Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease
Year: 2018
Type: article
Abstract: Fabry disease (FD) is an X-linked lysosomal storage disorder (LSD) caused by mutations of the α-galactosidase A gene. The lysosomal enzyme α-galactosidase A (GLA) mediates the hydrolysis of the terminal α-galactosyl moiety from globotriaosylceramide (Gb3). An enzymatic defect leads to the lysosomal accumulation of mainly Gb3 in different cells and tissues, causing a multisystemic disease. The first formulation of recombinant enzyme replacement therapy (ERT) was approved in Europe in 2001. Although ERT has been demonstrated to improve patient outcomes and disease course, especially when initiated early in the course of the disease, the intravenous infusion of the recombinant proteins can trigger a humoral immune response, resulting in infusion-associated reactions. Moreover, recent studies provide evidence that neutralizing antidrug antibodies (ADAs) seem to attenuate therapy efficacy in affected male patients, mediating disease progression despite ERT. The deleterious effect of ERT-related ADAs is well known in other LSDs. This review focuses on the efficacy of ERT, especially on the humoral response to continuous infusion of recombinant proteins in patients with FD, and considers the evidence about the effect of ERT-related neutralizing ADAs during ERT infusions and their effect on disease progression. It also proposes a model to explain how ADAs might mitigate therapy efficiency in FD. Finally, it discusses how clinical knowledge derived from immune tolerance induction protocols used in other LSDs might translate to FD, providing an approach to prevent ADA formation in ERT-naïve patients and decrease or supersaturate existing antibody titers in affected patients, leading to an improved disease course. Fabry disease (FD) is an X-linked lysosomal storage disorder (LSD) on the basis of mutations within the α-galactosidase A (GLA; Xq21.3-q22) gene. The worldwide incidence of FD has been estimated at 1 in 40,000 to 1 in 117,000 live male births.1 However, FD is probably underestimated because symptoms are often nonspecific. More than 900 GLA mutations have been identified, according to the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/), resulting in a wide spectrum of clinical symptoms and manifestations.2 The reduction or loss of enzymatic GLA activity results in a progressive lysosomal accumulation, mainly of globotriaosylceramide (Gb3).3 The deacetylated and, therefore, soluble form of Gb3, lyso-Gb3, seems to be a reliable biomarker for both disease progression and therapy efficacy, and can be detected in blood plasma as well as urine.4–10 The systemic cellular accumulation of Gb3 leads to progressive renal failure, cardiomyopathy, and recurrent cerebrovascular events, significantly limiting life expectancy in affected patients.3 The most common cause of death is cardiovascular disease.11–13 Although FD is an X-linked condition, females can also be severely affected,14 likely due to a skewed X-inactivation.15 However, onset of first symptoms in females is generally 5–10 years later than in males.16 In male patients, a definitive diagnosis of FD involves demonstrating a GLA deficiency of <5% of wild-type activity in leukocytes and the presence of a GLA mutation.17,18 In females, because of the high residual GLA activity, the diagnostic gold standard requires genetic analyses; in patients with an uncertain diagnosis, biopsy of an affected organ that demonstrates pathognomonic FD-typical deposits (zebra bodies) can confirm FD.17,18 Current treatment options for FD include two different recombinant enzyme replacement therapies (ERTs) (agalsidase-α and agalsidase-β), as well as chaperone therapy (migalastat). The latter, used in patients with certain amenable mutations, facilitates cellular clearance of Gb3 and an overall improvement of disease burden.19–21 The annual costs of FD-specific treatment in Europe are about €€250,000 per year. However, ERT can lead to infusion-associated reactions (IARs) in females and males, as well as the formation of neutralizing antidrug antibodies (ADAs) in about 40% of all ERT-treated males, leading to an attenuation of therapy efficacy.19,20,22–25 This review discusses the use of agalsidase-α and agalsidase-β ERT in FD, with a special focus on the humoral response to the infused recombinant proteins that leads to the formation of neutralizing ADAs in affected patients. It also presents immune tolerance induction protocols for other LSDs that might be translated to mitigating the development of ADAs in patients with FD who receive ERT. In addition, it discusses alternative therapeutic strategies, including chaperone therapy and substrate reduction therapy, and suggests areas for future research. FD-Specific Treatment ERT Depletion of accumulated Gb3 from affected cells and organs by ERT should lead to an improvement or at least a stabilization of effects in the kidney and other organs. In Europe, ERT has been in use since 2001, when agalsidase-α was approved. Two different formulations are currently available in Europe, agalsidase-α (Shire), which is produced from a modified human fibrosarcoma cell line, and agalsidase-β (Sanofi), which is produced in Chinese hamster ovary cells. The recommended dosage for agalsidase-α is 0.2 mg/kg intravenously every 2 weeks, and the advised dosage for agalsidase-β is 1.0 mg/kg intravenously every 2 weeks. In addition, two new plant-based products are currently in development: pegunigalsidase α, (Protalix Biotherapeutics),26 which is produced in BY2 tobacco cells, and moss-aGal (Greenovation),27 which is produced in moss. Both agalsidase-α and agalsidase-β have been demonstrated to benefit patients in the short term and, in observational studies, patients treated for up to 10 years showed stabilization of eGFR or a slowing of the progression of eGFR decline.19,20,28–36 The natural course of disease is associated with a rapid decline of renal function (eGFR decline up 12 ml/min per 1.83 m2 per year) and left ventricular hypertrophy.37Tables 1 to 5 provide a general overview of the effects of both ERTs on symptoms and manifestations in patients with FD. Table 1. - Effect of ERT in patients with FD Organ Background/Setting/Measures Effect on Renal Function Reference Kidney Agalsidase-α Randomized, placebo-controlled study, 26 males treated for 6 mo, eGFR improved by +2.1 ml/min per 1.73 m2 (P=0.02) Stabilization of eGFR 20 Retrospective FOS analysis, 201 patients treated for 24 mo, eGFR stabilized in 13 patients with CKD stages 2 and 3 during treatment (P>0.05) Stabilization of eGFR 28 Retrospective FOS analysis, 268 (135 males) patients treated for 5 yr, compared with untreated patients eGFRs in males with <60 and ≥60 ml/min per 1.73 m2 changed by −2.86 (95% CI, −3.90 to −1.83) and −1.68 (95% CI, −2.05 to −1.31) ml/min per 1.73 m2 per year, respectively, and in females with <60 ml and ≥60 ml/min per 1.73 m2 by 0.36 (95% CI, −0.47 to 1.19) and −0.43 (95% CI, −0.83 to −0.02) ml/min per 1.73 m2 per year, respectively Stabilization of eGFR 31 Observational single-center study, 45 (21 males) patients treated for 10 yr, eGFR analyzed as ml/min per 1.73 m2 per year reported to be stable Stabilization of eGFR 32 Observational single-center study, 12 male patients switched from biweekly to weekly infusions and observed for 10 yr, biweekly infusion resulted in yearly eGFR loss of −7.92±2.88 ml/min per 1.73 m2, weekly infusion resulted in an amelioration of −3.84±4.08 ml/min per 1.73 m2 per year (both P=0.01) Stabilization of eGFR 34 Retrospective FOS analysis, 188 patients treated for 12 mo, eGFR changes in patients with an eGFR 30 to 60 ml/min per 1.73 m2 as well as 60 to 90 ml/min per 1.73 m2 were NS Stabilization of eGFR 42 Single-center prospective open-label study, 24 male patients treated for up to 4.5 yr, eGFR changed by approximately −3 ml/min per 1.73 m2 per year (P=0.04) Slowing the progression of eGFR decline 43 Retrospective FOS analysis, 165 (115 males) patients treated for 3 yr, in males eGFR changed by −2.66±5.07 ml/min per 1.73 m2 per year (P<0.01) and in females by −1.20±3.28 ml/min per 1.73 m2 per year (P<0.01) Slowing the progression of eGFR decline 44 Prospective, randomized, placebo-controlled trial, 85 male patients treated for 2.5 yr, eGFR changed by −2.9±8.7 ml/min per 1.73 m2 per year (P=0.002) (patients with hyperfiltration were excluded) Slowing the progression of eGFR decline 45 Retrospective FOS analysis, 208 (134 males) patients treated for 7.4 yr, in males eGFR changed by −2.2 ( 95% CI, −2.8 to −1.7) ml/min per 1.73 m2 per year (P=0.01) and in females by −0.7 (95% CI, −1.4 to 0.0) ml/min per 1.73 m2 per year (P=0.05) Slowing the progression of eGFR decline 46 Open-label, multicenter study, 11 (ten males) pediatric patients treated for 6.5 yr, eGFR changed by +0.22 (95% CI, −2.84 to 3.28) ml/min per 1.73 m2 per year Stabilization of eGFR 47 Agalsidase-β Retrospective Fabry Registry analysis, 52 (50 males) patients treated for 10 yr, in patients with LRI eGFR changed by −1.89 ml/min per 1.73 m2 per year (P=0.001) and in patients with HRI eGFR changed by −6.82 ml/min per 1.73 m2 per year (P<0.001) Slowing the progression of eGFR decline 33 Observational multicenter study, 24 (21 males) patients treated at least for 24 mo, eGFR changed by 0.13 (95% CI, −3.75 to 5.00) ml/min per 1.73 m2 per year (P>0.05) Stabilization of eGFR 35 Multicenter phase 3 trial, 55 patients, treated for up to 3 yr, serum reported to be stable Stabilization of eGFR single-center open-label study, males) patients treated for up to 2 yr, in patients with a ml/min per 1.73 m2, by ml/min per 1.73 m2 in 24 patients with a ml/min per 1.73 m2 stable (P>0.05) Slowing the progression of decline phase 3 study, 52 (50 males) patients treated for 4.5 yr, eGFR changed by ml/min per 1.73 m2 per year Stabilization of eGFR Retrospective Fabry Registry analysis, males) patients treated for 2 yr, the for renal disease progression was an 95% CI, to P=0.01) and a from onset to treatment 95% CI, 2 to P=0.01) of renal function due to early treatment and of Observational multicenter study, males) patients treated for 12 mo, eGFR changed by ml/min per 1.73 m2 per year Stabilization of eGFR 52 observational study, 24 males) patients treated for 2 yr, eGFR changed in patients with by (95% CI, to ml/min per 1.73 m2 per year (P=0.01) and in patients with by (95% CI, to ml/min per 1.73 m2 per year (P=0.02) Stabilization of eGFR due to Fabry 95% CI, 95% renal high renal Table - Effect of ERT in patients with FD Organ Background/Setting/Measures Effect on Function Reference Agalsidase-α Retrospective FOS analysis, males) patients treated for 5 yr, were compared with untreated patients as (95% CI, 0.13 to per year in males and (95% CI, to per year in females of 31 Observational single-center study, 45 (21 males) patients treated for 10 yr, by −1.89 (95% CI, to (P<0.001) in males and by (95% CI, to in females of 32 Retrospective FOS analysis, 52 patients treated up to 2 yr, in patients with at and in patients with also of and 42 multicenter study, 11 (ten males) pediatric patients treated for 6.5 yr, changed by (95% CI, to per year Stabilization of 47 study, patients treated for 12 mo, changed by and by (P=0.02) of Randomized, placebo-controlled study, male patients treated for 6 mo, changed by (P=0.04) of 55 Retrospective FOS analysis, patients treated up to 5 yr, 5 changed in patients with at by (P=0.01) and by (P>0.05) of Single-center open-label of females treated for yr, of at (P<0.01) of Agalsidase-β Retrospective Fabry Registry analysis, 52 (50 males) patients treated for 10 yr, changed in patients with LRI by (P=0.05) and in patients with HRI by Stabilization of 33 Single-center open-label study, males) patients treated for 12 mo, of the left ventricular and of the changed by stabilization of and improvement of function Single-center open-label study, males) patients treated for 12 mo, and were significantly at least 12 of and Single-center open-label study, 11 males) patients treated for 45 mo, changed by and left ventricular changed by (both of and 60 Single-center open-label study, 32 males) patients by treated for 3 yr, and changed in patients by and (both of and due to early treatment Single-center open-label study, males) patients treated for mo, and changed by and of and amelioration of 95% CI, 95% Fabry renal high renal left ventricular left ventricular left ventricular left ventricular Table - Effect of ERT in patients with FD Organ Background/Setting/Measures Effect on Reference Agalsidase-α study, 26 male patients treated for 6 mo, blood changed by ml/min per of of blood study, male patients treated for mo, blood in certain improved of blood Agalsidase-β of phase study, 31 patients treated for 12 mo, in of significantly in and stable in the treated Stabilization of Table - Effect of ERT in patients with FD Organ Background/Setting/Measures Effect on Reference Agalsidase-α Randomized, placebo-controlled study, 26 males treated for 6 mo, changed by (P=0.02) of 20 Retrospective FOS analysis, patients treated for up to 2 yr, reported to decrease of 42 Retrospective FOS analysis, patients treated for up to 5 yr, changed by changed by P=0.01) of and Single-center prospective open-label study, females treated for yr, changed 12 from to (P=0.001) and stable of Retrospective FOS analysis, 20 males) patients treated for up to 2 yr, the year of Retrospective FOS analysis, patients treated for 3 yr, of Agalsidase-β Single-center prospective open-label study, male patients treated for up to mo, for changed from to for and (P<0.01) of improvement of function Fabry of Table - Effect of ERT in patients with FD Organ Background/Setting/Measures Effect on Reference Agalsidase-α Single-center open-label study, 11 males) patients treated for 6 mo, for the presence of and the of a reduction (both of and of Retrospective FOS analysis, males) patients treated for 24 mo, of significantly of Single-center clinical trial, male patients treated for to 3 yr, patients reported of and and of of and of and Retrospective Fabry Registry analysis, patients treated for up to yr, presence of changed by (P<0.01) and of by (P<0.01) of and of Table - of therapy for or of ADAs in patients with LSDs Reference tolerance induction in ERT-naïve patients FD due to with cell cell cell cell reduction of neutralizing ADAs FD ADA reduction by due to ADA plasma cell cell ADA plasma cell intravenous of disease. In most studies that early treatment is to resulting in a In stages of the disease, patients benefit from ERT. ERT has been demonstrated to lead to Gb3 in renal cells in and in a and ERT has been reported to renal function in of effect on and is ERT is has a improvement of and can be It also leads to a reduction of cerebrovascular and and improvement in of Moreover, ERT is associated with a reduction of symptoms as and and a reduction of a of disease effects of ERT can be by different disease and as the the and the In to ERT, of and the basis of enzyme and is to and However, recent reported a benefit of the use of to a in ERT efficacy is the formation of ADAs infused which is a focus of treatment chaperone therapy with was approved in Europe in of for treatment of FD in and years or with an amenable The recommended is every other and should be for at least 2 and 2 The is currently recommended for use in patients with an ml/min per 1.73 an chaperone that GLA enzyme and in the leads to enzymatic GLA activity in the of patients with an amenable are mutations that in enzymatic activity, caused by of the which the chaperone can are at least amenable and mutations the basis of an in in human kidney according to a by which patients with amenable mutations, as a alternative treatment for patients with In addition, recent the first substrate reduction therapy, which to of Gb3 by demonstrated that plasma as within 12 of is also for a therapy approach to of resulting in a clinical to ERT ERT is on the basis of the intravenous infusion of a recombinant a humoral response is at least in males with FD, who are also as that is a or form of GLA that can be by the immune as an In patients, infused enzyme might be as an immune studies patients with LSDs that patients have a high for immune ERT of it is when patients with FD to an immune response caused by continuous to ERT to the formation of neutralizing from in ERT-naïve patients with FD ERT mainly in males with or mutations of are to and with and as well as of infusion infusion However, also have been to the of patients treated with agalsidase-α with In of patients treated with agalsidase-β The of is are probably the of reactions and often 1 because of antibodies has been in a male patients to In were in patient with including other patient with during and with In addition, an agalsidase-β open-label reported patients with or a reported patients with by or a However, the of seems to be in patients with an The humoral response cells, cells, and cells response results in overview of a humoral immune response to recombinant GLA resulting in antibody In a immune response, the recombinant human GLA is by cells and to cells, which cells, in cells, which plasma patients with the general might an early response the formation of cell and which explain the observed is by antibody antibodies with lead to be and be or the studies the presence of and antibodies in patients with FD. antibodies seem to within of and of in affected patients be reported that most were observed during the first 13 Although of ERT-related in the first ERT clinical trial, to or protocols have been to studies and an early response were by the and their However, demonstrated that antibodies by an neutralizing activity that can be used to neutralizing and patients. This neutralizing activity was by other and the of antibodies in patients with ADAs was as studies have neutralizing ADAs their formation seems to be and that the of affected patients neutralizing 10 of patients treated with agalsidase-β and of patients treated with agalsidase-α This might be by the different of both and the different cell as well as the of the treated patients, which has been from an for formation of neutralizing ADAs in patients treated with Although the of the treated patients was their patients with FD. However, and later reported in ADA formation when the dosage mg/kg every 2 for both at ERT the of patients in studies was also in studies with and a of patients are it seems that the dosage is the most trigger for immune Although the presence of neutralizing ADAs was first early ERT the effect of ADAs on FD-specific has been a of ADA titers by have been associated with Gb3 in with effects on plasma Gb3 In by demonstrated that plasma Gb3 were significantly in patients with neutralizing and that Gb3 in patients also that ADAs are associated with a clearance of plasma Although have that ADAs to have effects on as eGFR and is evidence that patients with ADAs clinical including left ventricular and progressive loss of renal in outcomes might be due to an ERT effect on ADA observed that in patients with ADAs who been switched from an agalsidase-β of 0.2 to 1.0 mg/kg every 2 weeks, plasma and Gb3 significantly 1 might be the of a of antibodies due to ERT during A model of ERT and neutralizing ADAs during infusion by in the can explain therapy efficiency during to during infusions in patients ERT the cell and the and results in clearance of neutralizing ADAs are ERT is by ADAs in the In addition, of ADAs to ERT also leads to an of that leading to a decrease in the cellular of ERT. the ERT the antibody ERT can the of cells, resulting in an Gb3 clearance with therapeutic This is by recent outcomes by demonstrating an improved patients treated with of as agalsidase-β compared with agalsidase-α the of ADAs to ERT the cellular the or of by and and should be in future ADA titers cellular lysosomal Gb3 Current model of ERT and neutralizing ADAs during antibodies are ERT cells the leading to Gb3 clearance from antibodies are ERT activity by the In addition, ERT be and by antibodies than ERT are results in a cellular Gb3 clearance the ERT antibody ERT can the of cells, resulting in Gb3 clearance Current for other LSDs as and disease have on the effect of neutralizing ADAs on clinical outcomes and how to ERT to This focus is probably due to the that the clinical effect of ADAs in patients affected by LSDs in is and than in FD. In therapeutic can be the of ADA formation in ERT-naïve patients and the reduction of existing demonstrated in that of during ERT can prevent ADA formation and, therefore, immune tolerance in a FD model treated with A was in by the continuous of a humoral that also known as A effect of was also observed in demonstrating that the formation of cells, which might an tolerance to the of protocols to prevent ERT-naïve patients with FD from neutralizing ADAs have been focus on how to ERT to during infusion for a of agalsidase-α and agalsidase-β in patients with have been by and of ADA cell and in with disease ERT an immune tolerance induction to the immune response to recombinant and prevent the formation of A recent showed that patients with FD who therapy organ ERT demonstrated the therapy was that an as used for might also prevent ADA prevent ADA formation in ERT-naïve patients with FD, prospective studies are to to infusion protocols with in with ADAs The outcomes in studies the effect of ADAs on clinical symptoms and manifestations in patients ERT the to antibody especially because ADA titers can be by enzyme at a certain of The to ADA titers and to ERT efficacy might be to infused the approved of agalsidase-α and agalsidase-β per are and of be also in ADA titers is patients with disease progression who are of therapeutic options despite ERT might also benefit from in patients with FD can significantly decrease ADA and to prevent or decrease ADAs in patients with other LSDs has been in The most have of the by of or by cell treatment with 2 mg/kg in with mg/kg intravenous or with mg/kg and intravenous mg/kg every resulted in a decrease of antibody in the antibodies were for at least 3 Moreover, a treatment with and has been reported to antibody titers in have also use of of or as and 2 an overview of therapy that have been used for or of ADAs in patients with LSDs. and Treatment Current studies that treatment with 1.0 mg/kg agalsidase-β is associated with an for ADA is due to the or the of prospective studies with of both agalsidase-α and and including patients with should be to the of the two the ADA might patient a or of ADAs infusion might be of the most in future clinical with ERT. The of to ADA titers and infusions be to patients at and results in future it be in clinical to be to neutralizing ADA titers by from a blood This approach of the of ERT to supersaturate The of also of ADA of and future In addition, the short reported of ERTs in plasma for agalsidase-α and for future prospective studies should a decrease the for ADA formation in ERT-naïve patients. the currently approved might be by a infusion weekly with a as reported by or by use of chaperone and ERT which is reported to the of infused In addition, of ERTs as moss-aGal and pegunigalsidase be of The of of pegunigalsidase of of the GLA is especially approach is the of GLA as by who reported a GLA from that with ADAs from patients treated with currently approved ERT. It be of or the infusion of a every might also lead to a reduction of existing ADA use of immune to ADA titers be an and it is to be in clinical However, might be the development of a to supersaturate ADAs ERT In to causing of infused ADAs might also form immune 3 mediating and resulting in as reported for other ERT-treated is a cause of a in future studies renal to ERT should focus on Gb3 accumulation also on of and within of patients with therapy might benefit affected patients in two by of infused enzyme and by for neutralizing to that demonstrated for be of to within the recombinant with FD, who GLA at high for ADA formation when treated with ERT. This the of ERT strategies, because patients are with chaperone Moreover, substrate reduction therapy might be a therapeutic it has been approved for the development of ERTs for a humoral response or enzymatic as well as the of protocols to immune the approach might the treatment efficiency for male patients with FD the basis of reported in the to for and ERT should be initiated in male patients with an approved of 0.2 or mg/kg for agalsidase-α or ERT the patient should be for the presence of neutralizing ADA 13 infusions agalsidase-β be to 1.0 mg/kg the is ADAs are for In patients who with titers and infusions should be to ADAs are by ADAs are by ERT and the patient is from a the approved might be an to supersaturate therapy is an alternative for patients with a that is amenable to that a patient with ADAs has the of ERT or has that treatment with infused to as in might be the to therapy Table for therapy in patients with FD with neutralizing ADAs ERT. agalsidase-β is approved in of or 1.0 the approved for agalsidase-α is 0.2 that in male patients with FD treated with ERT, the presence of neutralizing ADAs the therapy efficacy and to or disease progression. is for ERT. of ADA titers to infused ERT are to supersaturate antibodies should be in clinical should in studies that the effect of FD-specific treatment on disease progression. and and from and of the a in or of
Authors: Malte Lenders, Eva Brand
Institution: University Hospital Münster
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2886692196