Enzyme Replacement Therapy
People who have Pompe disease have little or none of a lysosomal enzyme known as acid alpha-glucosidase (GAA). Enzyme replacement therapy (ERT) with Myozyme® (alglucosidase alfa) works by replacing the missing or deficient GAA enzyme. Enzyme replacement has been a treatment approach used with other lysosomal storage disorders such as Type 1 Gaucher disease and Fabry disease.
Recombinant Genetic Technology
Myozyme 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 Myozyme begins by inserting the human gene for the acid alpha-glucosidase (GAA) enzyme (the enzyme that is deficient in people with Pompe disease) into CHO (Chinese hamster ovary) cells.
Once the CHO cells have the gene, they will begin to manufacture the human GAA 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
Myozyme 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 Myozyme meets the highest standards. Each vial is inspected before it is released and made available to patients.
Making Myozyme is a complex process that takes several months and could only be accomplished after many years of development and testing.
Indication
MYOZYME (alglucosidase alfa) is a lysosomal glycogen-specific enzyme indicated for use in patients with Pompe disease (GAA deficiency). MYOZYME has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of MYOZYME in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy.
Important Safety Information
WARNING
Life-threatening anaphylactic reactions, severe allergic reactions and immune mediated reactions have been observed in some patients during MYOZYME infusions. Therefore, appropriate medical support should be readily available when MYOZYME is administered.
Risk of Cardiorespiratory Failure:
Patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation of their cardiac or respiratory compromise due to infusion reactions, and require additional monitoring.
Anaphylaxis and Allergic Reactions: Anaphylaxis and severe allergic reactions have been reported in some patients during and up to three hours after MYOZYME infusion, some of which were IgE-mediated. Some of the reactions were life-threatening and included: anaphylactic shock, cardiac arrest, respiratory distress, hypotension, bradycardia, hypoxia, bronchospasm, throat tightness, dyspnea, angioedema, and urticaria. Interventions have included: cardiopulmonary resuscitation, mechanical ventilatory support, oxygen supplementation, intravenous (IV) fluids, hospitalization, treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids.
In clinical trials and postmarketing safety experience with MYOZYME, approximately 1% of patients developed anaphylactic shock and/or cardiac arrest during MYOZYME infusion that required life-support measures. In clinical trials and expanded access programs with MYOZYME, approximately 14% of patients treated with MYOZYME have developed allergic reactions that involved at least 2 of 3 body systems, cutaneous, respiratory or cardiovascular systems. These events included: Cardiovascular: hypotension, cyanosis, hypertension, tachycardia, ventricular extrasystoles, bradycardia, pallor, flushing, nodal rhythm, peripheral coldness; Respiratory: tachypnea, wheezing/bronchospasm, rales, throat tightness, hypoxia, dyspnea, cough, respiratory tract irritation, decreased oxygen saturation; Cutaneous: angioedema, urticaria, rash, erythema, periorbital edema, pruritus, hyperhidrosis, cold sweat, livedo reticularis.
If anaphylactic or other severe allergic reactions occur, immediate discontinuation of the administration of MYOZYME should be considered, and appropriate medical treatment should be initiated. Because of the potential for severe allergic reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when MYOZYME is administered.
Risk of Acute Cardiorespiratory Failure: Acute cardiorespiratory failure requiring intubation and inotropic support has been observed up to 72 hours after infusion with MYOZYME in infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of MYOZYME. Patients with acute underlying respiratory illness, compromised cardiac function and/or sepsis may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during MYOZYME infusion, and infants with cardiac dysfunction may require prolonged observation times that should be individualized based on the needs of the patient.
Risk of Cardiac Arrhythmia and Sudden Cardiac Death During General Anesthesia for Central Venous Catheter Placement: Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in infantile-onset Pompe disease patients with cardiac hypertrophy, associated with the use of general anesthesia for the placement of a central venous catheter intended for MYOZYME infusion. Caution should be used when administering general anesthesia for the placement of a central venous catheter in infantile-onset Pompe disease patients with cardiac hypertrophy.
Infusion Reactions: Infusion reactions occurred in 20 of 39 (51%) of patients treated with MYOZYME in clinical studies. Severe infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: fever, decreased oxygen saturation, tachycardia, cyanosis and hypotension. Other infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturation, vomiting, tachypnea, agitation, increased blood pressure/hypertension, cyanosis, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness and wheezing. Some patients were pre-treated with antihistamines, antipyretics and/or steroids. Infusion reactions occurred in some patients after receiving antipyretics, antihistamines, or steroids. Infusion reactions may occur at any time during, or up to 2 hours after, the infusion of MYOZYME, and are more likely with higher infusion rates.
Immune Mediated Reactions: Severe cutaneous and systemic immune mediated reactions have been reported in postmarketing experience with MYOZYME in at least 2 patients, including ulcerative and necrotizing skin lesions, and possible type III immune complex-mediated reactions. Patients should be monitored for the development of systemic immune complex-mediated reactions involving skin and other organs while receiving MYOZYME.
Monitoring: Laboratory Tests: Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. Testing for IgG titers may also be considered if patients develop allergic or other immune mediated reactions. Patients who experience anaphylactic or allergic reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis.
Adverse Reactions: The most serious adverse reactions reported with MYOZYME were anaphylactic reactions, acute cardiorespiratory failure, and cardiac arrest. Anaphylactic reactions have been reported during and within 3 hours after MYOZYME infusion. Acute cardiorespiratory failure has been observed in a few infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa.
The most common serious treatment-emergent adverse reactions occurring in >10% of patients observed in clinical studies with MYOZYME were pneumonia, respiratory failure, respiratory distress, catheter-related infection, respiratory syncytial virus infection, gastroenteritis and fever. The most common treatment-emergent adverse reactions occurring in ≥ 20% of patients were fever, diarrhea, rash, vomiting, cough, pneumonia, otitis media, upper respiratory tract infection, gastroenteritis and decreased oxygen saturation.
The most common adverse reactions requiring intervention were infusion reactions. Twenty of 39 patients (51%) treated with MYOZYME in clinical studies developed infusion reactions.
Immunogenicity: The majority of patients (34 of 38; 89%) in the two clinical trials tested positive for IgG antibodies to alglucosidase alfa. Most patients who develop antibodies do so within the first 3 months of exposure. There is evidence to suggest that patients developing sustained titers ≥12,800 of anti-alglucosidase alfa antibodies may have a poorer clinical response to treatment, or may lose motor function as antibody titers increase. Five patients with antibody titers ≥ 12,800 at Week 12 had an average increase in clearance of 50% from Week 1 to Week 12. The effect of antibody development on the long-term efficacy of MYOZYME is not fully understood. However, CRIM-negative infants have shown poorer clinical response in the presence of high sustained IgG antibody titers and inhibitory and positive inhibitory antibodies. Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions. Therefore, these patients should be monitored more closely during administration of MYOZYME.
To report suspected adverse reactions, contact Genzyme at 800-745-4447, option 2 or FDA at 800-FDA-1088 or http://www.fda.gov/Safety/MedWatch
Please see full prescribing information for complete details, including boxed warning.