Fabrazyme: Clinical evidence

Efficacy in adult patients

Reductions in GL-3 inclusions were observed at 20 weeks in the capillary endothelium of
the kidney, heart, and skin.*

Study 1 design: Randomized, 1:1, double-blind, placebo-controlled study of 58 patients with Fabry disease (56 males, 2 females), aged 16 to 61 years, all naïve to enzyme replacement therapy. Patients received either 1 mg/kg of Fabrazyme or placebo every 2 weeks for 5 months. Primary endpoint was the proportion of patients in either group with a renal capillary GL-3 inclusion score of zero at week 20. All 58 patients in this study participated in the 54-month, open-label extension trial.

*Tissue biopsy specimens (kidney, heart, skin) were evaluated at baseline and at week 20 by light microscopy for the presence and number of GL-3 inclusions, using a semi-quantitative methodology.

Fabrazyme normalized plasma GL-3 levels in adult patients throughout the 5-year study period¹

In Study 1, GL-3 inclusion scores were 0 and plasma GL-3 was in the normal range* at 24 and 48 weeks.

Study 1 design: Randomized, 1:1, double-blind, placebo-controlled study of 58 patients with Fabry disease (56 males, 2 females), aged 16 to 61 years, all naïve to enzyme replacement therapy. Patients received either 1 mg/kg of Fabrazyme or placebo every 2 weeks for up to 60 months. All 58 patients from the original 20-week study participated in this 54-month, open-label extension trial.

*Normal level is ≤7.03 μg/mL as determined by liquid chromatography-tandem mass spectrometry.

Fabrazyme was evaluated for outcomes in clinically significant events vs placebo¹

Study 2 design: Randomized, 1:1, double-blind, placebo-controlled, multinational, multicenter study of 82 patients (72 males, 10 females) with Fabry disease, all naïve to enzyme replacement therapy. Patients were randomly assigned to Fabrazyme 1 mg/kg or placebo every 2 weeks for up to 35 months (median follow-up of 18.5 months).

In Study 2, the primary efficacy endpoint was the time to first occurrence of a clinically significant event.* A smaller percentage of patients in the Fabrazyme treatment group experienced a clinically significant event.

Twenty-eight percent of Fabrazyme-treated patients vs 42% of placebo-treated patients had renal, cardiac, or cerebrovascular events, or death (HR,† 0.57; 95% CI, 0.27-1.22; P=0.14).

*Defined as a renal, cardiac, or cerebrovascular event, or death.
^†The hazard ratio (HR) is a comparison between the probability of events in a treatment group and the probability of events in a control group.

The rate of kidney decline was studied in Fabrazyme- treated patients¹

Long-term observational study results showed a difference in the rate of decline in renal function (mean eGFR slope) between the Fabrazyme-treated and untreated patients.

Study 5 (adult) design: Data based on comparison of Fabrazyme-treated patients (aged ≥16 years) from the long-term observational study vs untreated patients from the natural history study. Median age at Fabrazyme initiation was 35 years; 72% of patients were male and median baseline eGFR was 93 mL/min/1.73 m2. Treated: n=122; eGFR slope: -1.5 (median follow-up time was 3 years). Untreated: n=122; eGFR: -3.2 (median follow-up time was 4.5 years). The maximum follow-up time for both groups was 5 years.

Additional long-term data: Fabrazyme’s effect on the incidence of clinically significant events in adult patients beyond 6 months of treatment³

In a retrospective study review, 1044 adults with Fabry disease (641 men, 403 women) were treated for up to 5 years with Fabrazyme.

Adapted from Ortiz A, et al. J Med Genet. 2016;53(7):495-502.

Study design: The incidence of several clinical events was studied in 1044 adult patients (641 males, 403 females) enrolled in the Fabry Registry who received Fabrazyme (average dose 1 mg/kg every 2 weeks) for up to 5 years. Patients with end-stage renal failure prior to initiation of Fabrazyme were excluded because their organ failure was considered irreversible. For ethical reasons, there was no placebo group included in this analysis. In this analysis, the mean time spent receiving Fabrazyme was 2.8 years, and the maximum time analyzed was 5 years.

Study limitation: The Fabry Registry is an international, multicenter observational database. Data entry is retrospective, voluntary, and dependent on physician submission.

^aRate per 1000 patient-years (95% CI) over time following initiation of enzyme replacement therapy.
^bPatients who had a renal event, cardiac event, stroke, or death.

Efficacy in pediatric patients

In Study 5 (pediatric), Fabrazyme was shown to normalize plasma GL-3 levels of pediatric patients aged 2 to <8 years¹

At baseline, all patients had elevated plasma GL-3 (i.e., >7.03 μg/mL).
 

After treatment, plasma GL-3 levels fell within the normal range (i.e., ≤7.03 μg/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of patients at 6, 12, and 24 months, respectively.

Fabrazyme is the only enzyme replacement therapy indicated for patients aged 2 years and older.* In an observational study analysis of 24 pediatric patients with Fabry disease, elevated plasma GL-3 levels were normalized.

Study 5 (pediatric) design: Data from an observational study were used to assess 24 Fabrazyme-treated pediatric patients with Fabry disease aged 2 to <8 years with elevated plasma GL-3 levels (>7.03 μg/mL) at baseline and at 6, 12, and 24 months.

*The efficacy and safety of Fabrazyme have not been evaluated in patients younger than age 2 years.

Fabrazyme also cleared GL-3 in pediatric populations¹

In Study 3 (pediatric), GL-3 inclusion scores were 0 and plasma GL-3 was in the normal range at 24 and 48 weeks.

The safety and effectiveness of Fabrazyme in Fabry disease have been established in pediatric patients based on adequate, well-controlled studies in adults; a single-arm, open-label study in 16 pediatric patients aged 8 to 16 years; and additional data in 24 patients aged 2 to 7 years.*

At baseline, all 14 males had elevated plasma GL-3 levels (>7.03 μg/mL). Twelve males also had GL-3 inclusions present on skin biopsy. The 2 female patients had normalized GL-3 plasma levels throughout and no GL-3 inclusions at baseline.

The overall efficacy and safety profile of Fabrazyme in pediatric patients was similar to that observed in adults.

Study 3 (pediatric) design: Open-label, uncontrolled, multinational, multicenter study to evaluate safety, pharmacokinetics, and pharmacodynamics of Fabrazyme treatment in pediatric patients. Study population: 16 pediatric patients (14 males, 2 females) aged 8 to 16 years at first treatment. Study dose: Fabrazyme 1 mg/kg every 2 weeks for up to 48 weeks.

*The efficacy and safety of Fabrazyme in patients younger than age 2 years have not been evaluated.

Safety data reported with Fabrazyme¹

In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe hypersensitivity reactions during Fabrazyme infusion.

In clinical trials with Fabrazyme, 59% of patients experienced infusion- associated reactions, some of which were severe. Infusion-associated reactions are defined as adverse reactions occurring on the same day as the infusion.

In patients experiencing infusion-associated reactions, pretreatment with an antipyretic and antihistamine is recommended. Infusion-associated reactions occurred in some patients after receiving pretreatment.

Higher incidences of hypersensitivity reactions were observed in adult patients with persistent anti-Fabrazyme antibodies and in adult patients with high antibody titer compared with those in antibody-negative adult patients.

Patients with advanced Fabry disease may have compromised cardiac
function, which may predispose them to a higher risk of severe complications from infusion-associated reactions. These patients should be monitored closely if Fabrazyme is administered.

Common* adverse reactions from 2 placebo-controlled clinical trials

Common adverse reactions that occurred in ≥20% of patients treated with Fabrazyme and >2.5% compared with placebo were upper respiratory tract infection, chills, pyrexia, headache, cough, paresthesia, fatigue, peripheral edema, dizziness, and rash.

*Reported at a rate of at least 5% in Fabrazyme-treated patients and greater than 2.5% compared with placebo-treated patients.
^aIncludes reports of upper respiratory infection, nasal congestion, sinusitis, respiratory tract congestion, and pharyngitis.
^bIncludes reports of chills and feeling cold.
^cIncludes reports of myalgia and muscle spasms.

Immunogenicity and antibodies¹

As with all therapeutic proteins, there is potential for immunogenicity.

Approximately 83% (110/133) of adult patients receiving Fabrazyme developed antibodies; 77% (102/133) of patients with classic Fabry disease who participated in the 2 initial studies developed neutralizing antibodies (NAbs) that inhibited in vitro Fabrazyme catalytic activity, which declined over time, and 6% (8/133) of patients developed NAbs that inhibited cellular uptake.

Irrespective of developing antibodies to Fabrazyme, over 90% of adult and pediatric patients treated with Fabrazyme in clinical trials achieved and maintained normalization of plasma GL-3 levels.

Most patients who developed antibodies did so within the first 3 months of treatment.

Approximately 18% of adult patients who developed antibodies became antibody negative by 74 weeks (median time). The incidence of infusion-associated reactions was 76% (84/110) in antibody-positive adult patients, compared with 30% (7/23) in antibody- negative adult patients.

Patients who have tested positive for Fabrazyme-specific IgE antibodies in clinical trials have been successfully rechallenged with Fabrazyme using a rechallenge protocol.
Please see the full Prescribing Information for additional details.

Dosing and administration of Fabrazyme¹

Fabrazyme’s multiple vial options may help optimize cost management based on
patient needs. Fabrazyme is supplied in single-dose vials containing a sterile,
nonpyrogenic, white to off-white lyophilized cake or powder.

• 35-mg vial: NDC 58468-0040-1
• 5-mg vial: NDC 58468-0041-1

Fabrazyme is administered by intravenous infusion after being reconstituted
in sterile water.

• Dilute 35-mg vial with 7.2 mL of sterile water
• Dilute 5-mg vial with 1.1 mL of sterile water

DOSAGE IS BASED ON BODY WEIGHT: 1 MG/KG EVERY 2 WEEKS^a,b

^aBecause of the potential for severe infusion-associated reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.
^bPatients who have had a positive skin test to Fabrazyme or who have tested positive for anti-Fabrazyme IgE may be successfully rechallenged with Fabrazyme.