Fabrazyme is intended to lower GL-3 by providing an exogenous source of the deficient α-galactosidase A enzyme. Fabrazyme is indicated for use in patients with Fabry disease. Lowering GL-3 and keeping it low are important therapeutic goals for these patients.
Fabrazyme reduces globotriaosylceramide (GL-3) deposition in the capillary endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.
In a 2003 publication, a consensus panel comprised of physicians with expertise in treating Fabry disease recommended that enzyme replacement therapy be promptly initiated as early as possible in symptomatic patients.1 Patients with Fabry disease should be followed carefully with regular physician visits to monitor renal and cardiac indicators of disease progression.
In order to better understand the variability and progression of Fabry disease in the population as a whole and in women in particular, and to monitor and evaluate long-term treatment effects of Fabrazyme, the Fabry Registry, sponsored by Genzyme, has been established. The Fabry Registry will also monitor the effect of Fabrazyme on pregnant women and their offspring. Patients should be informed of the Fabry Registry and encouraged to participate regardless of treatment status. They should be advised that their participation is voluntary and may involve long-term follow-up.
Both symptom management and enzyme replacement therapy can play a role in the medical management of patients with Fabry disease. Like diagnosis, disease management usually requires a team approach among medical specialties, since Fabry disease affects many organ systems.
Rationale for Enzyme Replacement Therapy
The molecular basis of Fabry disease is a deficiency of the α-GAL enzyme. Accumulation of GL-3 is a direct consequence of low or absent α-GAL levels and is thought to be the pathogenic basis for the clinical manifestations of Fabry disease. Fabrazyme is intended to provide an exogenous source of α-GAL in Fabry disease patients. Preclinical and clinical studies evaluating a limited number of cell types indicate that Fabrazyme will catalyze the hydrolysis of glycosphingolipids including GL-3.
GL-3 reduction in clinically relevant tissues may be an important marker of treatment efficacy, although the relationship between the reduction of GL-3 and attenuation of specific clinical manifestations of Fabry disease has not been established.
Cardiac Variants – No Vascular GL-3 Accumulation
The existence of patients with the cardiac variant of Fabry disease supports the rationale for enzyme replacement therapy.2 Unlike most male patients with Fabry disease, these patients produce residual amounts of α-GAL (<10% normal levels).2 However, they have few or none of the major clinical manifestations of Fabry disease and instead present with cardiomegaly and proteinuria at an age when other patients would be more severely affected or would have died.3-5 Tissue biopsies or autopsy studies of cardiac variants reveal GL-3 accumulation only in the myocardium, where GL-3 is difficult to clear, and not in the vasculature of the heart or other tissues.5-7 This suggests that residual levels of α-GAL can limit GL-3 accumulation in the vasculature.2
Receptor Pathway for Intracellular Delivery of Exogenous Enzyme
The α-GAL enzyme can be taken up from the circulation and delivered intracellularly to lysosomes through the mannose-6-phosphate receptor pathway8. The existence of this pathway supports the rationale of enzyme replacement therapy because it makes it possible for intravenously delivered exogenous enzyme to reach its intracellular target – the lysosome. Fabrazyme has the same amino acid sequence as the natural form of human α-GAL and contains consistent levels of both sialic acid and mannose-6-phosphate, two carbohydrates that affect the biodistribution of the enzyme and allow for appropriate lysosomal uptake.8
Indication and Usage
Fabrazyme® (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types.
The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.
Important Safety Information
Life-threatening anaphylactic and severe allergic reactions have been observed in patients during Fabrazyme infusions. In clinical trials and postmarketing safety experience, approximately 1% of patients developed anaphylactic or severe allergic reactions during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, antihistamines, epinephrine, and IV corticosteroids. If severe allergic or anaphylactic reactions occur, immediately discontinue administration of Fabrazyme and provide necessary emergency treatment. Because of the potential for severe allergic reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.
- In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended.
- Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.
- If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms.
- If severe infusion reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated.
- Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen when clinically indicated.
- Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.
Re-administration of Fabrazyme to patients who have previously experienced severe or serious allergic reactions to Fabrazyme should be done only after careful consideration of the risks and benefits of continued treatment, and only under the direct supervision of qualified personnel and with appropriate medical support measures readily available.
The most common adverse reactions reported are infusion reactions, some of which were severe. Infusion reactions occurred in approximately 50-55% of patients during Fabrazyme administration in clinical trials. Serious and/or frequently occurring (≥ 5% incidence) related adverse reactions consisted of one or more of the following: chills, fever, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence.
- Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion reactions. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.
- Other serious adverse events reported in clinical studies included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, hypoacousia, and nephrotic syndrome. These adverse events also occur as manifestations of Fabry disease; an alteration in frequency or severity cannot be determined from the small numbers of patients studied.
- Severe and serious infusion related reactions have been reported in postmarketing experience, some of which were life threatening including anaphylactic shock. In addition to the above adverse reactions, the following have been reported during postmarketing use of Fabrazyme: arthralgia, asthenia, erythema, hyperhidrosis, infusion site reaction, lacrimation increased, leukocytoclastic vasculitis, lymphadenopathy, hypoesthesia, oral hypoesthesia, palpitations, rhinorrhea, oxygen saturation decreased and hypoxia.
- Adverse reactions (regardless of relationship) resulting in death reported in the postmarketing setting with Fabrazyme treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, sepsis, cerebrovascular accident, myocardial infarction, renal failure, and pneumonia. Some of these reactions were reported in Fabry disease patients with significant underlying disease.
The safety and efficacy in patients younger than 8 years of age have not been evaluated.
Most patients who develop IgG antibodies do so within the first three months of exposure. IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme, a phenomenon rarely observed in adult patients.
In clinical trials, a few patients developed IgE or skin test reactivity specific to Fabrazyme. Physicians should consider testing for IgE in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies.
Fabrazyme is available by prescription only. Side effects should be reported promptly to Genzyme Medical Information at 800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Genzyme at 1-800-745-4447.
Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, Grabowski G, Packman S, Wilcox WR. Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338-46.
Eng CM, Banikazemi M, Gordon RE, Goldman M, Phelps R, Kim L, Gass A, Winston J, Dikman S, Fallon JF, Brodie S, Stacy CB, Mehta D, Parsons R, Norton K, O’Callaghan M, Desnick RJ. A Phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 2001;68:711-22.
Nagao Y, Nakashima H, Fukuhara Y, Shimmoto M, Oshima A, Ikari Y, Mori Y, Sakuraba H, Suzuki Y. Hypertrophic cardiomyopathy in late onset variant of Fabry disease with high residual activity of α-galactosidase A. Clin Genet 1991;39:233-7.
Yoshitama T, Nakao S, Takenaka T, Teraguchi H, Sasaki T, Kodama C, Tanaka A, Kisanuki A, Tei C. Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry’s disease. Am J Cardiol 2001;87:71-5.
Elleder M, Bradova V, Smid F, Budesinsky M, Harzer K, Kustermann-Kuhn B, Ledvinova J, Belohlavek, Kral V, Dorazilova V. Cardiocyte storage and hypertrophy as a sole manifestation of Fabry’s disease. Report on a case simulating hypertrophic non-obstructive cardiomyopathy. Virchows Arch A Pathol Anat Histopathol 1990;417:449-55.
von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, Olsen EGJ, Christomanou H, Kandolf R, Bishop D, Desnick RJ. An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 1991;324:395-9.
Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver C, Beaudet A, Sly W, et al., eds. Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill, 2001:3733-3774.
Mayes JS, Cray EL, Dell VA, Scheerer JB. Endocytosis of lysosomal alpha-galactosidase A by cultured fibroblasts from patients with Fabry disease. Am J Hum Genet 1982;34:602-10.