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

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}

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.

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.

^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.