^{How Fabrazyme is Made}

A replacement enzyme for people with Fabry disease was first studied experimentally in the 1970s and 1980s. The results were promising, but the enzyme could only be produced in small quantities.

Over the past 10 years, however, advances in genetic engineering have enabled scientists to develop a replacement enzyme that can be produced in large enough quantities to treat people with Fabry disease.

One of Genzyme Corporation’s manufacturing facilities, Allston, MA, U.S.

Fabrazyme^® (agalsidase beta) is made using recombinant genetic technology, a process that allows scientists to alter the genetic make-up of an organism to produce human proteins, including enzymes. This process, which takes place at Genzyme facilities, occurs in three stages.

^{Stage 1: Growing Cells to Produce Human Enzyme}

Making Fabrazyme begins by inserting the human gene for the alpha-GAL enzyme (the enzyme that is deficient in people with Fabry disease) into CHO (Chinese hamster ovary) cells.

The majority of biotechnology drug products produced today are from the CHO cell line. This well-characterized cell line is used to produce numerous recombinant human proteins for therapeutic use, including Fabrazyme.

Once the CHO cells have the gene, they will begin to manufacture the human alpha-GAL enzyme. For this to happen, the cells are kept under special conditions in large tanks called bioreactors. Each day, liquid is removed from the bioreactor, and the enzyme those cells have produced is collected for purification.

^{Stage 2: Enzyme Purification}

Because Fabrazyme is infused directly into the bloodstream, it must meet very high standards for purity and safety. At Genzyme, the enzyme is purified using a process called column chromatography. Chromatography is a method of separating and isolating the parts of a mixture to remove the unwanted substances. As the enzyme moves through multiple chromatography columns, it becomes more purified.

^{Stage 3: Filling and Finishing}

After purification, the enzyme is put into sterile glass vials. After the vials are filled, they are placed into a freeze dryer for about 48 hours. In the freeze dryer, water evaporates off the enzyme and leaves a cake-like dry substance. In this form, the enzyme is more stable. Multiple tests are conducted through the manufacturing process to help ensure Fabrazyme meets the highest standards. Each vial is inspected by hand before it is released and made available to patients.

Making Fabrazyme is an expensive process that takes several months and could only be accomplished after many years of development and testing.

Important Safety Information 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. The most serious and most common adverse reactions reported with Fabrazyme are infusion reactions.  Serious and/or frequently occurring related adverse reactions consisted of one or more of the following events: chills, pyrexia, 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. The occurrence of somnolence can be attributed to clinical trial specified pre-treatment with antihistamines.    Other reported serious adverse events 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. Infusion reactions occurred in many patients treated with Fabrazyme and some of the reactions were severe.  Patients should be given antipyretics prior to infusion.  Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.  Infusion reactions declined in frequency with continued use of Fabrazyme.  However, infusion reactions may still occur despite extended duration of Fabrazyme treatment.  Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.  Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme. Most patients develop IgG antibodies to Fabrazyme.  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.   Patients with Fabrazyme- specific IgE antibody have been treated using a rechallenge protocol.  Rechallenge of these patients should only occur under the direct supervision of qualified personnel, with appropriate medical support measures readily available. The safety and efficacy in patients younger than 8 years of age have not been evaluated.  IgE immunologic responses in pediatric patients may differ from those in adults, as IgG seroconversion was associated with prolonged half-life concentrations of Fabrazyme, which is rarely observed in adult patients. 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.