Incidence and risk factors for development of left ventricular hypertrophy in Fabry disease.

BACKGROUND: Left ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of patients with FD and no LVH at baseline evaluation. METHODS: Consecutively referred adult (aged ≥16 years) patients with FD were enrolled into an observational cohort study. Patients were prospectively followed in a specialist cardiomyopathy centre and the primary endpoint was the first detection of LVH (left ventricular mass index (LVMi) ≥115 g/m2 in men and ≥95 g/m2 in women). RESULTS: From a cohort of 393 patients, 214 (aged 35.8±13.8 years; 61 (29%) males) had no LVH at first evaluation. During a median follow-up of 9.4 years (IQR 4.7-12.7), 55 patients (24.6%) developed LVH. The estimated incidence of LVH was 11.3% (95% CI 6.5% to 16.1%) at 5 years, 29.1% (95% CI 21.5% to 36.7%) at 10 years and 45.0% (95% CI 33.8% to 62.4%) at 15 years of follow-up. On multivariable analysis, independent predictors for LVH development were age (HR 1.04 (95% CI 1.02 to 1.06) per 1-year increase, p<0.001), male sex (HR 2.90 (95% CI 1.66 to 5.09), p<0.001) and an abnormal ECG (HR 3.10 (95% CI 1.72 to 5.57), p<0.001). The annual rate of change in LVMi was +2.77 (IQR 1.45-4.62) g/m2/year in males and +1.38 (IQR 0.09-2.85) g/m2/year in females (p<0.001). CONCLUSIONS: Approximately one-quarter of patients with FD developed LVH during follow-up. Age, male sex and ECG abnormalities were associated with a higher risk of developing LVH in patients with FD.

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study.

BACKGROUND: Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). OBJECTIVE/METHODS: BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. RESULTS: Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m2 and plasma lyso-Gb3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was - 5.90 (1.34) mL/min/1.73 m2/year; 12 months post-switch, the mean eGFR slope was - 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m2/year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. CONCLUSION: Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN: NCT03018730. Date of registration: January 2017.

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.

Management of pain in Fabry disease in the UK clinical setting: consensus findings from an expert Delphi panel.

BACKGROUND: Fabry disease is a rare, X-linked inherited lysosomal storage disorder, that manifests as a heterogeneous disease with renal, cardiac and nervous system involvement. The most common pain experienced by people with Fabry disease are episodes of neuropathic pain reported in up to 80% of classical hemizygous male patients and up to 65% of heterozygous female patients. No clear consensus exists within UK clinical practice for the assessment and management of pain in Fabry disease based on agreed clinical practice and clinical experience. Here we describe a modified Delphi initiative to establish expert consensus on management of pain in Fabry disease in the UK clinical setting. METHODS: Delphi panel members were identified based on their demonstrated expertise in managing adult or paediatric patients with Fabry disease in the UK and recruited by an independent third-party administrator. Ten expert panellists agreed to participate in two survey rounds, during which they remained anonymous to each other. Circulation of the questionnaires, and collection and processing of the panel's responses were conducted between September 2021 and December 2021. All questions required an answer. RESULTS: The Delphi panel reached a consensus on 21 out of 41 aspects of pain assessment and management of pain in Fabry disease. These encompassed steps in the care pathway from the goals of therapy through to holistic support, including the use of gabapentin and carbamazepine as first-line analgesic medications for the treatment of neuropathic pain in Fabry disease, as well as the proactive management of symptoms of anxiety and/or depression associated with Fabry pain. CONCLUSIONS: The consensus panel outcomes reported here have highlighted strengths in current UK clinical practice, along with unmet needs for further research and agreement. This consensus is intended to prompt the next steps towards developing clinical guidelines.

Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively. OBJECTIVE: We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified. METHODS: We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas. RESULTS: 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05-1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation. CONCLUSION: Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought. PROSPERO DATABASE: CRD42019132045.

An expert consensus on the recommendations for the use of biomarkers in Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder caused by the accumulation of glycosphingolipids in various tissues and body fluids, leading to progressive organ damage and life-threatening complications. Phenotypic classification is based on disease progression and severity and can be used to predict outcomes. Patients with a classic Fabry phenotype have little to no residual α-Gal A activity and have widespread organ involvement, whereas patients with a later-onset phenotype have residual α-Gal A activity and disease progression can be limited to a single organ, often the heart. Diagnosis and monitoring of patients with Fabry disease should therefore be individualized, and biomarkers are available to support with this. Disease-specific biomarkers are useful in the diagnosis of Fabry disease; non-disease-specific biomarkers may be useful to assess organ damage. For most biomarkers it can be challenging to prove they translate to differences in the risk of clinical events associated with Fabry disease. Therefore, careful monitoring of treatment outcomes and collection of prospective data in patients are needed. As we deepen our understanding of Fabry disease, it is important to regularly re-evaluate and appraise published evidence relating to biomarkers. In this article, we present the results of a literature review of evidence published between February 2017 and July 2020 on the impact of disease-specific treatment on biomarkers and provide an expert consensus on clinical recommendations for the use of those biomarkers.

Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease.

Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes.

BACKGROUND: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear. METHODS: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated. RESULTS: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations. CONCLUSIONS: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs.

Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry.

BACKGROUND: Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD. RESULTS: FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies. CONCLUSION: FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease.

Do clinical guidelines facilitate or impede drivers of treatment in Fabry disease?

BACKGROUND: Variable disease progression confounds accurate prognosis in Fabry disease. Evidence supports the long-term benefit of early intervention with disease-specific therapy, but current guidelines recommend treatment initiation based on signs that may present too late to avoid irreversible organ damage. Findings from the 'PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease' (PREDICT-FD) initiative included expert consensus on 27 early indicators of disease progression in Fabry disease and on drivers of and barriers to treatment initiation in Fabry disease. Here, we compared the PREDICT-FD indicators with guidance from the European Fabry Working Group and various national guidelines to identify differences in signs supporting treatment initiation and how guidelines themselves might affect initiation. Finally, anonymized patient histories were reviewed by PREDICT-FD experts to determine whether PREDICT-FD indicators supported earlier treatment than existing guidance. RESULTS: Current guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT-FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations. CONCLUSIONS: Wider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally.

Cardiac device implantation and device usage in Fabry and hypertrophic cardiomyopathy.

BACKGROUND: Fabry disease (FD) is a treatable X-linked condition leading to progressive cardiac disease, arrhythmia and premature death. We aimed to increase awareness of the arrhythmogenicity of Fabry cardiomyopathy, by comparing device usage in patients with Fabry cardiomyopathy and sarcomeric HCM. All Fabry patients with an implantable cardioverter defibrillator (ICD) implanted in the UK over a 17 year period were included. A comparator group of HCM patients, with primary prevention ICD implantation, were captured from a regional registry database. RESULTS: Indications for ICD in FD varied with 72% implanted for primary prevention based on multiple potential risk factors. In FD and HCM primary prevention devices, arrhythmia occurred more frequently in FD over shorter follow-up (HR 4.2, p < 0.001). VT requiring therapy was more common in FD (HR 4.5, p = 0.002). Immediate shock therapy for sustained VT was also more common (HR 2.5, p < 0.001). There was a greater burden of AF needing anticoagulation and NSVT in FD (AF: HR 6.2, p = 0.004, NSVT: HR 3.1, p < 0.001). CONCLUSION: This study demonstrates arrhythmia burden and ICD usage in FD is high, suggesting that Fabry cardiomyopathy may be more 'arrhythmogenic' than previously thought. Existing risk models cannot be mutually applicable and further research is needed to provide clarity in managing Fabry patients with cardiac involvement.

Cognitive dysfunction and white matter hyperintensities in Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder with multi-system involvement including cerebrovascular disease. Patients with FD also have a high risk of ischaemic stroke and TIA. White matter hyperintensities are common, but their clinical impact on cognition remains uncertain. Previous studies have examined the neuropsychological profile of FD, but have been inconclusive in part due to methodological limitations including small sample sizes. We sought to address these limitations in a case-control study of 26 patients with Fabry disease with mild to moderate disease symptoms matched with 18 healthy controls for age and premorbid intellectual level. We obtained detailed neuropsychological data and MRI neuroimaging data on the severity of white matter changes. Mood was accounted for as a possible confounder. Our results showed significant compromise of executive functions and information processing speed for the FD group. Error analyses suggested that the compromise of executive functions could not be entirely accounted for by slowed information processing speed. We demonstrated significant correlations between cognitive decline and the overall volume of white matter hyperintensities in the FD group. Our results point to significant compromise of cognition in FD even without stroke or mood difficulties. This suggests that neuropsychological assessment and rehabilitation should be routinely offered to patients with FD.

In-depth phenotyping for clinical stratification of Gaucher disease.

BACKGROUND: The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study. RESULTS: At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery. CONCLUSION: Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability.

Prompt Agalsidase Alfa Therapy Initiation is Associated with Improved Renal and Cardiovascular Outcomes in a Fabry Outcome Survey Analysis.

BACKGROUND: The timing of enzyme replacement therapy initiation in patients with Fabry disease is hypothesized to be critical. In this study, we used Fabry Outcome Survey data to assess the impact of prompt versus delayed initiation of treatment with agalsidase alfa on cardiovascular and renal events in patients with Fabry disease. METHODS: Available genetic data at baseline were used to define patients with mutations associated with classical versus late-onset Fabry disease. Time to cardiovascular or renal events, from treatment initiation until 120 months, was compared for patients in prompt versus delayed groups. "Prompt" was defined as treatment initiation <24 months from symptom onset (analysis A) or diagnosis (analysis B), and "delayed" was defined as ≥24 months from symptom onset (analysis A) or diagnosis (analysis B). Kaplan-Meier curves and Log rank tests compared event-free probabilities and time to first event. Multivariate Cox regression estimated hazard ratios (HRs). RESULTS: Analysis by time from symptom onset included 1374 patients (172 prompt, 1202 delayed). In a multivariate Cox regression analysis, prompt versus delayed treatment initiation significantly reduced the probability of cardiovascular (HR=0.62; P<0.001) and renal (HR=0.57; P=0.001) events. History of cardiovascular or renal events was associated with increased risk of respective events. Analysis by time from diagnosis included 2051 patients (1006 prompt, 1045 delayed). In a multivariate Cox regression analysis, prompt treatment initiation significantly reduced the probability of cardiovascular events (HR=0.83; P=0.003) after adjusting for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis showed that the probability of renal events was significantly lower in the prompt group (P=0.018); this finding was attenuated in the multivariate Cox regression analysis. CONCLUSION: This analysis suggests that prompt treatment initiation with agalsidase alfa provided better renal and cardiovascular outcomes than delayed treatment in patients with Fabry disease.

Long-term follow-up of renal function in patients treated with migalastat for Fabry disease.

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were - 1.6 mL/min/1.73 m2 overall and - 1.8 mL/min/1.73 m2 and - 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were - 1.6 mL/min/1.73 m2 overall and - 2.6 mL/min/1.73 m2 and - 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was -1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: -0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

The myocardial phenotype of Fabry disease pre-hypertrophy and pre-detectable storage.

AIMS: Cardiac involvement in Fabry disease (FD) occurs prior to left ventricular hypertrophy (LVH) and is characterized by low myocardial native T1 with sphingolipid storage reflected by cardiovascular magnetic resonance (CMR) and electrocardiogram (ECG) changes. We hypothesize that a pre-storage myocardial phenotype might occur even earlier, prior to T1 lowering. METHODS AND RESULTS: FD patients and age-, sex-, and heart rate-matched healthy controls underwent same-day ECG with advanced analysis and multiparametric CMR [cines, global longitudinal strain (GLS), T1 and T2 mapping, stress perfusion (myocardial blood flow, MBF), and late gadolinium enhancement (LGE)]. One hundred and fourteen Fabry patients (46 ± 13 years, 61% female) and 76 controls (49 ± 15 years, 50% female) were included. In pre-LVH FD (n = 72, 63%), a low T1 (n = 32/72, 44%) was associated with a constellation of ECG and functional abnormalities compared to normal T1 FD patients and controls. However, pre-LVH FD with normal T1 (n = 40/72, 56%) also had abnormalities compared to controls: reduced GLS (-18 ± 2 vs. -20 ± 2%, P < 0.001), microvascular changes (lower MBF 2.5 ± 0.7 vs. 3.0 ± 0.8 mL/g/min, P = 0.028), subtle T2 elevation (50 ± 4 vs. 48 ± 2 ms, P = 0.027), and limited LGE (%LGE 0.3 ± 1.1 vs. 0%, P = 0.004). ECG abnormalities included shorter P-wave duration (88 ± 12 vs. 94 ± 15 ms, P = 0.010) and T-wave peak time (Tonset - Tpeak; 104 ± 28 vs. 115 ± 20 ms, P = 0.015), resulting in a more symmetric T wave with lower T-wave time ratio (Tonset - Tpeak)/(Tpeak - Tend) (1.5 ± 0.4 vs. 1.8 ± 0.4, P < 0.001) compared to controls. CONCLUSION: FD has a measurable myocardial phenotype pre-LVH and pre-detectable myocyte storage with microvascular dysfunction, subtly impaired GLS and altered atrial depolarization and ventricular repolarization intervals.

New drugs for the treatment of Anderson-Fabry disease.

Enzyme replacement therapy (ERT) of the Anderson-Fabry disease (AFD) has changed the outcome of patients. However, ERT has some limitations: a restricted volume of distribution, requirement for intravenous access, and stimulation of the production of anti-drug antibodies. Studies of new drugs aiming to improve the clinical effectiveness and convenience of therapy have been reported. Migalastat, a pharmacological chaperone, increases available enzymate activity in patients with mutations amenable to the therapy, is now available for clinical practice. It is orally administered, and while clinical trial results are promising, long term real world follow up is awaited. PEGylated enzyme has a longer half-life and potentially reduced antigenicity, compared with standard preparations; investigation of whether a longer dosing interval is viable is under way. Moss-derived enzyme has a higher affinity for mannose receptors, and appears to have access to renal tissue. Substrate reduction therapy is based on reducing the catabolism processes of the glycosphingolipids, and is currently under investigation as monotherapy. Gene therapy has now been initiated in clinical trail of in vivo and ex vivo technologies with early results are emerging. ERT represents a certain milestone of therapy for AFD with Migalastat now a newly available option. Other agents in clinical trial prevent further potential opportunities to improve outcomes in AFD.

Estimated impact of the COVID-19 pandemic on cancer services and excess 1-year mortality in people with cancer and multimorbidity: near real-time data on cancer care, cancer deaths and a population-based cohort study.

OBJECTIVES: To estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer. METHODS: We employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England. RESULTS: Declines in urgent referrals (median=-70.4%) and chemotherapy attendances (median=-41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=-44.5%) and chemotherapy attendances (median=-31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity. CONCLUSIONS: Dramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.

Effects of Baseline Left Ventricular Hypertrophy and Decreased Renal Function on Cardiovascular and Renal Outcomes in Patients with Fabry Disease Treated with Agalsidase Alfa: A Fabry Outcome Survey Study.

PURPOSE: The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment. METHODS: Eligible patients were males and females aged ≥18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≤50 g/m2.7 in males and ≤48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events. FINDINGS: Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P < 0.001) compared with patients with a normal eGFR at baseline. IMPLICATIONS: In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065.

White matter integrity correlates with cognition and disease severity in Fabry disease.

Cerebral white matter pathology is a common CNS manifestation of Fabry disease, visualized as white matter hyperintensities on MRI in 42-81% of patients. Diffusion tensor imaging (DTI) MRI is a sensitive technique to quantify microstructural damage within the white matter with potential value as a disease biomarker. We evaluated the pattern of DTI abnormalities in Fabry disease, and their correlations with cognitive impairment, mood, anxiety, disease severity and plasma lyso-Gb3 levels in 31 patients with genetically proven Fabry disease and 19 age-matched healthy control subjects. We obtained average values of fractional anisotropy and mean diffusivity within the white matter and performed voxelwise analysis with tract-based spatial statistics. Using a standardized neuropsychological test battery, we assessed processing speed, executive function, anxiety, depression and disease severity. The mean age (% male) was 44.1 (45%) for patients with Fabry disease and 37.4 (53%) for the healthy control group. In patients with Fabry disease, compared to healthy controls the mean average white matter fractional anisotropy was lower in [0.423 (standard deviation, SD 0.023) versus 0.446 (SD 0.016), P = 0.002] while mean average white matter mean diffusivity was higher (749 × 10-6 mm2/s (SD 32 × 10-6) versus 720 × 10-6 mm2/s (SD 21 × 10-6), P = 0.004]. Voxelwise statistics showed that the diffusion abnormalities for both fractional anisotropy and mean diffusivity were anatomically widespread. A lesion probability map showed that white matter hyperintensities also had a wide anatomical distribution with a predilection for the posterior centrum semiovale. However, diffusion abnormalities in Fabry disease were not restricted to lesional tissue; compared to healthy controls, the normal appearing white matter in patients with Fabry disease had reduced fractional anisotropy [0.422 (SD 0.022) versus 0.443 (SD 0.017) P = 0.003] and increased mean diffusivity [747 × 10-6 mm2/s (SD 26 × 10-6) versus 723 × 10-6 mm2/s (SD 22 × 10-6), P = 0.008]. Within patients, average white matter fractional anisotropy and white matter lesion volume showed statistically significant correlations with Digit Symbol Coding Test score (r = 0.558, P = 0.001; and r = -0.633, P ≤ 0.001, respectively). Average white matter fractional anisotropy correlated with the overall Mainz Severity Score Index (r = -0.661, P ≤ 0.001), while average white matter mean diffusivity showed a strong correlation with plasma lyso-Gb3 levels (r = 0.559, P = 0.001). Our findings using DTI confirm widespread areas of microstructural white matter disruption in Fabry disease, extending beyond white matter hyperintensities seen on conventional MRI. Moreover, diffusion measures show strong correlations with cognition (processing speed), clinical disease severity and a putative plasma biomarker of disease activity, making them promising quantitative biomarkers for monitoring Fabry disease severity and progression.