Clinical UM Guideline

Subject: Agalsidase beta (Fabrazyme®)
Guideline #:  CG-DRUG-54 Current Effective Date:    03/29/2017
Status: Reviewed Last Review Date:    02/02/2017


This document addresses the clinical indications for agalsidase beta (Fabrazyme, Genzyme Corporation, Cambridge, MA), a biosynthetic form of human alpha-galactosidase A enzyme. Agalsidase beta is an enzyme replacement therapy (ERT) approved by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with a lipid storage disorder called Fabry disease.

Clinical Indications

Medically Necessary:

Agalsidase beta is considered medically necessary for the treatment of an individual with Fabry disease when the following criteria are met:

  1. Diagnosis of Fabry disease is confirmed with eithe r of the following:
    1. Documentation of complete deficiency or less than 5% of mean normal alpha-galactosidase A (α-Gal A) enzyme activity in leukocytes, dried blood spots, or serum (plasma) analysis; or
    2. Documented galactosidase alpha gene mutation by gene sequencing; and
  2. The individual to be treated has one or more symptoms or physical findings attributable to Fabry disease, such as:
    1. Acroparesthesias; or
    2. Angiokeratomas; or
    3. Corneal verticillata (whorls); or
    4. Decreased sweating (anhidrosis or hypohidrosis); or
    5. Personal or family history of exercise, heat, or cold intolerance; or
    6. Personal or family history of kidney failure.

Not Medically Necessary:

Agalsidase beta is considered not medically necessary when the criteria above are not met and for all other indications.


The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

J0180 Injection, agalsidase beta, 1 mg (Fabrazyme)
S9357 Home infusion therapy, enzyme replacement intravenous therapy; (e.g., Imiglucerase); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-10 Diagnosis  
E75.21 Fabry (-Anderson) disease
Discussion/General Information

Description of the Condition

Fabry disease is an X-linked lysosomal (lipid) storage disorder related to a deficiency of the enzyme alpha-galactosidase A (also known as ceramide trihexosidase) required to metabolize lipids, fat-like substances that include oils, waxes, and fatty acids. Fabry disease affects about 3000 individuals worldwide, and is the only lipid storage disorder where the mother carries the affected gene on the X-chromosome. The alpha-galactosidase A enzyme functions in the glycosphingolipid pathway, removing a sugar residue attached to ceramide. In its absence, there is progressive accumulation of globotriaosylceramide (GL-3) and other glycosphingolipids in tissues, including vascular epithelium, heart, cornea, kidneys, skin, and brain. Accumulations in these tissues leads to manifestations of classic Fabry disease, such as angiokeratomas, hypohidrosis, painful acroparesthesias, corneal opacities, renal failure, cardiac disease, and cerebrovascular disease (Eng, 2001a; Fabrazyme Product Information [PI] Label, 2010; National Institute of Neurological Disorders and Stroke National [NINDS], 2016).

Fabry disease may not be suspected when symptoms first appear and the diagnosis may be delayed. Many individuals go decades before being diagnosed with the disease. Data from the Fabry Disease Registry reports a large gap between the average age of symptom onset (age 10.5) and diagnosis of Fabry disease (age 28.5) (Germain, 2015).

Clinical manifestations of the classic form of Fabry disease in males (that is, little or no alpha-galactosidase activity) usually begin in childhood or adolescence and progress throughout adulthood. Premature death may result around 40 years of age, or 50 years of age if treated with kidney dialysis or kidney transplantation. A milder form of Fabry disease may develop in some females due to variability of the X-chromosome inactivation within cells; however, clinical manifestations in female carriers range from asymptomatic to severe manifestations similar to those observed in males with classic disease.

Signs and symptoms of Fabry disease continue over decades and include burning sensations in the arms and legs (that worsens with exercise and hot weather), small, non-cancerous, raised reddish-purple blemishes on the skin, and clouding of the corneas. Other symptoms include decreased sweating, fever, and gastrointestinal difficulties. Lipid storage may lead to breathing and digestive problems, impaired circulation, and increased risk of cardiomyopathy, cerebrovascular accidents, and renal failure. A cardiac variant of Fabry disease that occurs in late adulthood is usually limited to myocardial dysfunction (for example, left ventricular hypertrophy), and there is no vascular endothelial accumulation of GL-3. This variant is characterized by residual mutant alpha-galactosidase A activity (up to 10% of normal), thus preventing appearance of classic manifestations. Galactose infusions, given to stabilize activity of residual alpha-galactosidase A may be useful in improving cardiac dysfunction (Eng, 2001a; Frustaci, 2001).

The National Society of Genetic Counselors (NSGC) (Laney, 2013) recommends testing for any individual with a family history of Fabry disease or corneal verticillata ("whorls") on slit lamp exam. In the absence of these factors, the NSGC recommends testing an individual who have any of the following 2 features:

Metha and Hughes (2013) provide diagnostic testing recommendations for individuals with suspected Fabry disease, stating:

In males, the most efficient and reliable method of diagnosing Fabry disease is the demonstration of deficient α-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. In females, measurement of α-Gal A enzyme activity is unreliable; although demonstration of decreased α-Gal A enzyme activity is diagnostic of the carrier state, many carrier females have normal α-Gal A enzyme activity. GLA is the only gene in which mutations are known to cause Fabry disease. Nearly 100% of affected males have an identifiable GLA mutation. Molecular genetic testing is the most reliable method of diagnosing carrier females.

Wang and colleagues (2011) provide recommendations from an American College of Medical Genetics (ACMG) Work Group for the diagnostic confirmation of Fabry disease as follows:

  1. Newborn screening (NBS) will detect primarily hemizygotes; because of the variability in α-gal A enzyme activity in heterozygotes, it will likely fail to detect a substantial percentage (40-60%) of female infants with Fabry disease.
    1. Because of this variability, any females identified by NBS will need molecular testing for confirmation.
    2. A male infant who screens positive for Fabry disease should have confirmatory testing performed by analyzing leukocyte α-gal A enzyme activity.
  2. If the enzyme activity is low (in males) or a GLA mutation is found (in females), the infant should be referred for evaluation and genetic counseling at a metabolic center.
  3. Confirmatory GLA sequencing should be performed in any male infant with low α-gal A enzyme activity, given the predicted high frequency of the D313Y pseudodeficiency allele.
    1. A detailed pedigree should be constructed to determine at-risk family members and testing offered, because most mutations are familial. If a mutation is not identified, pedigree analysis, measurement of biomarkers such as urinary GL-3, and molecular examination for deletions may clarify the patient's status.

Gal and colleagues (2011), on behalf of the European Consensus on Diagnostics in Fabry Disease, provide additional recommendations that include unique laboratory and genetic testing algorithms for males and females to assist in the clinical diagnosis of Fabry disease stating use of "…the assay of α-galactosidase A activity in leukocytes represents the diagnostic 'gold-standard' and…is the first step in the laboratory diagnosis of a patient suspected of having Fabry disease, unless there is a known familial GLA mutation." In addition, "Males with the classic Fabry disease phenotype can be reliably diagnosed by detecting complete deficiency or only negligible (< 5% of mean normal) α-galactosidase A activity in leukocytes (dried blood spot)." To evaluate carrier status in females, "low α-galactosidase A activity can be suggestive of carrier status but not definitive." In order to determine whether the proband has Fabry disease:

All or some of the following investigations should be carried out: (a) re-evaluation of clinical presentation, (b) analysis of family pedigree, (c) measurement of urinary Gb3, and (d) in absence of a Class 1 mutation, any sequence change detected in the GLA gene must be expressed in vitro to investigate its effect on activity and/or structure of enzyme.

ERT with exogenous alpha-galactosidase is indicated to reduce GL-3 deposits in capillary endothelium of the kidney and other cells types, and to improve some clinical manifestations of the disease, including a reduction in pain and preservation of organ function in some individuals with the disorder. Some individuals with advanced disease may require dialysis or kidney transplantation (Fabrazyme Product Information [PI] Label, 2010; National Institute of Neurological Disorders and Stroke National [NINDS], 2016).

The American College of Medical Genetics (ACMG) publication on the diagnosis and management of lysosomal storage diseases (Wang, 2011) states that in the case of Fabry disease, agalsidase beta is the standard of care for symptomatic individuals. ERT in this disease state has shown improvements in the rate of renal dysfunction, pulmonary and gastrointestinal symptoms. The ACMG guidelines also notes that ERT decreases renal, cardiac and CNS incidents.

Clinical Effectiveness and Safety of agalsidase beta for Fabry Disease

In 2003, the FDA approved agalsidase beta for use in individuals with Fabry disease (Fabrazyme Product Information [PI] Label, 2010). According to the FDA label, agalsidase is a beta biosynthetic (recombinant deoxyribonucleic acid [DNA] origin) form of human alpha-galactosidase, an enzyme that metabolizes glycosphingolipids and reduces GL-3 deposition in capillary of the kidneys and in other cells, such as, capillary endothelium of the skin and heart, mesangium (a central part of the renal glomerulus between capillaries), interstitium (a small area, space, or gap in the substance of an organ or tissue), and noncapillary endothelial cells of the kidneys. Agalsidase beta is the only FDA-approved ERT currently available for Fabry disease with orphan drug designation for this indication.

The safety and effectiveness of agalsidase beta were assessed in four clinical studies in individuals with classic Fabry disease. Eng and colleagues (2001b) conducted a randomized, double-blind, placebo-controlled, multi-national, multicenter study (Study 1) of 58 individuals with Fabry disease (56 males and 2 females), ages 16 to 61 years, all naïve to ERT. Subjects received either 1 mg/kg of agalsidase beta or placebo every 2 weeks for 5 months (20 weeks) for a total of 11 infusions. Thereafter, all subjects received agalsidase beta in an open-label extension study (Eng, 2001a). All subjects were pretreated with acetaminophen and an antihistamine to decrease or prevent infusion reactions. Oral steroids were an additional option to the pretreatment regimen for subjects who exhibited severe or recurrent infusion reactions. The primary efficacy endpoint was the percentage of subjects in whom renal microvascular endothelial deposits of GL-3 were cleared (reduced to normal or near-normal levels). A GL-3 inclusion score of 0 was achieved in 20 of 29 (69%) subjects treated with agalsidase beta compared to 0 of 29 treated with placebo (p<0.001). The investigators also evaluated the histologic clearance of microvascular endothelial deposits of GL-3 in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin (p<0.001). No differences between groups in symptoms or renal function were observed during this study. The investigators concluded that biweekly infusions of agalsidase beta at 1 mg/kg were highly effective in clearing renal microvascular endothelial deposits of GL-3. The incidence of most treatment-related adverse events was similar in the 2 groups, with the exception of mild-to-moderate infusion reactions (that is, rigors and fever), which were more common in the agalsidase beta group. Development of immunoglobulin G (IgG) antibodies to alpha-galactosidase occurred in 88% of subjects who received agalsidase beta during the controlled and/or open-label studies; however, the presence of antibodies did not appear to affect efficacy (based on clearance of GL-3), and the antibodies did not have a neutralizing effect (Fabrazyme PI Label, 2010).

All 58 subjects in Study 1 participated in an open-label extension study of agalsidase beta at 1 mg/kg every 2 weeks, which continued for an additional 54 months (Eng, 2001a). At the end of 6 months of agalsidase beta open-label treatment, most subjects achieved a GL-3 inclusion score of 0 in capillary endothelium. GL-3 was decreased to normal or near normal levels in mesangial cells, glomerular capillary endothelium, interstitial cells, and non-capillary endothelium. GL-3 deposition was still present in vascular smooth muscle cells, tubular epithelium and podocytes, at variably reduced levels. A total of 44 of the 58 subjects completed 54 months of the open-label extension study. Renal function was assessed by serum creatinine testing and estimated glomerular filtration rates (eGFR). Thirty-six of these 44 subjects underwent follow-up skin biopsy, and 31 of the 36 subjects maintained complete GL-3 clearance in the capillary endothelium of the skin. Follow-up heart and kidney biopsies were assessed in 8 of the 44 subjects, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in 8 subjects, and sustained GL-3 clearance in the capillary endothelium of the heart in 6 subjects. Plasma GL-3 levels were reduced to normal levels and remained at normal levels after up to 60 months of treatment. Median serum creatinine were reported as remaining "stable and normal" throughout the 54-month treatment period with a rise in mean serum creatinine observed between months 36 and 54, attributed to the renal disease progression of six participants; however, data was not reported with specific measurements of medium or mean serum creatinine levels. Pain severity related to Fabry disease and associated quality of life was not improved to a significant degree by agalsidase beta (Germain, 2007).

Study 2 was a randomized (2:1 agalsidase beta to placebo), double-blind, placebo-controlled, multi-national, multicenter study of 82 subjects (72 males and 10 females), ages 20 to 72 years, all naïve to ERT. Subjects received either 1 mg/kg of agalsidase beta or placebo every 2 weeks for up to a maximum of 35 months (median 18.5 months). There was significant difference in post-baseline plasma GL-3 levels in the agalsidase beta-treated subjects compared to placebo. The reduction in plasma GL-3 levels in the agalsidase beta group compared to the placebo group was significant at 1 year (p<0.0001) and at 2 years (p=0.0019). Fourteen subjects (8 in the agalsidase beta-treated and 6 in the placebo groups) had skin biopsies at first infusion and final visit. All agalsidase beta-treated subjects had capillary endothelium and deep vessel endothelium scores of zero at the final visit. Four of 6 placebo subjects had non-zero capillary endothelium scores (p=0.0150), and 6 of 6 placebo subjects had non-zero deep vessel endothelium scores (p=0.0003) (Fabrazyme PI Label, 2010).

A total of 67 subjects who participated in Study 2 subsequently entered into an open-label extension study in which all subjects received 1 mg/kg of agalsidase beta every 2 weeks for up to a maximum of 18 months. There was a statistically significant reduction in mean plasma GL-3 levels with durability in effect through the additional 18 months of treatment in the extension study from pretreatment baseline (Fabrazyme PI Label, 2010).

Wraith and colleagues (2008) conducted an open-label, uncontrolled, multi-national, multicenter study (Study 3) to evaluate safety, pharmacokinetics, and pharmacodynamics of agalsidase beta treatment in 16 pediatric subjects with Fabry disease (14 males, 2 females), ages 8 to 16 years at first treatment. All subjects received agalsidase beta 1 mg/kg every 2 weeks for up to 48 weeks. At baseline, all 14 males had elevated plasma GL-3 levels (that is, > 7.03 μg/mL), whereas the 2 female subjects had normal plasma GL-3 levels. Twelve of the 14 male subjects, and no female subjects, had GL-3 inclusions observed in the capillary endothelium on skin biopsies at baseline. No primary efficacy endpoint was specified. At weeks 24 and 48 of treatment, all 14 males had plasma GL-3 within the normal range. The 12 male subjects with GL-3 inclusions in capillary endothelium at baseline achieved GL-3 inclusion scores of 0 at weeks 24 and 48 of treatment. The 2 female subject's plasma GL-3 levels remained normal through study week 48. No new safety concerns were identified in the children in this study, and the overall safety and efficacy profile of agalsidase beta treatment in children was found to be consistent with that seen in adults.

Study 4 was an open-label, re-challenge study to evaluate the safety of agalsidase beta treatment in subjects who had a positive skin test to agalsidase beta or who had tested positive for agalsidase beta-specific IgE antibodies. In this study, 6 adult male subjects, who had experienced multiple or recurrent infusion reactions during previous clinical trials with agalsidase beta, were re-challenged with agalsidase beta administered as a graded infusion, for up to 52 weeks of treatment. The initial two re-challenge doses of agalsidase beta were administered as a 0.5 mg/kg dose per week at an initial infusion rate of 0.01 mg/min for the first 30 minutes (1/25th the usually recommended maximum infusion rate). The infusion rate was doubled every 30 minutes thereafter, as tolerated, for the remainder of the infusion up to a maximum rate of 0.25 mg/min. If the subject tolerated the infusion, the dose was increased to 1 mg/kg every 2 weeks (usually recommended dose), and the infusion rate was increased by slow titration upwards. Four of the 6 subjects treated in this study received at least 26 weeks of study medication, and 2 subjects discontinued prematurely due to recurrent infusion reactions (Fabrazyme PI Label, 2010).

Banikazemi and colleagues (2007) performed a randomized, double-blind, placebo-controlled study of Fabry disease in individuals with moderate kidney dysfunction (n=82). Agalsidase beta appeared to delay the time to renal, cardiovascular, and cerebrovascular events. Ancillary subgroup analyses found larger treatment effects in participants with baseline eGFR greater than 55 mL/min per 1.73 m2 (hazard ratio [HR] 0.19, confidence interval [CI], 0.05 to 0.82]; p=0.025) compared with 55 mL/min per 1.73 m2 or less (HR 0.85, CI 0.32 to 2.3; p=0.75). Clinical events occurred in 27% of the agalsidase beta group and 42% of the control group; although, the results were not statistically significant (p=0.06).

Wijburg and colleagues (2015) reported on the degree of early organ involvement in an ongoing randomized, open-label, parallel-group, phase IIIB clinical trial (FIELD) evaluating the long-term efficacy and safety of two low-dose treatment regimens of agalsidase beta in treatment- naïve children with Fabry disease without clinically significant involvement of major organs (that is, kidney, heart, and brain). A total of 31 males aged 5 to 18 years had baseline disease characteristics including cellular GL-3 accumulation in skin (n=31) and kidney biopsy (n=6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine). Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 participants, respectively. Plasma lyso-GL-3 was elevated in all participants. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23 of 31 participants) and deep vessel endothelial cells (23 of 29 participants). Other baseline measurements included the mean glomerular filtration rate (GFR) and the median urinary albumin/creatinine ratio. On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in 6 participants. In this small cohort of children with Fabry disease, the investigators reported histological evidence of GL-3 accumulation, and the presence of cellular and vascular injury in renal tissues at very early stages of the disease, identifying these characterizations before the onset of microalbuminuria and development of clinically significant renal events (for example, reduced GFR). The investigators suggest these data provide additional support to the consideration of early initiation of agalsidase beta as ERT to potentially improving long-term outcomes in individuals with Fabry disease.

Long-Term Outcomes and Other Outcomes for Use of agalsidase beta for Fabry Disease

The peer-reviewed medical literature includes a number of retrospective studies of varying sample sizes evaluating long-term treatment outcomes and other outcomes for the efficacy and safety of agalsidase beta in Fabry disease. These studies, in part, use cumulative data from the available clinical trials and the Fabry disease registry. The following studies are those that evaluate larger populations of individuals with Fabry disease treated with agalsidase beta.

Germain and colleagues (2015) reported on 10-year outcomes of ERT with agalsidase beta in subjects with classic Fabry disease. The study investigated 52 of 58 participants from the phase III clinical trial of agalsidase beta (using aggregate data from the trial and extension study [NCT00074971]) and the Fabry Registry (NCT00196742). Severe clinical events, renal function and cardiac structure following treatment with agalsidase beta (1 mg/kg/2 weeks) were recorded for over a 10-year median follow-up period. Disease progression rates were assessed for participants with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline. Data from 6 participants in the phase III trial were not available because they did not enroll in the Fabry Registry. The mean age of participants at treatment initiation was 30 years; however, those participants classified as having HRI at baseline were over 10 years older than those with LRI (38 years vs. 25 years; p<0.001). Eleven of the 52 participants were aged ≥ 40 years at baseline; 8 participants were classified as having HRI and 3 participants as LRI. The oldest participant was 62.2 years of age at baseline and was classified as HRI. Some participants with LRI already had significant evidence of kidney damage at baseline; 13% had ≥ 20% (but < 50%) sclerotic glomeruli. A total of 81% of participants (42 of 52) did not experience any severe clinical event during the treatment interval and 94% (49 of 52) were alive at the end of the study period. Ten participants reported a total of 16 events. The most frequent severe clinical event was stroke; 5 participants (9.6%; 4 LRI, 1 HRI) had a total of eight strokes. Four participants (7.7%), all HRI at baseline, had a severe renal event. Two cardiac events were reported: one cardiac-related death in a participant (age 52 years) with LRI and one myocardial infarction in a participant (age 53 years) with HRI. Two participants experienced multiple strokes (in their 20's) at the time of their first severe clinical event. Renal and cardiovascular events occurred most frequently in participants older than 40 years of age. During the initial 5-year clinical trial treatment interval, 7 participants had severe clinical events compared with 3 participants who had their first event in the later follow-up period. Participants classified as LRI started therapy 13 years younger than HRI (mean, 25 years vs. 38 years). Participants in the LRI group (mean age at baseline, 25 years) experienced some loss of eGFR (-1.89 mL/min/1.73 m2 /year) over the 10-year follow-up. According to the study authors, renal disease progression seems to be related, in part, to the severity of the disease before treatment. Participants with HRI, who began treatment at a mean age of 38 years and had significant pre-existing kidney involvement, showed the greatest decline in eGFR slope (-6.82 mL/min/1.73 m2/year). The authors stated this data "suggest that treatment before major damage to renal architecture occurs is critical and that there may be a point at which impaired glomeruli will inevitably progress to failure." Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged. Participants who initiated treatment at age ≥ 40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma GL-3 normalized within 6 months. In summary, participants who initiated treatment at a younger age and with less kidney involvement appeared to benefit the most from therapy, while participants who initiated treatment at older ages and/or had advanced renal disease experienced disease progression. Limitations of this study include evaluation of long-term registry data, which may be less reliable than data reported from the phase III study, and only reporting severe clinical events data. Other data on milder clinical events were not analyzed, including non-sustained cardiac arrhythmias, transient ischemic attacks, or hearing loss, which might contribute to disease burden and decreased quality of life. In addition, the study was not designed to evaluate the impact of concomitant therapies, such as adjunctive antiproteinuric (ACE inhibitors/angiotensin II receptor blockers) and antiplatelet therapies. The authors noted that treatment of comorbidities may have contributed to the improved outcomes.

Lenders and colleagues (2016) conducted an observational study of 89 adults with Fabry disease treated with reduced doses of agalsidase beta or switched to agalsidase alpha due to a shortage of agalsidase beta supply between 2009 and 2012. Individuals who had received agalsidase beta (1.0 mg/kg body weight) for > 1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3-0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase alpha (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase alpha (switch group, n=37). End organ damage and clinical symptoms were assessed with a focus on renal outcome after 2 years. The assessment of clinical symptoms included an assessment of clinical events (that is, death, myocardial infarction, severe arrhythmia, stroke, progression to end-stage renal disease), changes in cardiac and renal function, Fabry-related symptoms (such as, diarrhea, hypohidrosis, and diarrhea), and disease severity scores. The authors reported a determination of renal function by creatinine and cystatin C-based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group; the Mainz Severity Score Index (MSSI) (Mehta, 2006; Whybra, 2004) increased significantly in these 2 groups (p=0.02 and p<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. Outcomes for serious clinical events, such as stroke/transient ischemic attack, dialysis, renal transplantation, or a pacemaker/implantable cardioverter defibrillator, did not significantly differ between baseline and 2-year follow-up in any of the 3 groups. At baseline, all 3 groups did not significantly differ in eGFR on the basis of different formulas of agalsidase beta, and cardiac measures revealed only a slightly increased left ventricular diastolic diameter in the regular-dose group in comparison with the switch group (p<0.05). Neurologic outcome measures revealed no differences in baseline parameters between the groups. The study determined eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula on the basis of creatinine, cystatin C, and the combination of both. Participants on a regular agalsidase beta dose showed a stable renal function over 2 years irrespective of the CKD-EPI formula used. Albumin-creatinine ratio (ACR) was similar at baseline for all 3 groups and showed no significant change over the study period. The authors stated that those individuals treated with the reduced agalsidase beta dose for 12 months and subsequently switched to a regular agalsidase alpha dose for another 12 months, and those individuals who directly switched to agalsidase alpha, showed a significant decline in renal function (that is, eGFR, independent of the eGFR formula used), an increase of MSSI score, and a higher frequency of gastrointestinal pain. Limitations of this industry-sponsored study include the retrospective observational design, lack of randomization, and the total number of evaluable participants was lower than the initial study, in part, due to exclusion of participants who switched the therapy regimen more than twice during the follow-up period.

Other Considerations

Antibody formation has been reported with use of agalsidase beta in males, but not females (Linthorst, 2005); however, the impact of this on the overall efficacy of treatment is currently unknown.

To date, there are no clinical trials that definitively guide the timing of initiation of agalsidase beta and duration of therapy once started for either symptomatic or asymptomatic individuals with confirmed Fabry disease.

In 2015, a European Fabry Working Group drafted consensus recommendations for initiation and cessation of ERT in individuals with Fabry disease (Biegstraaten, 2015). A summary of the recommendations state:

For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥ 16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical Fabry disease (FD) should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m2 ) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of < 1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (New York Heart Association [NYHA] class IV), cessation of ERT should be considered…

These recommendations are suggested as a benchmark for initiation and cessation of ERT; however, the authors state that "final decisions should be made on an individual basis," with the need for future collaborative efforts to optimize these recommendations.

The most common adverse reactions reported with agalsidase beta use are infusion reactions. In the clinical trials of agalsidase beta, 4 serious infusion reactions occurred in 3 subjects during agalsidase beta infusions, including bronchospasm, urticaria, hypotension, and development of agalsidase beta-specific antibodies. Other infusion-related reactions occurring in more than 1 subject during the study included rigors, hypertension, nausea, vomiting, and pruritus (Fabrazyme PI Label, 2010). Although the safety and efficacy data available in female subjects in the clinical studies are limited, there is no indication that females respond differently to agalsidase beta compared to males.

FDA Warnings and Precautions for Use of Fabrazyme

Warnings and Precautions for Use of agalsidase beta (Fabrazyme PI Label, 2010)

Dosing Information and Use in Specific Populations


Deoxyribonucleic acid (DNA): The molecule that carries genetic information in all living systems.

Enzyme replacement therapy (ERT): A treatment provided, usually via intravenous infusion, to provide enzymes in an individual unable to make sufficient amounts of that enzyme on their own.

Gene: Hereditary unit found in chromosomes which determine individual characteristics of an organism.

Mainz Severity Score Index (MSSI): A tool composed of four sections (general, neurological, cardiovascular, and renal) that weight the signs and symptoms associated with Fabry disease according to their contribution to the morbidity of the disease.


Peer Reviewed Publications:

  1. Banikazemi M, Bultas J, Waldek S, et al.; Fabry Disease Clinical Trial Study Group. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007; 146(2):77-86.
  2. Eng CM, Banikazemi M, Gordon R, et al. A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet. 2001a; 68:711-722.
  3. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human αgalactosidase A replacement therapy in Fabry's disease. N Engl J Med. 2001b; 345:9-16.
  4. Frustaci A, Chimenti C, Ricci R, et al. Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. N Engl J Med. 2001; 345(1):25-32.
  5. Gal A, Hughes DA, Winchester B. Toward a consensus in the laboratory diagnostics of Fabry disease - recommendations of a European expert group. J Inherit Metab Dis. 2011; 34:509-514.
  6. Germain DP, Charrow J, Desnick RJ, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in subjects with Fabry disease. J Med Genet. 2015; 52(5):353-358.
  7. Germain DP, Waldek S, Banikazemi M, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol. 2007; 18(5):1547-1557.
  8. Hughes DA, Elliott PM, Shah J, et al. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart. 2008; 94(2):153-158.
  9. Kampmann C, Perrin A, Beck M. Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: cardiac outcomes after 10 years' treatment. Orphanet J Rare Dis. 2015; 10:125.
  10. Lenders M, Canaan-Kühl S, Krämer J, et al. Patients with Fabry disease after enzyme replacement therapy dose reduction and switch-2-year follow-Up. J Am Soc Nephrol. 2016; 27(3):952-962.
  11. Linthorst GE, Vedder AC, Aerts JM, Hollak CE. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta. 2005; 353:201-203.
  12. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004; 34(3):236-242.
  13. Whybra C, Kampmann C, Krummenauer F, et al. The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet. 2004; 65(4):299-307.
  14. Wijburg FA, Bénichou B, Bichet DG, et al. Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial. PLoS One. 2015; 10(5):e0124987.
  15. Wilcox WR, Banikazemi M, Guffon N, et al.; International Fabry Disease Study Group. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet. 2004; 75(1):65-74.
  16. Wraith JE, Tylki-Szymanska A, Guffon N, et al. Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease. J Pediatr. 2008; 152(4):563-570.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Agalsidase Beta. In: DrugPoints® System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated August 12, 2016. Available at: Accessed on December 27, 2016.
  2. Agalsidase Beta Monograph. Lexicorp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Corp., Inc. Last revised January 1, 2006. Accessed December 27, 2016.
  3. Biegstraaten M, Arngrímsson R, Barbey F, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015; 10:36.
  4. El Dib RP, Nascimento P, Pastores GM. Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database Syst Rev. 2013;(2):CD006663.
  5. Fabrazyme [Product Information], Cambridge, MA. Genzyme Corporation, Inc.; May 14, 2010. Available at: Accessed on December 27, 2016.
  6. Laney DA, Bennett RL, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2013; 22 (5):555-564.
  7. Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.
  8. Mehta A, Hughes DA. Fabry Disease. 2002 Aug 5 [Updated 2013 Oct 17]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available at: Accessed on December 27, 2016.
  9. U.S. National Institutes of Health (NIH). Agalsidase beta. Available at: . Accessed on December 27, 2016.
  10. Wang RY, Bodamer OA, Watson MS, Wilcox WR; American College of Medical Genetics (ACMG) Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011; 13(5):457-484.
Websites for Additional Information
  1. Fabrazyme Disease Registry. Genzyme Corporation (Cambridge, MA). Available at: Accessed on December 27, 2016.
  2. National Institute of Neurological Disorders and Stroke (NINDS). National Institutes of Health. NINDS Fabry Disease Information Page. Available at: Accessed on December 27, 2016.

Agalsidase beta

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.





Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Discussion/General Information, References, and Websites for Additional Information sections.
New 11/03/2016 MPTAC review. Initial document development.