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Clinical Studies of Fabrazyme

Table 1 below summarizes the clinical trial history of Fabrazyme (agalsidase beta), followed with detail descriptions of the major trials:

Phase 1/2 Study

The phase 1/2 clinical study of Fabrazyme involved 15 male patients with Fabry disease. In this study, Fabrazyme was tested at five different dosing regimens: 0.3, 1.0 or 3.0 milligrams (mg) per kilogram (kg) of body weight administered by IV infusion every 2 weeks or 1.0 or 3.0 mg per kg of body weight administered every 48 hours. Patients received a total of 5 infusions. This small study provided preliminary information on how Fabrazyme acts in the body, as well as information about the safety of Fabrazyme infusions.

Phase 3 Placebo-Controlled Study

A double-blind, randomized, placebo-controlled phase 3 clinical study was conducted in 8 centers in the United States and Europe. [1] The 58 participants (56 men and 2 women) had Fabry disease with below normal α-GAL activity (<1.5 nmol/hr/mL in plasma, and <4 nmol/hr/mg in leukocytes), and ranged in age from 16 to 61 years, with an average age of approximately 30 years. Patients were randomized to receive an infusion of Fabrazyme (n=29) or placebo (n=29) every 2 weeks for 20 weeks (11 doses). There were no statistically significant differences in baseline characteristics (including age, height, weight, gender, and race) between the placebo and Fabrazyme groups. Patients who were dependent on prophylactic drugs or analgesics for pain relief were allowed to continue on these medications for the duration of the trial. All patients were pretreated with acetaminophen and an antihistamine. Since renal failure is a common devastating feature of Fabry disease, and accumulation of GL-3 in renal endothelial cells may play a role in renal failure, reduction in GL-3 inclusions in renal interstitial capillary endothelial cells was chosen prospectively as the primary efficacy endpoint of this study.

Phase 3 Results

Fabrazyme infusions resulted in statistically significant (p<0.001) reduction to normal or near normal levels of GL-3 from the renal capillary endothelium. Twenty of the 29 Fabrazyme-treated patients (69%) achieved a score of 0 (no or trace vessel inclusions) at 20 weeks. Of the remaining 9 Fabrazyme-treated patients, 8 had scores of 1 (including 5 who improved and 3 who had a score of 1 at baseline) and the remaining patient had a missing biopsy and was assigned a score of 3. In contrast, none of the 29 patients treated with placebo had a 0 score (p<0.001). Figure 1 shows the difference in the appearance of the kidney vasculature at baseline and after 20 weeks of treatment in one representative patient. Figure 2 shows the percentage of Fabrazyme patients after 20 weeks of treatment with mean capillary endothelium scores of zero in the kidney (69%), skin (100%), and heart (72%). Plasma GL-3 levels decreased to below the limit of detection in the treated patients, and these decreases correlated with histological findings in the kidney vasculature.

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.

Mean serum creatinine values were normal at baseline and remained normal to Week 20 in both treatment groups. Pain scores significantly improved from Baseline to Week 20 in both treatment groups, but since there was no statistically significant difference between the groups, an actual effect cannot be separated from a placebo effect. No differences between groups in symptoms or renal function were observed during this five month study.

Table 2 lists adverse events and selected laboratory abnormalities that occurred during the phase 3 placebo-controlled study in at least 2 patients more in the Fabrazyme group than was observed in the placebo group. A statistically significant difference was observed for three adverse events that were reported more frequently in patients treated with Fabrazyme compared to placebo. These adverse experiences were rigors (15/29 [52%] vs. 4/29 [14%]), fever (14/29 [48%] vs. 5/29 [17%]), and skeletal pain (6/29 [21%] vs. 0/29 [0%]) in the Fabrazyme vs. placebo treatment groups. Skeletal pain reported during this study represents isolated musculoskeletal events and is most likely not due to the infusion of Fabrazyme. Rigors and fever represent primarily infusion-associated reactions. The initial presentation of these most often coincided with IgG seroconversion, which occurred in 83% of patients treated with Fabrazyme. When rigors and fever occurred, they were generally mild to moderate in nature and were successfully managed by a temporary reduction in infusion rate and treatment with acetaminophen and diphenhydramine.

Phase 3 Extension Study

All 58 patients in the randomized study chose to enroll in an open-label extension study of Fabrazyme at 1.0 mg/kg every two weeks indefinitely.[1, 2] At the end of six months of open-label treatment, most patients achieved a GL-3 inclusion score of 0 in the capillary endothelium of the kidney, heart, and skin. Additionally, 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. Plasma GL-3 levels were reduced to levels below the limit of detection and remained so up to 18 months of treatment. Reduction was maintained in the superficial and deep vessel skin capillary endothelium up to 36 months of treatment.

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.

After 30-36 months of Fabrazyme treatment in the phase 3 extension study, the most common treatment-related adverse events occurring on the day of infusion were rigors, somnolence, temperature change sensation, fever, rhinitis, nausea, and headache. The adverse events associated with Fabrazyme infusions were successfully managed using standard medical practices. All patients were pretreated with antipyretics with/without an antihistamine. Infusion reactions occurred in some patients after receiving antipyretics, antihistamines, and oral steroids. Infusion reactions declined in frequency with continued use of Fabrazyme; however, serious infusion reactions occurred after extended durations of Fabrazyme treatment. A majority of patients completed 1 or more full infusions in 2.0 hours or less. Individual response to Fabrazyme infusion times may vary.

Fifty-two out of 58 (89%) patients developed anti-Fabrazyme IgG antibodies; however, after 30-36 months of treatment, antibody titers decreased in approximately half of all seroconverted patients. Seven patients have tested IgG negative upon repeat antibody testing but will continue to be monitored long-term to assess tolerization. The clinical relevance of a decrease in antibody titers is unknown. Some patients developed IgE or skin test reactivity specific to Fabrazyme. Of those patients, some were successfully reinfused with Fabrazyme after developing these reactions. 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. There are no marketed tests for antibodies against Fabrazyme. If testing is warranted, contact your local Genzyme representative or Genzyme Corporation toll-free at 800-745-4447.

For more on the safety and adverse events, visit the Safety page.

For full detail of the Fabrazyme clinical trials, download the Fabrazyme Product Monograph.

Indications 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.

References

1. Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ. Safety and efficacy of recombinant human α-galactosidase A-replacement therapy in Fabry's disease. N Engl J Med 2001; 345:9-16.

2. Wilcox W, Banikazemi M, Guffon N, Waldek S, Lee P, Linthorst G, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet 2004;75:65-74.


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