The WORLDSymposium™ was held as a hybrid meeting this year (7–11 February 2022) and brought together key opinion leaders from the field of lysosomal disorders and rare diseases. Here you can access summaries from the meeting, including reports with a specific focus on Fabry disease.

Satellite symposium supported by Takeda

Professor Roberto Giugliani (Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil) chaired the Takeda symposium and began by providing a brief overview of Fabry disease, highlighting that the kidney and heart are the major organs usually affected in patients with Fabry disease, with significant impact on morbidity and often leading to early mortality.1 He went on to explain that the main goal in the management plan of patients with Fabry disease is to provide long-term cardiac and renal protection, ultimately prolonging survival.2

Professor Guillem Pintos-Morell (University Hospital Vall d’Hebron, Barcelona, Spain) provided an insight into the cardiovascular complications associated with Fabry disease. He explained that cardiac disease is common in male and female patients with Fabry disease, and is one of the major causes of morbidity and mortality.3 Furthermore, as the GLA gene is located on the X-chromosome, males generally tend to be affected by Fabry disease more severely than females.4 Symptom onset usually occurs later in life in females, with cardiomyopathy being the most common and most severe symptom.5

Professor Pintos-Morell went on to present data which showed that after 10 years of agalsidase alfa treatment, heart failure score was improved by at least one class in 22 of 42 patients, with the majority of the remaining patients achieving stabilisation.4 Interestingly, in patients with no left ventricular hypertrophy (LVH) prior to treatment initiation, left ventricular mass index (LVMI) values were maintained over 10 years in both males and females.4 For patients in whom LVH was present prior to agalsidase alfa treatment, although improvements were apparent after just 1 year, normal LVMI values were not reached after treatment.4

Professor Pintos-Morell then provided a brief introduction to the Fabry Outcome survey (FOS) — an international outcomes database which was initiated and funded by Shire and is now continued to be funded by Takeda. It has been used to collect longitudinal data on patients with Fabry disease since 2001.3,6 He presented 10-year FOS data demonstrating that in patients treated with agalsidase alfa, and without LVH at baseline, cardiac mass remained stable in both males and females.7 Additionally, among cardiac cohort patients without renal involvement (estimated glomerular filtration rate [eGFR] >90 mL/min/1.73 m2 and urinary protein <0.5 g/day) at baseline, LVMI values also remained stable after treatment with agalsidase alfa.7  

Professor Pintos-Morell went on to present evidence that better cardiovascular (p<0.0001) and renal (p=0.0007) outcomes were obtained when enzyme replacement therapy (ERT) was initiated in patients without LVH compared with patients who presented with LVH at initiation of treatment.8 Similarly, renal impairment at initiation of ERT was associated with worse cardiovascular and renal outcomes (both p<0.0001).8 In addition to this, the 10-year FOS data reported that early initiation of agalsidase alfa treatment was associated with greater improvements in LVMI compared with delayed initiation of treatment — patients who received treatment aged ≤30 years showed a more stable disease compared with patients who were treated with ERT aged >30 years.9

Professor Pintos-Morell concluded his presentation by reiterating that cardiomyopathy is one of the main complications and causes of mortality in patients with Fabry disease, and that approved treatments for Fabry disease may protect against cardiac damage, mainly when they are initiated early in the disease.10,11

Professor Christine Kurschat (University of Cologne, Cologne, Germany) furthered the discussion of the importance of organ protection in Fabry disease by providing an insight into the renal complications associated with the disease. To begin her presentation, she briefly highlighted the specific treatments for Fabry disease, including ERT12,13 and chaperone therapy.14  

Professor Kurschat presented 10-year FOS data which demonstrated that in patients treated with agalsidase alfa, eGFR was stable over time in female patients, but a slow decline in eGFR was observed in male patients.7

She then went on to discuss the treatment of Fabry patients with agalsidase beta, and presented data from a Phase III extension study showing a marked reduction of globotriaosylceramide (Gb3) deposition in the kidney after long-term (54 months) treatment with agalsidase beta.15 This study concluded that long-term agalsidase beta therapy can stabilise renal function in patients without renal involvement at baseline, maintains reduction of plasma globotriaosylsphingosine (lyso-Gb3) and sustains lyso-Gb3 clearance in capillary endothelial cells and multiple renal cell types.15 This study showed that during the 54-month treatment period, patients with high (>1 g/24 h) baseline proteinuria consistently had lower median eGFR values compared with those with lower (≤1 g/24 h) proteinuria at baseline, regardless of agalsidase beta.15

Professor Kurschat continued by presenting results from the long-term study of migalastat treatment in Fabry disease. Data from the ATTRACT study (an open-label, randomised, Phase III study), demonstrated stable renal function after 30 months in patients receiving migalastat treatment, who had previously received ERT.16 Following on from this, more recent data presented by Professor Kurschat demonstrated stable renal function in patients receiving migalastat treatment for ≥2 years.17

She then posed the question “when do we start Fabry-specific therapy?” To answer this question, she presented results from the 10-year FOS study in which patients with Fabry disease who began treatment with agalsidase alfa at a younger age were shown to maintain their eGFR more effectively than those patients who initiated treatment at an older age.9

Professor Kurschat concluded her presentation by highlighting that kidney disease adds significantly to the disease burden in patients with Fabry disease.18,19 However, Fabry-specific therapy slows kidney disease, and early initiation of therapy is essential in reducing disease burden. This was then discussed further by Professor Giugliani in his presentation.9,10

Professor Giugliani opened his presentation by highlighting the progressive nature of Fabry disease, with adverse impact on cells and tissues, and progressive build-up of irreversible damage usually occurring early in the disease process.20

He presented data showing the probability of patients with Fabry disease developing renal syndromes and hypertension, as well as the probability of survival prior to ERT treatment; renal events and hypertension were shown to be progressive and led to early mortality.21 He continued by presenting FOS data to demonstrate changes in mortality over time in both male and female patients. In the 2001 FOS data (n=181), the major cause of death in affected male relatives was renal failure (42%), and in affected female relatives it was cerebrovascular disease (25%). However, in the 5-year FOS data (n=42), cardiac disease was the main cause of death in both male (34%) and female (57%) patients.22

Five-year FOS data reporting cardiac, renal, stroke or death rates in patients treated with agalsidase alfa compared with untreated patients showed that treatment with agalsidase alfa slowed the progression of renal impairments and cardiomyopathy, and delayed the onset of both morbidity and mortality.23 The median age at first event was also greater in males and females receiving ERT (48 years and 56.9 years, respectively) compared with untreated patients (~41 years and ~53 years, respectively). In addition, the estimated median survival of patients receiving agalsidase alfa (n=677) was 77.5 years23 in males, compared with untreated patients in the original Fabry disease trials (n=279), in whom estimated survival was 60 years.23,24

Professor Giugliani presented 10-year FOS data investigating the effect of early treatment on proteinuria level over time — a slower increase in the level of proteinuria was observed in patients who initiated ERT at a younger age compared with those who initiated treatment at an older age.9

He then presented results from a FOS analysis which highlighted that early (<24 months) ERT initiation after symptom onset was associated with a significantly lower risk of cardiovascular (p<0.001) and renal events (p=0.001) compared with delayed (≥24 months) treatment initiation.10

Professor Giugliani concluded his presentation by summarising that Fabry disease is progressive, causing damage to critical organs over time,20 that both cardiac and renal manifestations are key contributors to morbidity and mortality in patients with Fabry disease,22 and that therapy may provide long-term cardiac and renal protection (resulting in reduced morbidity and prolonged survival).2

Satellite symposium supported by Sanofi Genzyme

Dr Maryam Banikazemi (New York Medical College, Valhalla, NY, USA) presented this symposium, which spanned multiple topics in Fabry disease, including testing and monitoring, Fabry disease in women, treatment guidelines and clinical trial data. She began with a review of Fabry disease, explaining that diagnostic delays may be substantial, reducing life expectancy by ~15 years in women and ~20 years in men.25-28 She also stated that as Fabry disease progresses, the risks of severe complications and resulting premature death increase.29 Dr Banikazemi highlighted the importance of multi-systemic monitoring, which is recommended to focus on the four systems in the body most affected by Fabry disease: the renal, cardiovascular, cerebrovascular and vascular systems.25

The next part of the symposium focused on Fabry disease in female patients. Dr Banikazemi highlighted that women may experience substantial symptoms of Fabry disease, depending on their level of X-chromosome inactivation.26 Throughout her own career, she has observed the shift from the earlier theory that women were only asymptomatic carriers of Fabry disease to the current hypothesis that women can be as affected and symptomatic as males.25 Dr Banikazemi presented data comparing the symptoms of Fabry disease in women compared with the general population. For example, the risk of left ventricular hypertrophy has been found to be nearly twice as high in women than in the general population.30,31 She noted that International Panel Consensus guidelines state that treatment for female patients with Fabry disease is recommended to begin when they are considered symptomatic.32,33 These guidelines also recommend that enzyme replacement therapy should be considered upon early signs of organ involvement indicative of Fabry disease in women.32,33 The availability of treatments differs between countries. For further information, please consult your local prescribing information.

Introducing the concept of ERT, Dr Banikazemi began by describing the mechanism of action of agalsidase beta.13 She then went on to discuss the clinical evidence that supported its approval in some countries, including the randomised, double-blind, placebo-controlled, multicentre study of 58 patients (56 male, 2 female; aged 16–61 years) with Fabry disease, who received (1:1) 1 mg/kg of agalsidase beta or placebo every other week.13,34 The trial was designed to investigate the level of Gb3 deposit in the vascular endothelium from biopsy samples of the kidney, heart and skin (a score of 0 indicated no or only trace amounts of Gb3 present; a score of 3.0 indicated substantial accumulation of Gb3).34 In the agalsidase beta group, 69% achieved a score of 0 in the kidney, whereas no patients achieved clearance in the placebo group (p<0.001). This finding was replicated in the decrease in Gb3 in the heart and skin samples in the agalsidase beta group versus placebo (p<0.001). In the open-label part of the trial, all patients (n=58) received agalsidase beta, including those who had been receiving placebo previously. After 6 months, 98% achieved clearance in the kidney, 75% in the heart and 96% in the skin.34 Follow-up assessments of the heart and kidney biopsies of eight patients assessed at 54 months demonstrated sustained Gb3 clearance in the capillary endothelium of the kidney in all eight patients. The majority of patients achieved and maintained normalisation of plasma Gb3 levels, across a period of 5 years.13

A randomised, double-blind, placebo-controlled, multinational, multicentre study was then conducted, including 82 patients (72 male, 10 female) with Fabry disease and mild to moderate kidney disease, in which patients received (2:1) 1 mg/kg agalsidase beta or placebo every other week for 35 months.13,35 The primary endpoint was the time to first occurrence of a clinically significant event (renal, cardiac or cerebrovascular event, or death). Dr Banikazemi explained that a smaller percentage of patients in the agalsidase beta group experienced a clinically significant event than those in the placebo group (27% vs 42%; unadjusted treatment-related hazard ratio 0.57; CI 0.27–1.22; p=0.14). To investigate agalsidase beta in paediatric patients, an open-label, single-arm study was conducted in 16 paediatric patients (14 male, 2 female) aged 8–16 years at first treatment.13 Patients received agalsidase beta 1 mg/kg every other week and appeared to show sustained Gb3 clearance in the vascular endothelium of the skin. Dr Banikazemi summarised that, in her clinical opinion, the overall efficacy and safety profile of agalsidase beta in paediatric patients was similar to that seen in adults. The last part of the symposium was an interactive session in which Dr Banikazemi described case studies of Fabry disease in females and children, and asked the audience to comment on the challenges and considerations associated with managing these patients.

Satellite symposium supported by Sanofi Genzyme

Dr Robert J Hopkin (Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA) opened the symposium by listing the main aims of the session:

  • Review the natural history of Fabry disease in females
  • Compare organ involvement and symptoms experienced by females with Fabry disease with those among age-matched females in the general population
  • Consider the impact of Fabry disease on quality of life (QoL) experienced by affected women and girls in the context of more common, better-understood conditions.

Dr Hopkin went on to explain that females with Fabry disease may experience major disease-associated complications, such as cardiac involvement, decline in kidney function, neurologic symptoms and cerebrovascular events.26 Furthermore, compared with females in the general population, females with Fabry disease have poorer QoL and a reduced overall survival.27,36

Dr Hopkin explained that Fabry disease is inherited in an X-linked manner25 — all daughters of males with Fabry disease will inherit the pathogenic variant, and females with a GLA mutation have a 50% chance of passing the variant to each of their offspring.25 He continued by highlighting that genotype impacts event-free survival in females with Fabry disease, presenting data from the Fabry Registry which showed that females with the classical Fabry mutation have a higher event rate than females with later-onset disease.37

Dr Hopkin highlighted that females with Fabry disease are susceptible to serious events, and presented data demonstrating that 20% of females with Fabry disease may experience a major cardiac, cerebrovascular or renal event during the natural history period.26 Furthermore, females with either classical or late-onset Fabry disease can suffer significant events at early ages. He presented data from Arends et al., who explored the percentage of female patients with classical or late-onset Fabry disease who experienced events prior to their clinical visits — the study concluded that females with classical Fabry disease were more likely to develop complications than females with late-onset Fabry disease (p<0.001).38

The presentation continued with Dr Hopkin discussing cardiovascular (CV) disease in female patients with Fabry disease. He highlighted data which showed that 50% of females with Fabry disease died due to CV disease at a median age of 66 years.39 He went on to explain that cardiac involvement is found in 59% of females with Fabry disease, and presented data from a study in which cardiac events were reported to be experienced by 35% of female patients.24,40 

Dr Hopkin then presented data showing that 72% of females with Fabry disease who experienced a major CV event had their first event between the ages of 45 and 65 years41; the age at first myocardial infarction in female patients with Fabry disease was 56.2 years.26 He then went on to highlight that arrhythmias are the most common cardiac events in adult females with Fabry disease, occurring in 27% of patients, and arrhythmias in these patients appeared their early 20s.24

Dr Hopkin continued by discussing cerebrovascular complications in females with Fabry disease, and presented data showing that cerebrovascular events (including stroke and transient ischaemic attack) occurred in 25% of females with Fabry disease at a mean onset age of 38.8 years40; of the females who experienced a stroke, 17% experienced their first stroke before the age of 30 years.42 For comparison, Dr Hopkin presented data showing that females with Fabry disease are at an increased risk of early-onset stroke compared with the general population (mean age at first stroke onset: 45.7 years vs 81 years, respectively).42

Following on from this, Dr Hopkin went on to discuss renal involvement in female patients with Fabry disease. He highlighted that proteinuria and reduced estimated glomerular filtration rate (eGFR) occur in 40% of females with Fabry disease, and that eGFR declines significantly with age in these patients.26,40 He further explained that in females with Fabry disease, higher baseline proteinuria is associated with more rapid progression rates.24 Dr Hopkin then presented data showing that the median age at first kidney replacement therapy was 38 years and the median time from first kidney replacement to death was 6 years43 — in comparison, a female patient with chronic kidney disease who presents with end-stage renal disease at the age of 35–39 years has a life expectancy of an additional 11.7 years on dialysis, or 32.4 years after successful transplant.44

Assistant Professor Dawn A Laney (Department of Human Genetics, Emory University, Atlanta, GA, USA) focused her presentation on the impact that disease-associated signs and symptoms can have on the QoL of female patients with Fabry disease.

She highlighted that in females with Fabry disease, 45% may experience abdominal pain and 39% may experience diarrhoea during the natural history period.45 Female paediatric patients (aged <18 years) with Fabry disease experience gastrointestinal symptoms at a median age at onset of 9.5 years.36 Assistant Professor Laney then went on to discuss the effect that neuropathic pain can have on the QoL of females with Fabry disease. She presented data showing that neuropathic pain occurs in 40.5% of female paediatric patients with Fabry disease (32.3% experience chronic pain), with a median age at onset of 9 years.36

Assistant Professor Laney presented data from a study of females with Fabry disease showing that a range of disease-related pains had a significant disabling effect.46 She then presented data demonstrating that females with Fabry disease have a poor QoL47 and also have impaired QoL compared with the general population.26 As a comparison with other diseases, Assistant Professor Laney also showed data which reported that women with Fabry disease have significantly lower general health scores compared with females with rheumatoid arthritis (p=0.0003) and females with multiple sclerosis (p=0.01).48 She highlighted that females with Fabry disease are at an increased risk of depression, and that among 110 females with Fabry disease, clinically significant depression was reported in 22% of patients.49

Satellite symposium supported by Chiesi Global Rare Diseases

Professor Emeritus David G Warnock (Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USA) opened the symposium by giving an overview of Fabry disease. He presented the primary signs and symptoms of Fabry disease in childhood including gastrointestinal issues, pain, reduced sweating, and intolerance to heat or cold and exercise.50 He noted that Fabry disease symptoms may be misdiagnosed, and that patients have variable Fabry disease presentations depending on the phenotype. In particular, no or low (<1%) alpha-galactosidase A (α-Gal A) enzyme activity levels are associated with classical Fabry disease,51,52 and residual (3‒30%) enzymatic activity levels are associated with late-onset Fabry disease.53 The deficiency in the enzymatic activity of α-Gal A leads to the accumulation of cellular globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), leading to organ damage.54

Dr Warnock recommended that treatment of patients with Fabry disease may include enzyme replacement therapy and adjunctive therapies to manage complications that arise in patients.32 He also referred to chaperone therapy as a treatment for Fabry disease, noting that its indication is limited to patients with Fabry disease with amenable GLA gene variants.50 The availability of treatments differs between countries. For further information, please consult your local prescribing information.

The objectives for the remainder of the session were then outlined as follows:

  • Discussing remaining gaps in the evidence for optimising the management of patients with Fabry disease
  • Discussing unmet needs in the real-world setting and how the success of therapy is assessed
  • Highlighting differences in disease monitoring between clinical trials and real-world studies.

The next presentation, given by Associate Professor Eric Wallace (Telehealth and Home Dialysis Program, University of Alabama at Birmingham, Birmingham, AL, USA), focused on assessing the clinical trial setting of Fabry disease and discussing some hypothetical patient cases.

Dr Robert Hopkin (Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA) then continued the session by discussing a selection of long-term follow-up studies of clinical trials of patients with Fabry disease. He acknowledged that renal function and cardiac health have been more frequently assessed as outcomes in patients with Fabry disease compared with clinical events, pain, quality of life and gastrointestinal symptoms.26,36,55-60 He subsequently identified that the focus of clinical trials of patients with Fabry disease may be different to the focus of clinical care for these patients. Dr Hopkin concluded with some recommended assessments for monitoring organ involvement in adult patients with Fabry disease, including glomerular filtration rate (measured or estimated), monitoring the heart for intermittent rhythm abnormalities and evaluating the patient with brain magnetic resonance imaging or tomography,32 before discussing a series of hypothetical patient case studies.

Satellite symposium supported by Amicus Therapeutics, Inc.

Assistant Professor Dawn A. Laney (Department of Human Genetics, Emory University, Atlanta, GA, USA.) chaired the symposium and outlined that one of the main aims of this symposium was to share insights regarding Fabry disease manifestations in female patients, defining the multisystemic impacts and broad phenotypic heterogeneity in females.

Professor Michael Mauer (Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA) focussed his presentation on renal disease in females with Fabry disease. He began his talk by presenting data comparing the time to events (renal, cardiac, cerebrovascular and any events) in both male and female patients with Fabry disease – his key message being that compared with male patients, events are delayed in female patients.26  However, he caveated this point by stating that this is not always the case in all patients. He then presented data highlighting the yearly rate at which both male and female patients with Fabry disease lose kidney filtration function; in one study, 71% of males (n=86/121) had more rapid loss of kidney function than an unaffected adult population (loss of estimated glomerular filtration rate [eGFR] > ‒1 mL/min/1.73 m2/year), compared with 39% of females (n=133/341) reporting more rapid kidney function loss.61 Additionally, female patients with lower baseline eGFR and age were also associated with renal disease progression, and females who experienced clinical events reported more rapid loss of kidney function.61

He furthered his presentation by showing results investigating podocyte loss in patients with Fabry disease and highlighted that podocyturia was 3.6‒fold greater in patients with Fabry disease than in healthy individuals (p = 0.001).62 In all patients with Fabry disease with normoproteinuria, podocyturia was >2‒fold greater than that of healthy individuals. He continued to explain that podocyturia was directly related to urine protein/creatinine ratio in all patients with Fabry disease (r = 0.33; p = 0.04) and was inversely related to eGFR in male patients (r = ‒0.69; p = 0.003).62

The symposium continued with a presentation from Dr Antonia Camporeale (IRCCS Policlinico San Donato, San Donato Milanese, Italy) which focussed on cardiac manifestations of Fabry disease in female patients. She highlighted that in female patients with Fabry disease, the onset of left ventricular hypertrophy (LVH) is reportedly delayed by ~10 years and is generally less severe compared with males.63 Furthermore, there is a wide spectrum of morphological phenotypes in Fabry disease, but there is no typical pattern for female patients.63 In addition, late gadolinium enhancement (LGE) has been shown to be significantly more prevalent in male patients compared with females (59% and 37%, respectively; p = 0.015),64 and whilst males usually show a direct correlation between severity of LVH and LGE, females can develop some replacement fibrosis without hypertrophy.63 Dr Camporale presented data showing that in the pre-hypertrophic phase, there is a higher proportion of males with low T1 and abnormal electrocardiogram (ECG) compared with females (low T1 male 79% [n=15/19] versus female 54% [n=44/81], p<0.05; and abnormal ECG male 63% [n=12/19] versus female 36% [n=29/81], p<0.05), and with increasing LV mass, T1 falls in both males and females but more markedly in males.64,65

Satellite symposium supported by Sanofi Genzyme

Professor Perry Elliot (St. Bartholomew’s Hospital, London, UK) began the session, noting that one of the major challenges associated with the treatment of patients with Fabry disease is the complex and heterogeneous disease landscape, which is partly determined by the multiple phenotypes of the disease (classical and late-onset) as well as the effect of gender seen in patients with Fabry disease.66

He then went on to discuss ERT, and acknowledged a pivotal study which showed that infusion of alpha-galactosidase A (α-Gal A) reduces tissue Gb3 storage in patients with Fabry disease.67 These findings were followed by two clinical trials, which demonstrated the therapeutic efficacy of α-Gal A in patients with Fabry disease.34,68 A summary of learnings from the last 20 years of ERT was provided, with key points including:

  • Two intravenous ERTs are available for patients with Fabry disease: agalsidase alfa and agalsidase beta, which help to address the underlying α-Gal A enzyme deficiency in patients with Fabry disease thus reducing the amount of Gb3 accumulation in tissues.69 The availability of treatments differs between countries. For further information, please consult your local prescribing information.
  • Patients with Fabry disease >40 years of age and patients with more severe pre-treatment disease may experience a poorer response to ERT.10

Professor Elliot also discussed chaperone therapy and referred to a clinical trial of migalastat treatment in patients with Fabry disease. Patients with amenable GLA variants who received migalastat for up to 24 months showed an annualised decrease from baseline in the GFR (estimated and measured). The left ventricular mass index also decreased significantly from baseline, particularly when hypertrophy was present, and the severity of gastrointestinal symptoms decreased.70 Another study using data from a Phase III trial of migalastat in patients with Fabry disease showed that, in a subset of male patients with classical Fabry disease and migalastat-amenable variants, migalastat provided clinical benefit to patients.71

Dr Fellype C. Barreto (Federal University of Paraná, Curitiba, Brazil) continued the session and also drew on data from studies of enzyme replacement therapy in Fabry disease to discuss the long-term safety of this therapeutic approach. In particular, he referred to a 10-year study of recombinant α-Gal A, in which the majority (81%) of patients did not experience any severe clinical events during the treatment interval. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy, and it was highlighted by the speaker that patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.55 Another study evaluating time to treatment benefit for adult patients with Fabry disease receiving agalsidase beta showed that the largest decrease in incidence rates of severe clinical event was among male patients and those aged ≥40 years when ERT was initiated.72

Dr Barreto went on to compare the two currently available enzyme replacement therapies, referring to a study which showed that after 2 years of observation, patients with Fabry disease receiving a regular-dose of agalsidase beta had a stable disease course, whereas those with dose reduction and switch to agalsidase alfa experienced a decline in renal function.73 He then discussed the effect of enzyme replacement therapy on the pathophysiology of Fabry disease, noting that higher doses may result in a saturation of anti-drug antibodies, decreasing lyso-Gb3 levels and thus improving outcomes over time.74 Finally, oral chaperone therapy was reintroduced, and Dr Barreto discussed the benefits of migalastat, including its potential to reduce left ventricular mass index in patients with Fabry disease.

Professor Linhart (Charles University, Prague, Czech Republic) closed the session by discussing the impact of Fabry disease on patient’s QoL. He concluded that quality of life may be significantly reduced in patients with Fabry disease, particularly due to pain,75 and that enzyme replacement therapy may improve or stabilise QoL measures.76

Satellite symposium supported by Sanofi Genzyme

Dr Virginia Kimonis (University of California Irvine, CA, USA) introduced the symposium, focussing on the role of glucosylceramide synthase (GCS) in lysosomal diseases. She began by reviewing the general pathology and symptoms of Fabry disease. Next, Professor James Shayman (University of Michigan, MI, USA) provided an overview of GCS and the importance of GCS inhibition in lysosomal diseases. He explained how most glycosphingolipids, which are plasma membrane components, are synthesised from ceramide via GCS.77 He described how GCS and galactosylceramide synthase, which catalyses similar reactions, have different biological functions and properties. For example, galactosylceramide synthase is distributed in the brain and kidney and localised to the endoplasmic reticulum while GCS is ubiquitously distributed and localised to the Golgi apparatus.77 Synthesis inhibition was proposed as a novel strategy for the treatment of lysosomal diseases, with the goal of finding a reversible inhibitor of GCS to prevent production of defective substrate.78 Professor Shayman described research that attempted to accomplish this, which eventually resulted in the discovery of eliglustat.79

The goals of the next generation of GCS inhibitors based on limitations of eliglustat were then discussed. In Professor Shayman’s opinion, these included to overcome extensive metabolism by cytochrome P450 2D6 (CYP2D6) and the low central nervous system penetrance. In the rest of his talk, Professor Shayman investigated novel enzymes and GCS inhibitors. In the final part of the symposium, Professor Johannes Aerts (Leiden University, Leiden, Netherlands) discussed sphingolipid metabolism in Fabry disease and Gaucher disease. He described the concept of substrate reduction therapy, introducing migalastat and eliglustat therapy.79,80 He went on to present data demonstrating reduced disease-related biomarkers, including glucosylceramide, during eight years of eliglustat therapy in adult patients with Gaucher disease Type 1.81 

DISCLAIMER: The views expressed here are the views of the presenting physicians. The content presented in this report is not reviewed, approved, or endorsed by WORLDSymposiumTM, or any of its employees, agents, or contractors. No speakers or staff were interviewed directly or involved in the development of this report. Satellite Symposia are not part of the official WORLDSymposiumTM programme and WORLDSymposiumTM does not approve or endorse any commercial products or services discussed during the Satellite Symposia or offered for sale by any corporate supporter of the Satellite Symposia. Unofficial content. Official content is available only to registered attendees of WORLDSymposiumTM 2022. All trademarks are property of their respective owners.

C-ANPROM/INT/FAB/0153; C-ANPROM/INT/FAB/0154; C-ANPROM/INT/FAB/0155; C-ANPROM/INT/FAB/0156; Date of preparation: February 2022