemoglobin concentration, platelet counts, and spleen and liver volume from baseline to the last lyso-Gb1 assessment. Results Of 2007 patients enrolled in the Gaucher Outcome Survey as of February 25, 2022, 435 met the inclusion criteria and were included in the study: 318 treated (‘all treated’; 277 receiving treatment at baseline, 41 treatment naive at baseline), 38 receiving treatment at baseline who stopped treatment before the last lyso-Gb1 assessment, and 79 untreated. Lyso-Gb1 concentrations decreased from baseline to the last lyso-Gb1 assessment for all treated patients (median change − 8.6 ng/mL), and increased for untreated patients (median change 25.0 ng/mL) and those who stopped treatment (median change 19.5 ng/mL). Decreases were greater for all treatment-naive than previously treated patients (median change − 120.5 vs. − 3.3 ng/mL) and for velaglucerase alfa–treated patients vs. the overall treated cohort (–32.6 vs. − 8.6 ng/mL). Small improvements in hemoglobin concentrations, platelet counts, and spleen volume were observed for treated patients but not untreated/stopped treatment cohorts. Conclusions In this study, changes in lyso-Gb1 concentrations from DBS were reflective of responses to enzyme replacement therapy initiation or withdrawal in most patients. These findings confirm that the use of DBS samples for routine monitoring of lyso-Gb1 concentrations in patients with GD is feasible in real-world settings and may be useful to assess treatment response.

Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting.

Introduction Le pegunigalsidase alfa est une thérapie enzymatique de remplacement (TER) approuvée pour la maladie de Fabry à la dose de 1mg/kg administrée par voie intraveineuse toutes les deux semaines (T2S). Afin d’alléger le fardeau du calendrier d’administration T2S, le schéma posologique alternatif de 2mg/kg toutes les quatre semaines (T4S) a été étudié dans l’essai BRIGHT/F50 et son extension (BRIGHT-F51/CLI-06657AA1-03). Matériels et méthodes Afin d’explorer l’expérience des patients avec la pegunigalsidase alfa administrée T4S, les sujets enrôlés dans l’essai BRIGHT-F51 ont été invités à participer à l’étude qualitative transversale PEOPLE axée sur les résultats centrés sur le patient tels que les signes/symptômes et l’impact sur la qualité de vie (QdV). 17/29 entretiens ont été réalisés en suivant un guide d’entretien semi-structuré. Le codage des transcriptions des entretiens a été effectué à l’aide du logiciel d’analyse qualitative MAXQDA. Résultats En décrivant leur expérience, les patients ont signalé 54 signes/symptômes uniques (par exemple, fatigue, diminution de la transpiration et douleur dans les extrémités) et 24 impacts uniques sur la QdV. Les répercussions sur les activités de la vie quotidienne et la productivité au travail ou à l’école sont les concepts les plus fréquemment signalés comme affectant “gravement” la qualité de vie des patients. Les patients ont également été invités à décrire les avantages ou les inconvénients de l’horaire T4S par rapport à l’horaire T2S. L’horaire T4S a été perçu comme plus pratique et permettant aux patients de mieux gérer leur temps et leurs activités et d’être plus productifs. L’horaire T4S est également perçu comme permettant aux patients de mener une vie plus normale. Les patients ont également attribué l’amélioration de la qualité de vie à l’atténuation de certains signes/symptômes (par exemple, la fatigue, la diarrhée et les douleurs aux extrémités) qu’ils associaient à l’efficacité du médicament. En outre, l’avantage de ne pas avoir sommeil en raison de l’absence de prise d’antihistaminique avant la perfusion a été mentioné par les patients. Pour la plupart des patients, ces avantages l’emportent sur l’inconvénient d’une durée de perfusion plus longue que celle de le TER précédent. Conclusion Dans l’ensemble, les points de vue des patients de cette étude mettent en évidence les avantages et l’amélioration de la qualité de vie associés au traitement par la pegunigalsidase alfa administré en 4heures.

Background/Objectives: Patients with Gaucher disease have a high risk of bone disease, with osteonecrosis representing the most debilitating complication. The pathogenesis of osteonecrosis has not been fully elucidated yet, and there is an unmet need for predictive biomarkers of bone complications. We aimed to assess the utility of angiogenesis and bone turnover biomarkers as predictors of osteonecrosis in Gaucher disease. Methods: Angiogenesis and bone turnover biomarkers were measured in 146 Gaucher disease patients (70M:76F, median age 49.5 [IQR 36.7 to 61]) with/without osteonecrosis enrolled in the UK-based registry GAUCHERITE [enrolment 2015–2017]. Receiver-operating characteristic curve analysis was used to compare the osteonecrosis predictive value of angiogenesis and bone turnover biomarkers and determine the optimal cut-off values for each biomarker. Results: Sixty-two patients had osteonecrosis before study enrolment, 11 had osteonecrosis during follow-up, and 73 remained osteonecrosis-free. Patients with osteonecrosis showed increased osteopontin and matrix metalloproteinase (MMP)-2 levels and decreased MMP-9 and vascular endothelial growth factor (VEGF)-C compared with those free from osteonecrosis. MMP-9 predicted future osteonecrosis with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC] 0.84 [95% CI 0.84–0.99]; sensitivity/specificity 82%/75%; cutoff value ≤ 72,420 pg/mL) than osteopontin, MMP-2 and VEGF-C when taken alone. The combination of MMP-9 and VEGF-C further increased the discriminating accuracy. Conclusions: The osteopontin–MMPs–VEGF axis is dysregulated in Gaucher disease patients with osteonecrosis. The combination of MMP-9 and VEGF-C circulating levels may serve to identify Gaucher disease patients at risk of osteonecrosis.

Background: Gaucher disease (GD) is a rare, autosomal, recessive condition characterized by hepatosplenomegaly, thrombocytopenia, anemia, and bone abnormalities, often requiring life-long treatment. Velaglucerase alfa has improved hematologic and visceral parameters in clinical trials; however, limited long-term efficacy and safety data are available. Methods: The Gaucher Outcome Survey (GOS), a structured and validated international registry for patients with confirmed GD, provides an opportunity to evaluate long-term data from patients receiving velaglucerase alfa. Results: This analysis included 376 treatment-naïve children and adults with GD enrolled in GOS, including 20 with type 3 GD, who initiated velaglucerase alfa through participation in clinical trials or as part of their clinical management and continued treatment for a mean (range) time of 6.6 (0.003–18.6) years. Initial improvements in hematologic and visceral parameters and the biomarkers glucosylsphingosine (lyso-GL1) and chitotriosidase were observed after one year of treatment and were maintained throughout the follow-up period. Of 129 (34.3%) patients who developed adverse events during the follow-up period, events were considered related to treatment in 33 (8.8%). None led to treatment discontinuation. There were 21 deaths overall, none of which were considered related to treatment. Conclusions: This analysis of data from the GOS registry supports the safety and efficacy of velaglucerase alfa in patients with GD.