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Fabry disease (FD) is a multisystem, X-linked disorder of glycosphingolipid metabolism caused by enzyme deficiency of α-galactosidase A. Affected patients have symptoms including acroparesthesias, angiokeratomas, and hypohidrosis. More serious manifestations include debilitating pain and gastrointestinal symptoms, proteinuria and gradual deterioration of renal function leading to end-stage renal disease, hypertrophic cardiomyopathy, and stroke. Heterozygous females may have symptoms as severe as males with the classic phenotype. Before 2001, treatment of patients with FD was supportive. The successful development of enzyme replacement therapy (ERT) has been a great advancement in the treatment of patients with FD and can stabilize renal function and cardiac size, as well as improve pain and quality of life of patients with FD. In this review, we have provided a critical appraisal of the literature on the effects of ERT for FD. This analysis shows that data available on the treatment of FD are often derived from studies which are not controlled, rely on surrogate markers, and are of insufficient power to detect differences on hard clinical endpoints. Further studies of higher quality are needed to answer the questions that remain concerning the efficacy of ERT for FD.
Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal hydrolase, α-galactosidase A (α-Gal A). The enzymatic defect leads to the accumulation of glycosphingolipids, mainly globotriaosylceramide (GL-3), in body fluids, in the lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels, in ganglion cells, and in many cell types in the heart, kidneys, eyes, and most other tissues.1
Clinical manifestations in classically affected hemizygous males who have no detectable enzyme activity include early childhood or adolescent onset of pain (acroparesthesias) in the extremities, angiokeratoma in skin and mucous membranes, and hypohidrosis. Corneal and lenticular opacities are also seen as early findings. Gastrointestinal problems, such as diarrhea, constipation, and abdominal pain, are common. Endocrine abnormalities include thyroid disease and fertility problems in both males and females. With increasing age, proteinuria, hyposthenuria, and lymphedema appear. Severe renal impairment leads to hypertension and uremia. Death usually occurs from renal failure or from cardiac or cerebrovascular disease. Atypical hemizygotes with residual enzyme activity may have later onset of symptoms, and such symptoms may be limited to the heart in some cases (the ‘cardiac variant’).1 Heterozygous females can be as severely affected as hemizygous males, although the range of symptoms varies widely. A frequent clinical finding in females is the characteristic whorl-like corneal epithelial dystrophy observed by slit-lamp microscopy (cornea verticillata).1
Confirmation of the clinical diagnosis in males requires the demonstration of deficient α-Gal A activity in plasma, leukocytes, or fibroblasts, or increased levels of GL-3 in plasma or urinary sediment. Heterozygous females may have intermediate or even normal levels of enzymatic activity and accumulated substrate, so accurate diagnosis of heterozygous females requires identification of a molecular lesion in the α-Gal A gene or by linkage analysis in families with an affected male.1
Before 2001, treatment of patients with FD was exclusively supportive. Advancement of molecular genetic techniques led to the development of enzyme replacement therapy (ERT). There are two forms of (ERT): agalsidase α (AGALA) (Replagal®; Shire Human Genetic Therapies Inc, Cambridge, MA) and agalsidase β (AGALB) (Fabrazyme®; Genzyme Corporation, Cambridge, MA). Table 1 compares the two forms of available ERT.2,3 In this review, we have examined the literature on the effects of ERT for FD with the aim of providing a critical appraisal of the literature and its limitations.
We formulated a comprehensive search strategy in an attempt to identify all relevant studies published in the English language. An Ovid search was conducted using the Ovid databases: MEDLINE® (1950 to present with daily update) and Embase (1980 to date). Details of the search strategy are presented in Table 2. After the exclusion of case reports, studies not on ERT effects, studies not on FD, and general reviews on FD, 41 studies were included in this review.2, 4–7, 9–45 Abstracts were reviewed using the evidence grading system developed by Oxford Centre for Evidence-based Medicine – Levels of Evidence (March 2009).46
The grading of the evidence available on ERT for FD is listed in Table 3. A summary of the effects of ERT on various Fabry-related endpoints is provided in Table 4. While reading through the information in the tables, it is important to remember that, regardless of whether a disease is rare or common, studies of adequate quality are needed to distinguish true findings from false findings. There is a real need to critically appraise the literature available on ERT for FD for several reasons listed below.
Given the recommended dosage of AGALA and AGALB, the cost of treatment for a 70-kg patient exceeds US$200,000 per year, and therefore, accurate information on the effects of ERT on hard clinical outcomes, such as the need for dialysis and stroke, is needed to be able to calculate the cost-effectiveness of therapy.
The studies of natural history regarding FD are very heterogeneous,47–53 resulting in imperfect understanding of the natural history of this rare disease. As most of the publications on FD do not contain a prospective, untreated control group, accurate natural history data are essential for determining the effect of therapy. For example, natural history data are discordant when considering the risk of stroke. Studies report that rates of stroke range from 4.2% to 27% in females and from 6.7% to 24% in males. Even more confusing, successive publications from the same registry cite conflicting rates of stroke.47,48,50,51 The data on glomerular filtration rate (GFR) are just as confusing. For example, in one of the earliest reports on the natural history of FD, a retrospective chart review of males with FD estimated annual decline in estimated GFR at 12.2 mL/min per year.54 Another study that summarized the results of three separate clinical trials that were conducted at different times and sites showed rates of decline ranging from 2.9 to 7 mL/min/year/1.73 m2 in untreated males.44 As most of the reported literature on FD and ERT does not include a control group, the lack of accurate natural history information makes the effects of ERT difficult to interpret.
Several studies investigating FD in dialysis patients in the United States and European registries reported prevalence to be 0.0168% and 0.0188% respectively,55 with the prevalence among dialysis males about 0.027% in both registries while a study in Austria reported higher results in dialysis males with a prevalence of 0.264% and prevalence in overall dialysis patients of 0.161%.56 A recent systematic review demonstrated that the overall FD prevalence on dialysis was 0.33% in males and 0.10% in females.57 These data may underestimate the prevalence of FD in females on dialysis, however, as 91% of the screening studies in women were performed using α-Gal A activity analysis as the primary screening method, which is unreliable for detection of FD in female patients.57 Newborn screening studies showed that the incidence of Fabry mutations in Taiwan Chinese and Italian populations to be 1:1400 and 1:3100 males, respectively,58,59 which is 15–30 times higher than previous estimates.1 More accurate data on disease prevalence are needed to identify the degree of ascertainment bias which may be present in the large multinational registries that provide most of the available data on the effects of ERT therapy.
Treatment of Fabry patients may induce the formation of neutralizing antibodies toward AGALA and AGALB, and this may influence the effects of therapy. Antibody formation is more common in males.7 The significance of these antibodies on clinical endpoints, though, is unclear as most of the studies on this have evaluated only surrogate endpoints and not all studies report on the presence of antibodies. One trial in male patients showed that the urinary GL-3 levels failed to decline in patients with IgG antibodies, whereas a reduction could be detected in patients without IgG antibodies.6,7 This is in contrast to a study showing that 1.0 mg/kg of AGALB did reduce cardiac mass in small group of patients who were antibody positive. Using a surrogate marker like GL-3, which is an unreliable indicator of disease severity, may contribute to the poor understanding of inhibitory effect of IgG antibodies.53,60
When evaluating the medical literature on the effects of ERT on disease activity in FD, it is important to look critically for certain points including 1) the presence of a concurrent control group rather than using conflicting retrospective natural history data, 2) clear delineation of the origins of the patient cohort including a discussion of the number of subjects who were excluded from analysis and the reasons for exclusion, 3) use of hard clinical endpoints, appropriate randomization and blinding techniques, and 4) clear description of the power of the study to detect a significant difference in the primary outcome. As these features seem to be a basic requirement of any data evaluating a therapeutic modality, many of these key points are missing in the available data on ERT for FD.
The single Grade 1 study25 has a placebo-controlled and blinded design, but nonetheless has significant limitations. The primary endpoint of this study was to show the effects of ERT on a composite clinical endpoint, which included renal, cardiac, and neurological events. Although the effects of AGALB on the composite outcome were of borderline significance (P =0.06), secondary analyses of protocol-adherent patients adjusted for baseline proteinuria demonstrated a more pronounced treatment effect compared with the placebo group (P = 0.034). Although these data are encouraging, the raw data suggest that the effects of therapy on the composite outcome were primarily driven from one of the renal endpoints which was, in fact, a surrogate measure (33% increase in serum creatinine) rather than hard renal endpoints like dialysis or transplantation. The 33% increase in serum creatinine comprised 10/14 events in the AGALB group and 7/13 events in the placebo group. Another possible limitation of this study is that only about one-third of the patients in each group were receiving antiproteinuric therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). As therapy directed at the renin-angiotensin system is beneficial in Fabry nephropathy,61 the underutilization of such supportive therapies may have served to increase the perceived benefit of ERT.
To measure the outcome of interest, 98% of the studies used surrogate endpoints. Surrogate measures are often used when the disease is so rare or the desired outcome is so far in the future that it would take an unreasonably long follow-up period to obtain a sufficient number of outcomes. Even though the association between the surrogate measure and the true outcome may be biologically plausible, using the surrogate measure may produce misleading results if the association with the true outcome is not based on hard endpoints. The surrogate marker used in the first large study of AGALB was GL-3.5 This trial demonstrated that therapy with AGALB led to clearance of GL-3 from biopsy specimens of the kidney, heart, and skin. Although these results were used to gain approval for AGALB in the United States, subsequent studies have shown that the relationship between GL-3 and clinical endpoints are less clear.53,62
Many of the publications include data obtained by cross-sectional surveys,47,48 database registries12,35,40,42,43,49–52 or historical cohorts,53 which are subject to different sources of bias including selection bias, ascertainment bias, reporting bias, survivor bias (based on the early death of more severely affected patients), incomplete and missing data (leading to misclassification), and importantly, the absence of simultaneous controls. There are two large multinational registries: the Fabry Outcome Survey (FOS) sponsored by Shire Human Genetic Therapies, manufacturer of AGALA, and the Fabry Registry sponsored by Genzyme Corporation, manufacturer of AGALB. There are numerous publications from these registries which contribute to the medical literature on FD.12,35,39,41,42,63 As these registries are able to combine large number of patients from around the world with different genetic backgrounds, they provide valuable information on the progression of Fabry-related complications and the effects of ERT, and can also help to define some of the less frequent manifestations of an already rare disease. However, there are some problems with the data inherent in both the registries in that data collection is voluntary and, therefore, incomplete. This results in publications where the total number of patients included in the studies is often less than the total number of eligible patients, which can compromise conclusions drawn from these studies. For example, one study from the FOS includes only 201 patients, while at the time of analysis, 608 patients (358 receiving ERT) were enrolled in the registry.35 Another publication included only 71 men and 59 women, while at time of analysis, 3182 patients were enrolled in the registry.63 Although it is admittedly difficult to perform high-quality randomized studies in diseases of low prevalence, it is not impossible in that such studies have been done in other types of kidney diseases with similar prevalence to FD.64
The major effects of ERT on different organ systems are summarized in Table 4 along with the limitations of the studies from which these effects have been determined. In summarizing the literature to date on ERT for FD, some conclusions can be drawn. It is clear that FD is a multisystem, progressive disorder in both males and females.49 It is clear that ERT is an effective treatment for neuropathic pain in FD.4 It is also clear that ERT can stabilize renal function or at least slow the decline of renal function in many patients with Fabry nephropathy12,25,28,35,36,38,41,44 and stabilize or improve surrogate parameters like cardiac size in those with cardiomyopathy.12,20,29,34
There are many unanswered questions such as the following:
Although the ERT is a step forward in the management of FD, the requirement for frequent infusions, the enormous cost for lifelong therapy, the inability of ERT to traverse the blood–brain barrier, and uncertainty about the long-term effectiveness on hard clinical endpoints in Fabry patients make other modalities of treatment candidates for consideration. Two such novel approaches are chaperone therapy71–75 and gene therapy.76
Chaperone therapy is a novel approach that uses small molecules that specifically bind to and stabilize the functional form or shape of a misfolded protein in the endoplasmic reticulum (ER) of a cell. When a protein (enzyme) is misfolded because of a genetic mutation, it becomes unable to adopt the correct functional shape. This misfolded protein is recognized by the quality control system in the cell and is destroyed, leading to a decreased amount of enzyme that gets transported from the cell’s ER to the cell’s lysosome, and hence, reduced enzyme activity. The binding of the chaperone molecule helps the protein fold into its correct shape. This allows the protein to be properly trafficked from the ER and distributed to the lysosome in the cell, thereby increasing enzyme activity and cellular function and reducing substrate and stress on cells.77 The advantage of such an approach includes better biodistribution of therapeutic agents, and such agents are able to traverse through the blood–brain barrier unlike ERT. Chaperone therapies can be administered orally, which may reduce the impact on quality of life caused by the need for biweekly infusions of ERT. In a trial of 27 patients with FD, treated for up to 2 years with 1-deoxygalactonojirimycin (DGJ) or Migalastat, the drug was safe and well tolerated. Migalastat increased the leukocyte, kidney, and skin α-Gal A activities and reduced the substrate (GL-3) levels in the urine and kidney biopsies of 24 patients.78 Furthermore, the chaperone response of patients was similar to that predicted by models of in vitro responsiveness of α-Gal A gene mutations,78 suggesting that there may be an easy way to determine which patients would be appropriate for the use of chemical chaperones. In another study, the response of T cells in normal individuals or in Fabry patient’s to treatment with DGJ showed 28% increase in α-Gal A activity, whereas the response in Fabry individuals was mutation dependent ranging from no increase to fully normal activity.71 Although these studies are promising, long-term trials looking at hard clinical endpoints are required.
Promising results have also been achieved in gene therapy experiments with the mouse model of FD. Adult Fabry model mice have been successfully treated by various viral vectors. Using adeno-associated viral vectors, long-term enzymatic and functional corrections in various organs of the Fabry mouse have been attained.79,80 One study showed a single neonatal injection was effective to inhibit GL-3 accumulation in mice. If these data can be replicated in humans, this approach may be useful to prevent major organ failure developing later in life in patients with FD.76 The advantages of gene therapy include persistent correction after a single procedure and cross-correction by enzymes secreted by organs. However, much work is still needed before this can be translated into the clinical setting.78
ERT for FD is a major step forward for patients and has revolutionized care for patients with this fatal disease. However, as the field moves forward, questions need to be answered, some of which stem from the fact that most of the studies are observational and/or uncontrolled. The availability of registries for FD currently is an excellent step to collect a large sample size. These registries could be used to draw participants for possible randomized-controlled studies which could generate Grade 1 data. Observational information from those registries, although useful to generate hypotheses, should never replace data from randomized-controlled trial. Crossover studies are a useful approach, but they present ethical challenges given that, at the current time, disease-modifying therapy for FD other than ERT is not available outside the clinical trial setting. In future, innovative approaches to research in rare diseases will be needed to obtain data of high quality while ensuring that there are no undue delays in translating the results of laboratory research into the clinical setting.
Dr Sirrs has received speaking fees and has attended conferences with travel support sponsored by both Shire Human Genetic Therapies and Genzyme Corporation. She is also an investigator in the Canadian Fabry Disease Initiative, which receives funding from both Shire Human Genetic Therapies and Genzyme Corporation. Dr Alfadhel has no relevant disclosures.