The Changing Landscape of Fabry Disease

Abstract

Introduction Fabry disease is a rare X-linked lysosomal storage disorder due to mutations in the GLA gene causing complete or partial deficiency of the enzyme α-galactosidase A (α-Gal A), and subsequent slow accumulation of mainly globotriaocylceramide (Gb3 or GL3) and its deacylated derivative globotriaosylsphingosine (lyso-GL3, also called Lyso-Gb3) in several cell types and body fluids. Early and often asymptomatic cellular damage typically precedes various degrees of organ affection and late organ failure. Clinical symptoms are highly variable and mostly nonspecific (1). Kidney cells, cardiomyocytes, and vascular endothelium are target cells of particular interest in a usually slowly progressive disease. Major complications are secondary to kidney, cardiac, and/or central nervous system affection, usually from the fourth decade onward (2). The disease has had a long journey from the original description of cutaneous angiokeratoma in 1898 (3) to the current recognition of a treatable, highly complex, and heterogenous multisystem disease carrying a high rate of morbidity and mortality (4). The grim natural disease course in the era before enzyme replacement therapy should not be forgotten and was described in 2002 by Branton et al. (5) in 105 hemizygous classic male patients; only 25 of 105 patients survived until the age of 50 and no patients survived past age 60 years. Before the advent of dialysis and kidney transplantation, the most common cause of death was uremia, at a mean age of 41 years (6). Overall, before enzyme replacement was available, a reduced life span of about 25 years in males and 10 years in females was expected compared with the general population (7). Although the pathophysiology is still only partly understood (Figure 1), increasing knowledge of the complexity of mutations and disease manifestations has been fueled by a surge in clinical research and numerous publications after the introduction of enzyme replacement therapy nearly 20 years ago. Agalsidase α and agalsidase β were approved in Europe and the United States (agalsidase β only) in 2001; licensed doses are 0.2 mg/kg per every other week and 1.0 mg/kg per every other week, respectively (8,9). Ten-year follow-up registry data clearly demonstrate a modifying effect of enzyme replacement therapy on serious organ complications and mortality (10,11), and there has been a change in all-cause mortality from predominantly kidney to cardiac deaths (12,13).Figure 1.: Pathomechanisms of Fabry nephropathy [Eikrem et al. ( 81 )]. GL3, globotriaocylceramide; Lyso-Gb3, globotriaosylsphingosine.Historically, the disease has been hampered by diagnostic delays and subsequent delays of therapeutic intervention until irreversible organ damage prevails. Hence, the median age at diagnosis was 24 years in males and 31 years in females in a survey of >2200 patients, and the median time between onset of symptoms (usually neurologic pain and gastrointestinal dysfunction) and diagnosis was about 11 years in both sexes (14). The rationale for the increasing focus on early therapy has been clearly demonstrated by several reports highlighting the serious prognostic effect of diagnostic and therapeutic delays (15,16). Epidemiology, Genetics, and Characterization of Phenotypes Over the last two decades, general knowledge of Fabry disease and therapeutic challenges have changed dramatically, and prognosis has improved for several reasons. Enormous progress in genetic sequencing technology has led to a paradigm change in the understanding of the complexity of genotype–phenotype interactions. Recently, a general description of clinically relevant categories of variants in Mendelian disorders using the terminology “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” or “benign” has been suggested (17,18). This is especially relevant for the classification of clinical phenotypes harboring GLA missense mutations accounting for about 60% of >900 known mutations (Human Gene Mutation Database, www.hgmd.org). Importantly, the increasing incidence and prevalence of late-onset, nonclassic mutations, and genetic variants of unclear significance, with milder disease phenotypes have been acknowledged (17,19), with symptoms often confined to a single organ (especially cardiac) and some of these presumably accompanied by no clinical disease at all (17,20). The wide phenotypic spectrum of disease severity, even within the same family, and the fact that not all mutations are causing disease (e.g., polymorphisms) highlight the necessity of careful individual diagnostic and prognostic assessment, to allow correct and timely intervention, as well as avoidance or postponement of unnecessary high-cost treatment in patients with non–disease-causing mutations or very mild disease (19–22). The increasing birth prevalence of GLA mutations, from previous estimates of 1:40,000–170,000 (23) up to 1:1250 in newborn screening studies (19,24,25), reflects the existence of a majority of nonclassic mutations and variants of unknown significance where natural history and effectiveness of enzyme replacement are unknown (19). Currently, research on clinically relevant genotype–phenotype relationships is increasingly prioritized. Clear criteria exist for the diagnosis of classic early-onset Fabry disease (also called Type 1) with absent or low levels of enzyme activity, and typical symptoms (4). However, precise diagnosis may be difficult in late-onset, nonclassic (also called Type 2) male and female patients harboring any variant in the GLA gene with residual enzyme activity, and variable X-chromosome inactivation patterns (females), often presenting with cardiac, minimal, or unclear symptoms (26,27) in early or late adulthood (17,28,29). A widely used algorithm for diagnosing Fabry disease in these latter categories has been published by van der Tol et al. (19,30,31). New Insight into the Effectiveness of Enzyme Replacement Therapy The introduction of intravenous enzyme replacement has fueled a tremendous amount of research, opening many new avenues for collaborative work, involving experts from key medical specialties. The way forward has served as a model for learning and organizing clinical research, defining challenges and caveats in the field of rare metabolic diseases (15,32). Although enzyme replacement therapy has undoubtedly turned Fabry disease into a treatable disease, it has become obvious that intervention should be regarded as a disease modifier rather than a cure, and persistent risk of serious complications and increased mortality raises major concerns over current therapeutic strategies (32,33). Furthermore, numerous observational studies and case series published the last decade have disclosed a conundrum of Fabry disease heterogeneity, highlighting the necessity of individual assessment and targeting of therapy, even in patients within the same family (15,34,35). Given a slowly progressive heterogenous disease, new light has been shed on the validity of biases and limitations of few small randomized controlled trials of short duration in comparison with numerous long-term follow-up studies with a large number of patients (36–38). The value of analysis of unpooled data from systematic comprehensive literature searches of observational studies and case series/reports through January 2017 has recently been reported (38). These much larger patient cohorts and attempts to separate data among relevant clinical phenotypes (e.g., children, females, males, classic, and nonclassic), some of them treated for >15 years, have provided new insight that helps the treating physician better define individual patient risk and adequate therapeutic goals. Importantly, this knowledge has strengthened the need for an individual comprehensive multidisciplinary approach, carefully addressing genotype, phenotype, family history, and biomarkers including kidney histology when possible (34,35,39,40). Individual Therapeutic Goals and Risk Profiles Organ-specific therapeutic goal recommendations, covering altogether 249 publications (67% male patients including 36 clinical trials), suggest a significant slowing of decline of eGFR and reduction/stabilization of cardiac mass (adult males). The kidney and cardiac therapeutic benefits provide new information expanding the knowledge reported in a previous meta-analysis (33). Although a cardiac benefit was suggested in both sexes, recent data have been generally less robust in females, likely because of a wider disease spectrum ranging from asymptomatic to severely (rare) affected individuals (40). Interestingly, quality of life outcomes were improved in both sexes (34,40). The prognostic importance of younger age and an absence of organ damage when enzyme replacement therapy is initiated have been shown in several studies (10,41). Germain et al. (10) defined “low renal involvement” as urine protein creatinine ratio <0.5 g/g and <50% sclerotic glomeruli in a well-defined observational 10-year follow-up study of 52 classic patients (2 females), mean age 30 years and normal eGFR at start of agalsidase β 1.0 mg/kg every other week. The low renal involvement group (n=32) was younger (mean 25 years at treatment initiation) than the “high renal involvement” group and showed less deterioration of eGFR (mean slope −1.89 versus −6.82 ml/min per 1.73 m2 per year). Of note, 94% of the patients were alive at the end of the study and 81% did not experience any events. In patients on enzyme replacement therapy, lower eGFR and higher levels of proteinuria strongly predict faster disease progression (16). Supplemental therapy with renin angiotensin system inhibition to lower proteinuria to ≤0.5 g/d and potentially stabilize GFR should be considered in classic patients with reduced GFR and severe proteinuria (15,42). The effects of enzyme replacement therapy on cerebrovascular events remains unknown, although a recent meta-analysis suggested a potential benefit on stroke prevention (43). Although no clear consensus exists, recommendations for considering withdrawal of enzyme replacement in patients with advanced disease have also been published (44). Is Higher Agalsidase Dose Beneficial? Although in vitro milligram per milligram equipotency of agalsidase α and β has been demonstrated (45), the discussion about clinical equipotency of licensed drug regimens remains unsettled. The beneficial effect of higher cumulative agalsidase dose on kidney histology has been reported by Skrunes et al. (41) in serial kidney biopsies in 20 classic patients (median age 21 years, 12 males) with stable microalbuminuria and normal measured GFR followed for 10 years. A clear dose-dependent effect on clearance of podocyte GL3 deposits was found in this cohort, and residual lyso-GL3 correlated with the cumulative enzyme dosage in male patients. The clinical benefits of higher enzyme doses have been corroborated and likely underscored in a larger observational multicenter study with systematic follow-up of a high number of patients of both sexes from three European Fabry centers. The compulsory switch from agalsidase β 1.0 mg/kg every other week to agalsidase α 0.2 mg/kg every other week in many patients (due to the worldwide shortage of agalsidase β supply from June 2009 to January 2012) and subsequent reswitch to agalsidase β 1.0 mg/kg every other week in a number of patients showed conspicuous dose-dependent benefits regarding GFR slopes, lyso-GL3 levels, and gastrointestinal symptoms (46). Moreover, an overview of available evidence indicates that higher doses of agalsidase are beneficial given optimal timing of therapy and selection of patients with classic phenotypes (47,48). Importantly, the majority of literature-based observations of dose-dependent clinical effects so far are confined to classic male patients, and further long-term studies in expanded cohorts of high-risk patients are warranted. Long-term data on therapy outcomes in general are insufficient in female patients and sex-mixed study populations, likely because of variations in X-chromosome inactivation, which are usually not reported in clinical studies (34,40). This may also in part be the reason why no differences were found in clinical events in a recent European multicenter study including a mixture of classic and nonclassic patients [n=387 (192 females), mean age 46±15 years at therapy initiation] comparing licensed doses of agalsidase α and β (49). However, a more robust decrease of lyso-GL3 and better reduction in left ventricular mass were reported in patients receiving a higher enzyme dose (49). There is one study reporting kidney benefit of increasing the dose of agalsidase α to 0.2 mg/kg every week in a limited number of patients (50), but no such evidence is reported for agalsidase β. Although current enzyme substitution regimens fail to normalize elevated lyso-GL3, a clear dose- and age-dependent decrease of lyso-GL3 has been observed after therapy (41,49,51), and the recent therapeutic goal initiative recommends to strive at the lowest possible level of lyso-GL3 (35). More importantly, enzyme replacement therapy has limited effect when started late in the course (15,49,52). Neutralizing Anti-Agalsidase Antibodies A major reason for treatment failure is the formation of neutralizing antidrug antibodies (ADAs), which is reported to affect 40% of male patients treated with agalsidase β or α, and leads to subsequent decline of GFR and increase in lyso-GL3 (53). Lenders et al. (53) elegantly demonstrated that agalsidase dose escalation may overcome the detrimental inhibitory effects of these antibodies. A potential therapeutic approach has recently been published, highlighting the need to standardize assays and methods for individual dose escalations to obtain a saturated ADA status (54). Furthermore, future prospective studies are warranted to elucidate the clinical effect of ADAs (54). The role of immunosuppressive therapy is unknown. Initiation of Pharmacologic Therapy: How Early Is Early Enough? The strategy of “early treatment” of Fabry disease has been a major focus and is based on the experience in classic patients that progressive disease is more frequent when therapy is delayed until irreversible organ damage is manifest (16,17,52). Our experience in a youngish classic symptomatic patient cohort with normal heart, normal measured GFR, and normo/microalbuminuria suggests that enzyme replacement should be initiated within the teens (before the age of 18 years) (41,51,55), with the goal to prevent or delay the progression to irreversible kidney and heart damage. This “window of opportunity” approach is supported by several authors (15,39,44). Earlier start of therapy in childhood has to be decided on individual basis in patients with severe symptoms and signs. Systematic follow-up to define the individual appropriate window for “early therapy,” often at higher age, is mandatory, especially in slowly progressive nonclassic, late-onset patients (usually females) (34,35,40). New Therapies The need for more effective therapies for Fabry disease has stimulated research addressing alternative mechanisms to enhance the efficacy of endogenous or infused enzymes. Substrate reduction therapy (56) and gene therapy trials as listed by ClinicalTrials.gov (57) are currently recruiting patients for phase 1–3 studies. Migalastat, a small-molecule pharmacological chaperone first approved in Europe in 2016 and the US in 2018, was developed as a stabilizer of specific mutant (amenable) forms of α-Gal to facilitate its normal lysosomal trafficking (58,59). In an 18-month phase 3 trial in predominantly female patients, this agent was well tolerated and was associated with a decrease in left ventricular mass index. Migalastat and enzyme replacement therapy had similar effects on kidney function (59). Another phase 3 study showed modest reduction of GL3 in interstitial capillaries and glomerular cells after 6 and 12 months of therapy (58,60). Thus, migalastat could represent an oral monotherapy alternative to enzyme replacement in such patients (59). Notably, the concept of in vitro and in vivo amenability is under scrutiny, especially in patients with lower range (<10%) enzymatic activity (61). Pegunigalsidase α, a novel polyethylene glycol incubated (PEGylated) enzyme replacement agent, has a prolonged half-life and potential benefits regarding immunogenicity compared with agalsidase. Phase 1 and 2 studies, as well as switch (from agalsidase α) and comparative (agalsidase β) studies, have recently been launched (62). Plasma and Tissue-Specific Markers There is no single ideal biomarker in Fabry disease. Elevated plasma lyso-GL3 has been designated a hallmark of Fabry disease (63). Currently, measurement of plasma lyso-GL3 has increasingly replaced plasma and urine GL3 as the most significant, and technically more easily measured, noninvasive diagnostic biomarker (64), supplementing standard measurements of leukocyte GLA enzyme activity and genetic analysis. Lyso-GL3 allows better discrimination between patients with classic and nonclassic disease and subjects without Fabry disease. Furthermore, elevated lyso-GL3 has been linked to clinical events and a higher disease X-chromosome inactivation may between cells and in females, a normal plasma lyso-GL3 value not the existence of Fabry disease of enzyme replacement therapy, a reduction in lyso-GL3 levels is in classic males, a decline or typically in most nonclassic patients and females a of disease, lyso-GL3 is likely also in disease the of and mechanisms that are in Fabry disease A novel persistent in of podocyte GL3 was recently published new light on potential of to vascular and progressive of assays for lyso-GL3 and limited of the analysis in many are still a of the of lyso-GL3 is a of research, especially in late-onset variants with cardiac disease Markers of in Fabry disease are not in clinical In lysosomal deposits of mainly GL3, are of Fabry these are especially conspicuous in and easily be by after a kidney Recently, measurement of has been as a potential early diagnostic and prognostic noninvasive in of progressive disease and disease in patients with classic disease has even been reported in very affected of the future role of this is cardiac biomarkers may also be in a assessment and risk for the patient Kidney clinical and are of early progressive Fabry the other the assessment of specific and nonspecific or irreversible early information on kidney even in patients with normal GFR and These are diagnostic for optimal therapeutic strategies and follow-up of high-risk patients In a kidney is in Fabry patients with symptoms and unclear often with normal kidney as well as in patients with disease course and diseases A conspicuous in recent case series is the beneficial effect of enzyme replacement therapy on of GL3 from and glomerular and cells, with a of vascular In the study of et al. in 12 classic patients age years at treatment 1 treated for years, clearance of podocyte GL3 was in the patient and microalbuminuria in nearly of the patients. These were further expanded by Skrunes et al. reported serial kidney biopsies after 10 years of treatment in an expanded cohort classic patients, 12 males, median age 21 a dose-dependent effect on the of podocyte GL3 deposits (Figure 2) with a persistent failure to cells in of kidney This suggests that current therapy is insufficient to prevent long-term vascular The of serious even in patients, was further by the randomized multicenter study of 31 classic males with disease symptoms and normal measured GFR age 12 receiving enzyme replacement (agalsidase for years comparing two treatment regimens mg/kg every 2 or 1.0 mg/kg every patients age had kidney of cells with was in all biopsies showed progression in all but one patient a mean reduction of lyso-GL3 of of Fabry clearance of podocyte GL3 in two with classic Fabry disease, and years at of enzyme replacement are and lower left and after and years of agalsidase 6 years of enzyme replacement therapy, the younger was to agalsidase β 1.0 mg/kg every other week. the the were of GL3, a lower cumulative agalsidase to have a podocyte after a of years et al. kidney biopsies are in Fabry disease, and further prospective studies are warranted to disease mechanisms and potential with clinical may allow early between patients with or no risk of progressive and unnecessary treatment be when normal or only affected or disease, is Kidney biopsies provide the and most into cellular and vascular which are of disease New methods have shown for assessment of therapeutic after 1 of therapy and potentially relevant kidney biopsies be used by the of A study from sequencing of from of serial long-term kidney biopsies with Fabry increased of to the and compared with Thus, sequencing is in Fabry disease kidney and may to potential novel disease and therapeutic reports receiving a from on the of and and and from and all of the reports receiving from and of the This is supported by the

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