Idursulfase Solution

Dosage Forms And Strengths

Injection: 6 mg/3 mL (2 mg/mL) in single-use vials

Storage And Handling

ELAPRASE is supplied as a sterile injection in a 5 mL Type I glass vial. The vials are closed with a butyl rubber stopper with fluororesin coating and an aluminum overseal with a blue flip-off plastic cap.

Each carton contains a single vial NDC 54092-700-01

Store ELAPRASE vials in the carton at 2°C to 8°C (36°F to 46°F) to protect from light. Do not freeze or shake. Do not use ELAPRASE after the expiration date on the vial.

Manufactured by: Shire Human Genetic Therapies, Inc. 300 Shire Way Lexington, MA 02421. Phone # 1-866-888-0660. Revised: 06/2013

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Hypersensitivity Reactions Including Anaphylaxis [see WARNINGS AND PRECAUTIONS]

In clinical trials, the most common adverse reactions ( > 10%) following ELAPRASE treatment were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and headache. Most hypersensitivity reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, corticosteroids or both prior to or during infusions.

In clinical trials, the most frequent serious adverse reactions following ELAPRASE treatment were hypoxic episodes. Other notable serious adverse reactions that occurred in the ELAPRASE-treated patients but not in the placebo-treated patients included one case each of: cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia.

A 53-week, double-blind, placebo-controlled clinical trial of ELAPRASE was conducted in 96 male patients with Hunter syndrome, ages 5-31 years old. Of the 96 patients, 83% were White, non-Hispanic. Patients were randomized to three treatment groups, each with 32 patients: ELAPRASE 0.5 mg/kg once weekly, ELAPRASE 0.5 mg/kg every other week, or placebo. Hypersensitivity reactions were reported in 69% (22 of 32) of patients who received once-weekly treatment of ELAPRASE.

Table 1 summarizes the adverse reactions that occurred in at least 9% of patients ( ≥ 3 patients) in the ELAPRASE 0.5 mg/kg once weekly group and with a higher incidence than in the placebo group.

Table 1: Adverse Reactions that Occurred in the Placebo-Controlled Trial in At Least 9% of Patients in the ELAPRASE 0.5 mg/kg Once Weekly Group and with a Higher Incidence than in the Placebo Group (5 Years and Older)

Additional adverse reactions that occurred in at least 9% of patients ( ≥ 3 patients) in the ELAPRASE 0.5 mg/kg every other week group and with a higher incidence than in the placebo group included: rash (19%), flushing (16%), fatigue (13%), tachycardia (9%), and chills (9%).

An open-label extension trial was conducted in patients who completed the placebo-controlled trial. Ninety-four of the 96 patients who were enrolled in the placebo-controlled trial consented to participate in the extension trial. All 94 patients received ELAPRASE 0.5 mg/kg once weekly for 24 months. No new serious adverse reactions were reported. Approximately half (53%) of patients experienced hypersensitivity reactions during the 24-month extension trial. In addition to the adverse reactions listed in Table 1, common hypersensitivity reactions occurring in at least 5% of patients ( ≥ 5 patients) in the extension trial included: rash (23%), pyrexia (9%), flushing (7%), erythema (7%), nausea (5%), dizziness (5%), vomiting (5%), and hypotension (5%).

A 53-week, open-label, single-arm, safety trial of once weekly ELAPRASE 0.5 mg/kg treatment was conducted in patients with Hunter syndrome, ages 16 months to 4 years old (n=20) and ages 5 to 7.5 years old (n=8) at enrollment. Patients experienced similar adverse reactions as those observed in clinical trials in patients 5 years and older, with the most common adverse reactions following ELAPRASE treatment being hypersensitivity reactions (57%). A higher incidence of the following common hypersensitivity reactions were reported in this younger age group: pyrexia (36%), rash (32%) and vomiting (14%). The most common serious adverse reactions occurring in at least 10% of patients ( ≥ 3 patients) included: bronchopneumonia/pneumonia (18%), ear infection (11%), and pyrexia (11%).

Twenty-seven patients had results of genotype analysis: 15 patients had complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations and 12 patients had missense mutations.

Safety results demonstrated that patients with complete gene deletion, large gene rearrangement, nonsense, frameshift, or splice site mutations are more likely to experience hypersensitivity reactions and have serious adverse reactions following ELAPRASE administration, compared to patients with missense mutations. Table 2 summarizes these findings.

Table 2: Impact of Antibody Status and Genetic Mutations on Occurrence of Serious Adverse Reactions and Hypersensitivity in Patients 7 Years and Younger Treated with ELAPRASE

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials in patients 5 years and older, 63 of the 64 patients treated with ELAPRASE 0.5 mg/kg once weekly or placebo for 53 weeks, followed by ELAPRASE 0.5 mg/kg once weekly in the extension trial, had immunogenicity data available for analysis. Of the 63 patients, 32 (51%) patients tested positive for anti-idursulfase IgG antibodies (Ab) at least one time (Table 2). Of the 32 Ab-positive patients, 23 (72%) tested positive for Ab at three or more different time points (persistent Ab). The incidence of hypersensitivity reactions was higher in patients who tested positive for Ab than those who tested negative.

Thirteen of 32 (41%) Ab-positive patients also tested positive for antibodies that neutralize idursulfase uptake into cells (uptake neutralizing antibodies, uptake NAb) or enzymatic activity (activity NAb) at least one time, and 8 (25%) of Ab-positive patients had persistent NAb. There was no clear relationship between the presence of either Ab or NAb and therapeutic response.

In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with ELAPRASE 0.5 mg/kg once weekly tested Ab-positive. Of the 19 Ab-positive patients, 16 (84%) tested positive for Ab at three or more different time points (persistent Ab). In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) NAb-positive patients having persistent NAb.

All 15 patients with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations tested positive for Ab (Table 2). Of these 15 patients, neutralizing antibodies were observed in 13 (87%) patients. The NAbs in these patients developed earlier (most reported to be positive at Week 9 rather than at Week 27, as reported in clinical trials in patients older than 5 years of age) and were associated with higher titers and greater in vitro neutralizing activity than in patients older than 5 years of age. The presence of Ab was associated with reduced systemic idursulfase exposure [see CLINICAL PHARMACOLOGY].

The immunogenicity data reflect the percentage of patients whose test results were positive for antibodies to idursulfase in specific assays, and are highly dependent on the sensitivity and specificity of these assays. The observed incidence of positive antibody in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to idursulfase with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of ELAPRASE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In post-marketing experience, late-emergent symptoms and signs of anaphylactic reactions have occurred up to 24 hours after initial treatment and recovery from an initial anaphylactic reaction. In addition, patients experienced repeated anaphylaxis over a two-to four-month period, up to several years after initiating ELAPRASE treatment [see WARNINGS AND PRECAUTIONS].

A seven year-old male patient with Hunter syndrome, who received ELAPRASE at twice the recommended dosage (1 mg/kg weekly) for 1.5 years, experienced two anaphylactic events after 4.5 years of treatment. Treatment has been withdrawn [see OVERDOSAGE].

Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory failure, respiratory distress, cardiac failure, and pneumonia.

Mechanism of Action

Hunter syndrome (Mucopolysaccharidosis II, MPS II) is an X-linked recessive disease caused by insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. This enzyme cleaves the terminal 2-O-sulfate moieties from the glycosaminoglycans (GAG) dermatan sulfate and heparan sulfate. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.

ELAPRASE is intended to provide exogenous enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to the M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism of accumulated GAG.

Pharmacodynamics

Decreases in urinary GAG levels were observed following treatment with ELAPRASE. The responsiveness of urinary GAG to dosage alterations of ELAPRASE is unknown, and the relationship of urinary GAG to other measures of clinical response has not been established. Patients who tested positive for anti-idursulfase antibodies (Ab) experienced a less pronounced decrease in urinary GAG levels [see ADVERSE REACTIONS and Clinical Studies].

Pharmacokinetics

The pharmacokinetic characteristics of idursulfase were evaluated in 59 patients with Hunter syndrome. The serum concentration of idursulfase was quantified using an antigen-specific ELISA assay. The area under the concentration-time curve (AUC) increased in a greater than dose proportional manner as the dose increased from 0.15 mg/kg to 1.5 mg/kg following a single 1-hour infusion of ELAPRASE. The pharmacokinetic parameters at the recommended dose regimen (0.5 mg/kg ELAPRASE administered weekly as a 3-hour infusion) were determined at Week 1 and Week 27 in 10 patients 7.7 to 27 years of age (Table 3). There were no apparent differences in PK parameter values between Week 1 and Week 27 regardless of the antibody status in these patients.

Table 3: Pharmacokinetic Parameters in Patients 7.7 to 27 Years of Age

Idursulfase pharmacokinetics was evaluated in 27 patients with Hunter syndrome 16 months to 7.5 years of age who received ELAPRASE 0.5 mg/kg once weekly as a 3-hour infusion. The presence of anti-idursulfase antibody (Ab) was associated with a reduced systemic exposure of idursulfase. Eight of the 18 Ab-positive patients had no measurable idursulfase concentrations. An additional 9 Ab-positive patients had decreased Cmax, AUC, and t½ at Week 27 compared to Week 1 (Table 4). Idursulfase pharmacokinetics was similar between Week 1 and Week 27 in Ab-negative patients (Table 4).

Table 4: Pharmacokinetic Parameters in Patients 16 months to 7.5 Years of Age

All patients with the complete gene deletion or large gene rearrangement genotype (n = 8) developed Ab at Week 27. Five of these eight patients had no measurable idursulfase concentrations at Week 27, and three had a lower systemic exposure at Week 27 compared to Week 1.

Clinical Studies

Clinical Trials in Patients 5 Years and Older

The safety and efficacy of ELAPRASE were evaluated in a 53-week, randomized, double-blind, placebo-controlled clinical trial of 96 patients with Hunter syndrome. The trial included patients with deficiency in iduronate-2-sulfatase enzyme activity and a percent predicted forced vital capacity (% predicted FVC) less than 80%. The age of patients ranged from 5 to 31 years. Patients received ELAPRASE 0.5 mg/kg once per week (n=32), ELAPRASE 0.5 mg/kg once every other week (n=32), or placebo (n=32).

The primary efficacy outcome assessment was a two-component composite score based on the sum of the ranks of the change from baseline to Week 53 in distance walked in six minutes (6minute walk test) and the ranks of the change in % predicted FVC. This two-component composite primary endpoint differed statistically significantly between the three groups, and the difference was greatest between the placebo group and the once weekly treatment group (once weekly ELAPRASE vs. placebo, p=0.0049).

Examination of the individual components of the composite score showed that, in the adjusted analysis, the weekly ELAPRASE-treated group experienced a 35 meter greater mean increase in the distance walked in six minutes compared to placebo. The changes in %-predicted FVC were not statistically significant (Table 5).

Table 5: Clinical Trial Results

Pharmacodynamic assessments included urinary GAG levels and changes in liver and spleen size. Urinary GAG levels were elevated in all patients at baseline. Following 53 weeks of treatment, mean urinary GAG levels were reduced in the ELAPRASE once weekly group, although GAG levels still remained above the upper limit of normal in half of the ELAPRASE-treated patients. Urinary GAG levels remained elevated and essentially unchanged in the placebo group. Sustained reductions in both liver and spleen volumes were observed in the ELAPRASE once weekly group through Week 53 compared to placebo. There were essentially no changes in liver and spleen volumes in the placebo group.

Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. During the extension trial, all patients received ELAPRASE 0.5mg/kg once weekly for 24 months.

Patients who were treated with ELAPRASE once weekly and every other week in the placebo-controlled trial demonstrated improvement in distance walked in the 6-minute walk test for an additional 8 months of treatment in the extension trial. There was no change in mean %predicted FVC in all Hunter syndrome patients after 6 months of treatment in the extension trial; however, a slight decrease in mean %-predicted FVC was demonstrated through to month 24 of the extension trial. The long-term effect of ELAPRASE on pulmonary function in Hunter syndrome patients is unclear.

There were no further reductions in mean urinary GAG levels in patients initially treated with ELAPRASE once weekly; however, the patients treated with ELAPRASE every other week during the placebo-controlled trial experienced further reductions in mean urinary GAG levels after changing to a more frequent dosing regimen during the extension trial. The persistence of reduced urinary GAG levels did not correlate with the long term effect demonstrated by the 6minute walk test distance or %-predicted FVC.

Clinical Trial in Patients 7 Years and Younger

A 53-week, open-label, multicenter, single-arm trial was conducted to assess the safety, pharmacokinetics, and pharmacodynamics of ELAPRASE 0.5 mg/kg once weekly in male Hunter syndrome patients aged 7 years and younger. Safety results demonstrated that patients with complete gene deletion or large gene rearrangement mutations are more likely to develop antibodies, including neutralizing antibodies, and to experience hypersensitivity reactions with ELAPRASE administration [see ADVERSE REACTIONS]. In patients who remained antibody negative, the pharmacokinetic profile, reduction in urinary GAG excretion levels, and reduction in spleen volume were similar to those of adults and children 5 years and older. In patients who were persistently antibody positive, the presence of anti-idursulfase antibody was associated with reduced systemic exposure of idursulfase and a less pronounced decrease in urinary GAG levels.

Idursulfase is used to treat some of the symptoms of a genetic condition called Hunter's syndrome. Hunter syndrome is also called mucopolysaccharidosis (MYOO-koe-pol-ee-SAK-a-rye-DOE-sis).

Hunter syndrome is a metabolic disorder in which the body lacks the enzyme needed to break down certain sugars and proteins. These substances can build up in the body, causing enlarged organs, abnormal bone structure, changes in facial features, breathing problems, heart problems, vision loss, and changes in mental or physical abilities.

Idursulfase may improve walking ability in people with this condition. However, this medication is not a cure for Hunter syndrome.

Idursulfase may also be used for purposes not listed in this medication guide.

You should not receive this medication if you are allergic to idursulfase.

Before receiving idursulfase, tell your doctor if you are allergic to any drugs, or if you have asthma or other breathing disorder.

You may be more likely to have a reaction to idursulfase if you have a breathing disorder. You may need to receive other medications to prevent an symptoms of a reaction to idursulfase. Follow your doctor's instructions.

Your name may need to be listed on a Hunter Outcome Survey while you are using this medication. The purpose of this registry is to track the progression of this disorder and the effects that idursulfase has on long-term treatment of Hunter syndrome.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether idursulfase passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are receiving idursulfase.