Clinical Data

Fabrazyme was filed with the Food & Drug Administration (FDA) under an accelerated approval mechanism. Under FDA’s Accelerated Approval regulations, marketing approval may be granted on the basis of adequate and well-controlled clinical trials that establish that the product has an effect upon a surrogate endpoint that is reasonably likely to predict clinical benefit. Approval under these regulations requires that the applicant study the product further to verify the clinical benefit. Sanofi Genzyme chose GL-3 reduction in renal interstitial capillary endothelial cells as the primary surrogate marker, since reduction of this lipid would likely predict benefit to the patient. Sanofi Genzyme continues to collect safety and efficacy data on Fabrazyme.

Phase 1/2 Study

The phase 1/2 clinical trial of Fabrazyme was a single-center, open-label, dose-ranging study that involved 15 male patients with Fabry disease (plasma α-GAL activity <1.5 nmol/hr/mL).1 Five dosing regimens, 0.3, 1.0, or 3.0 mg/kg every 2 weeks, or 1.0 or 3.0 mg/kg every 48 hours, were employed for a total of 5 infusions. The study was conducted to evaluate the safety, pharmacokinetics and in vivo activity of Fabrazyme infusions, and to provide preliminary efficacy data for enzyme replacement therapy in Fabry disease. Efficacy assessments were based on change from baseline to end of study in plasma GL-3 concentration, urine sediment, and GL-3 concentration in tissue biopsies as evaluated by light and electron microscopy.

The results of this small study provided preliminary data on safety, pharmacokinetics, and in vivo activity of Fabrazyme in patients with Fabry disease. Based upon the results of this study, further studies were conducted using a 1 mg/kg dose.

Renal Capillary Endothelium Before and After Fabrazyme


These photomicrographs of the kidney (methylene blue/azure II stain) are from a patient in the phase 3 placebo-controlled study who received 11 treatments with Fabrazyme. Before treatment (Panel A), the capillary endothelium is heavily laden with glycosphingolipid inclusions (histology score of 3). After treatment (Panel B), glycosphingolipid inclusions have been reduced in the capillary endothelium (histology score of 0).

Clinical Studies

The safety and efficacy of Fabrazyme® (agalsidase beta) were assessed in four clinical studies in patients with Fabry disease.

Study 1

Study 1 was a double-blind, randomized, placebo-controlled phase 3 clinical study conducted in 8 centers in the United States and Europe.2 The 58 participants (56 males and 2 females) 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 to decrease or prevent infusion-associated reactions.
  • Oral steroids were an additional pretreatment option for patients who exhibited recurrent or severe infusion reactions.

Since renal failure is a common manifestation 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. The endpoint was assessed by light examination of tissue biopsy samples obtained before and after 20 weeks of treatment. Three independent expert pathologists, who were blinded to treatment assignment and time of biopsy, examined an average of 233 capillaries in each specimen and assigned each biopsy a composite score of 0 (normal or near normal) to 3 (severe vessel inclusions). On the basis of pathophysiologic considerations, treatment success was defined as a score of 0 at week 20. Other endpoints evaluated included GL-3 reduction in the vascular endothelium of the heart and skin, reduction of GL-3 in plasma, and maintenance of mean serum creatinine levels.

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 6 who improved and 2 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). The percentage of patients after 20 weeks of treatment with mean capillary endothelium scores of zero in the kidney was 69%, skin was 100%, and heart was 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 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. No differences between groups in renal function were observed during this five-month study.

Reduction of GL-3 (Score of Zero) in Vascular Endothelium of Kidney, Skin, and Heart in Phase 3 Study of Fabrazyme


Yellow denotes patients treated with Fabrazyme for 20 weeks; orange denotes patients treated with placebo. Patients treated with Fabrazyme demonstrated a marked improvement in GL-3 levels in the vascular endothelium of kidney, skin, and heart.

Study 1 Extension

All 58 patients from the phase 3 placebo-controlled  study (Study 1) participated in an open-label extension study. All patients received Fabrazyme at 1.0 mg/kg for an additional 54 months. After 6 months, all 24 former placebo patients with available biopsies attained a GL-3 inclusion score of 0 for renal vasculature. Overall, 47/49 (96%) biopsied patients had a histologic score of 0 for vascular endothelium in kidney; 32/40 (80%) had a score of 0 in the heart vasculature; and 51/53 (96%) had a score of 0 in the skin vasculature.

Forty-four of the 58 patients completed 54 months of the open-label extension study. Thirty-six of these 44 patients underwent follow-up skin biopsy, and 31 of these patients showed sustained GL-3 clearance in the capillary endothelium of the skin. Follow-up heart and kidney biopsies were assessed in only 8 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in 8 patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 6 patients. Plasma GL-3 levels were reduced to normal levels (<7.03 μg/mL determined by LC/MS/MS) and remained at normal levels after up to 60 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.

In addition to reversing GL-3 accumulation from endothelial cells in the kidney vasculature, Fabrazyme reduced GL-3 to normal or near normal levels in other renal cell types, such as interstitial capillary endothelium, glomerular capillary endothelium, mesangial cells, interstitial cells, and noncapillary (arterial/arteriolar) endothelium . GL-3 deposition was still present in vascular smooth muscle cells, tubular epithelium and podocytes, at variably reduced levels.

Median Plasma GL-3 Concentrations in the Fabrazyme-Treated and Placebo-Treated Patients in the Double-Blind and Open-Label Phase 3 Trial

Plasma levels of GL-3 were determined by a quantitative ELISA at baseline and Week 20 (visit 11) of the double-blind study and after 6 and 12 months of open-label treatment. Plasma GL-3 values below the limit of detection (<1.2 ng/μl) were recorded as 0. All patients who had been in the placebo group during the double-blind study received Fabrazyme during the open-label study.

Study 2

Study 2 was a randomized (2:1 Fabrazyme to placebo), double-blind, placebo-controlled, multinational, and multicenter study of 82 patients (72 males and 10 females), ages 20 to 72 years, all naïve to enzyme replacement therapy. Patients received either 1 mg/kg of Fabrazyme or placebo every two weeks for up to a maximum of 35 months (median 18.5 months). There was significant difference in post-baseline plasma GL-3 levels in the Fabrazyme-treated patients compared to placebo. The reduction in plasma GL-3 levels in the Fabrazyme group compared to the placebo group was significant at one year (p<0.0001) and at two years (p=0.0019). Fourteen patients (8 in Fabrazyme treated and 6 in placebo) had skin biopsies at first infusion and final visit. All Fabrazyme-treated patients had capillary endothelium and deep vessel endothelium scores of zero at the final visit. Four (4) of 6 placebo patients had non-zero capillary endothelium scores (p=0.0150), and 6 of 6 had non-zero deep vessel endothelium scores (p=0.0003).

Study 2 Extension

Sixty-seven patients who participated in Study 2 were subsequently entered into an open-label extension study in which all patients received 1 mg/kg of Fabrazyme every two weeks for up to a maximum of 18 months. There was a statistically significant reduction in mean plasma GL-3 levels with durability in effect through the additional 18 months of treatment in the extension study from pretreatment baseline.

Study 3

Study 3 (Pediatric Study) was an open-label, uncontrolled, multinational, multicenter study to evaluate safety, pharmacokinetics, and pharmacodynamics of Fabrazyme treatment in 16 pediatric patients with Fabry disease (14 males, 2 females), who were ages 8 to 16 years at first treatment. All patients received Fabrazyme 1 mg/kg every two weeks for up to 48 weeks. At baseline, all 14 males had elevated plasma GL-3 levels (i.e., >7.03 μg/mL), whereas the two female patients had normal plasma GL-3 levels. Twelve of the 14 male patients, and no female patients, had GL-3 inclusions observed in the capillary endothelium on skin biopsies at baseline. At weeks 24 and 48 of treatment, all 14 males had plasma GL-3 within the normal range. The 12 male patients with GL-3 inclusions in capillary endothelium at baseline achieved GL-3 inclusion scores of 0 at weeks 24 and 48 of treatment. The two female patients’ plasma GL-3 levels remained normal through study week 48.

No new safety concerns were identified in pediatric patients in this study, and the overall safety and efficacy profile of Fabrazyme treatment in pediatric patients was found to be consistent with that seen in adults. Immunologic responses in pediatric patients may differ from those in adults, as IgG seroconversion in pediatric patients was associated with prolonged half-life concentrations of Fabrazyme, a phenomenon rarely observed in adult patients.

Patients younger than 8 years of age were not included in clinical studies. The safety and efficacy in patients younger than 8 years of age have not been evaluated.

Study 4

Study 4 was an open-label, rechallenge study to evaluate the safety of Fabrazyme treatment in patients who had a positive skin test to Fabrazyme or who had tested positive for Fabrazyme-specific IgE antibodies. In this study, 6 adult male patients, who had experienced multiple or recurrent infusion reactions during previous clinical trials with Fabrazyme, were rechallenged with Fabrazyme administered as a graded infusion, for up to 52 weeks of treatment. The initial two rechallenge doses of Fabrazyme were administered as a 0.5 mg/kg dose per week at an initial infusion rate of 0.01 mg/min for the first 30 minutes (1/25th the usually recommended maximum infusion rate). The infusion rate was doubled every 30 minutes thereafter, as tolerated, for the remainder of the infusion up to a maximum rate of 0.25 mg/min. If the patient tolerated the infusion, the dose was increased to 1.0 mg/kg every two weeks (usually recommended dose), and the infusion rate was increased by slow titration upwards. Four of the six patients treated in this study received at least 26 weeks of study medication, and two of six patients discontinued prematurely due to recurrent infusion reactions.

Immunogenicity and Rechallenge

In clinical trials with Fabrazyme, a few patients developed IgE antibodies or skin test reactivity specific to Fabrazyme. Two of six patients in the rechallenge study discontinued treatment with Fabrazyme prematurely due to recurrent infusion reactions. Four serious infusion reactions occurred in three patients during Fabrazyme infusions, including bronchospasm, urticaria, hypotension, and development of Fabrazyme-specific antibodies. Other infusion-related reactions occurring in more than one patient during the study included rigors, hypertension, nausea, vomiting, and pruritus. Physicians should consider testing for IgE antibodies in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies.

Patients who have had a positive skin test to Fabrazyme or who have tested positive for Fabrazyme-specific IgE antibody have been rechallenged with Fabrazyme 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.

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. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1‑800‑FDA‑1088. You may also contact Sanofi Genzyme at 1-800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Sanofi Genzyme at 1-800-745-4447.

References

  1. 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.
  2. 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;345:9-16.56.