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Committed to MPS II Care

CLINICAL TRIAL OUTCOMES

ELAPRASE® (idursulfase) was studied in a pivotal clinical trial involving Hunter syndrome patients aged 5 years and older. It was also studied in an open-label extension study and a safety study involving patients aged 7 years and younger.1

Pivotal trial design

In the pivotal trial, ELAPRASE achieved the primary endpoint, improved walking capacity, reduced urinary GAG levels, and reduced liver and spleen volume in patients ≥5 years old.1 Read the ELAPRASE Important Safety Information here.

PIVOTAL TRIAL DESIGN

  • Safety and efficacy evaluated in a 53-week, randomized, double-blind, placebo-controlled clinical trial of 96 patients with Hunter syndrome, ages 5 to 31 years old.1
  • Patients received either:1,2
    Pivotal Trial Design
  • 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 6 minutes (6-minute walk test [6-MWT]) and the ranks of the change in %-predicted forced vital capacity (%-FVC).1,2
  • Pharmacodynamic assessments included urinary GAG levels and changes in liver and spleen volume.1

Pivotal trial safety profile

  • Hypersensitivity reactions were reported in 69% (22 of 32) of patients in the ELAPRASE once-weekly group.1

Adverse reactions that occurred in at least three patients (≥9%) in the ELAPRASE once-weekly group and had a higher incidence than in the placebo group included: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)

System organ class
adverse reaction		 ELAPRASE
(0.5 mg/kg weekly)
N=32 n (%)		 Placebo
N=32 n (%)
Gastrointestinal disorder
Diarrhea 3 (9%) 1 (3%)
Musculoskeletal and
connective tissue disorders
Musculoskeletal pain 4 (13%) 1 (3%)
Nervous system disorders
Headache 9 (28%) 8 (25%)
Respiratory, thoracic, and
mediastinal disorders
Cough 3 (9%) 1 (3%)
Skin and subcutaneous
tissue disorders
Pruritus 8 (25%) 3 (9%)
Urticaria 5 (16%) 0 (0%)

Additional adverse reactions that occurred in at least three patients (≥9%) in the ELAPRASE every-other-week group with a higher incidence than in the placebo group included: rash (19%), flushing (16%), fatigue (13%), tachycardia (9%), and chills (9%).1

Please see the ELAPRASE Important Safety Information here.

Pivotal trial primary endpoint

The 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).

The changes from baseline to Week 53 in %-predicted FVC were not statistically significant.1,2

The results are displayed below:

ELAPRASE weekly
n=32*		 Placebo
N=32*		 ELAPRASE
Once weekly
- Placebo
Baseline Week 53 Change† Baseline Week 53 Change† Difference in change
Results from the 6-minute walk test (Meters)
Mean
±
SD		 392
±
108		 436
±
138		 44
±
70		 393
±
106		 400
±
106		 7
±
54		 37 ± 16‡
35 ± 14◊
(p=0.01)
Median 397 429 31 403 412 -4
Percentiles
(25th, 75th)		 316,
488		 365,
536		 0,
94		 341,
469		 361,
460		 -30,
31
Results from the forced vital capacity test (% of predicted)
Mean
±
SD		 55.3
±
15.9		 58.7
±
19.3		 3.4
±
10.0		 55.6
±
12.3		 56.3
±
15.7		 0.8
±
9.6		 2.7 ± 2.5‡
4.3 ± 2.3◊
(p=0.07)
Median 54.9 59.2 2.1 57.4 54.6 −2.5
Percentiles
(25th, 75th)		 43.6,
69.3		 44.4,
70.7		 −0.8,
9.5		 46.9,
64.4		 43.8,
67.5		 −5.4,
5.0
*One patient in the placebo group and one patient in the ELAPRASE group died before Week 53; imputation was by last observation carried forward in the intent-to-treat analysis.
†Change, calculated as Week 53 minus baseline.
‡Observed mean ± SE.
◊ANCOVA model-based mean ± SE, adjusted for baseline disease severity, region, and age.

Read the ELAPRASE Important Safety Information or see below for more clinical trial data.

Pivotal trial secondary endpoints

Walking capacity

  • ELAPRASE was shown to improve the distance walked in 6 minutes by a mean distance of 37 meters compared with placebo (p=0.01).1,2
  • The 6-MWT is a self-paced assessment that reflects the pace and ability to carry out daily physical activities.3
Change in walking capacity in patients treated weekly with ELAPRASE versus placebo

Pulmonary function

  • The changes from baseline to Week 53 in %-FVC were not statistically significant.1,2

Urinary GAG levels

  • ELAPRASE was shown to reduce mean urinary GAG (uGAG) levels.1
    • - uGAG levels were elevated in all patients at baseline; following 53 weeks of treatment, 50% of ELAPRASE-treated patients had uGAG levels below the upper limit of normal and 50% still remained above the upper limit of normal.1
    • - Patients who tested positive for anti-idursulfase antibodies experienced a less-pronounced decrease in urinary GAG levels. The responsiveness of urinary GAG levels to dosage alterations of ELAPRASE is unknown.1,2
  • uGAG levels represent the excretion of excess GAGs; therefore, a reduction in uGAG levels is a biochemical indication of ELAPRASE enzyme activity.4,5 However, the relationship of uGAG levels to other measures of clinical response has not been established.1
Change in uGAG levels in patients treated weekly with ELAPRASE versus placebo

Liver volume and spleen volume

  • ELAPRASE was shown to reduce mean liver and spleen volumes from baseline to Week 53 in the ELAPRASE once-weekly group.1,2
  • There were essentially no changes in liver and spleen volumes in the placebo group.1,2
Change in liver and spleen size in patients treated weekly with ELAPRASE versus placebo

Extension trial design

  • The extension trial was designed to evaluate the efficacy and safety of extended weekly treatment with ELAPRASE. The study ran for 24 months after the initial 53-week period.
  • Patients in the pivotal trial were eligible to continue treatment in the open-label extension trial; 94 of 96 participants continued into the extension trial. All patients in the extension trial received ELAPRASE 0.5 mg/kg once weekly for 24 months.1
  • The co-primary endpoints were 6-MWT and %-FVC.6

Extension trial safety profile

  • No new serious adverse reactions were reported during the extension study.1
  • Approximately half (53%) of patients experienced hypersensitivity reactions during the 24-month extension trial.

In addition to the frequently experienced adverse reactions (see Table 1) in the ELAPRASE once-weekly group in the pivotal trial (diarrhea [9%], musculoskeletal pain [13%], headache [28%], cough [9%], pruritus [25%], and urticaria [16%]), common hypersensitivity reactions occurring in at least five patients (≥5%) in the extension trial included:1

  • Rash (23%)
  • Pyrexia (9%)
  • Flushing (7%)
  • Erythema (7%)
  • Nausea (5%)
  • Dizziness (5%)
  • Vomiting (5%)
  • Hypotension (5%)

Read more about the ELAPRASE Important Safety Information here.


Extension trial data

Walking capacity

  • Patients treated with ELAPRASE demonstrated improvement in distance walked in the 6-MWT in both the placebo-controlled and extension trial.1
Placebo-controlled trial and extension trial analysis: improvement in 6-MWT with ELAPRASE

Pulmonary function

  • There was no change in mean %-FVC in all Hunter syndrome patients after 6 months of treatment in the extension trial, followed by a slight decrease for the remainder of the 24-month period.1
  • The %-FVC measure is affected by patient height; MPS II patients do not have normal growth rates, and so the interpretation of these data is not straightforward.6
  • The long-term effect of ELAPRASE on pulmonary function in Hunter syndrome patients is unclear.1

Urinary GAG levels and liver/spleen volumes

  • Reductions in uGAG levels displayed during the placebo-controlled trial were sustained during the extension trial.1
  • Among patients treated with weekly ELAPRASE, no further reduction was observed during the extension trial.1
  • The persistence of reduced uGAG levels did not correlate with the long-term effect demonstrated by the 6-MWT distance or %-FVC.1
Placebo-controlled trial and extension trial analysis: mean uGAG levels
  • Reductions in liver and spleen volumes observed during the placebo-controlled trial were sustained during the extension trial.6

Under 7s trial design

Under 7s trial designs

Under 7s Safety profile

  • Patients aged 16 months to 7.5 years experienced similar adverse reactions to those observed in clinical trials in patients aged ≥5 years. The most common adverse reactions following ELAPRASE treatment were hypersensitivity reactions (57%).1
  • A higher incidence of the following common hypersensitivity reactions was reported in this younger age group: pyrexia (36%), rash (32%), and vomiting (14%).1
  • The most common serious adverse reactions occurring in at least three patients (≥10%) included bronchopneumonia/pneumonia (18%), ear infection (11%), and pyrexia (11%).1
  • Patients with complete gene deletion or large gene rearrangement mutations are more likely to develop antibodies, including neutralizing antibodies, and to experience hypersensitivity reactions and serious adverse events, compared with patients with missense mutations with ELAPRASE administration.1

Under 7s trial outcomes

In patients who remained antibody-negative:1

  • A reduction in urinary GAG levels was observed, similar to the uGAG reduction seen in the pivotal trial.
  • A reduction in spleen volume was observed, similar to the spleen volume reduction seen in the pivotal trial.

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 uGAG levels.1

In contrast, no apparent differences in pharmacokinetic parameter values between Week 1 and Week 27 were observed in the placebo-controlled trial among patients aged ≥5 years old receiving 0.5 mg/kg ELAPRASE (n=10), regardless of their antibody status.1

Read the ELAPRASE Important Safety Information here.

Important Safety Information
Important Safety Information

WARNING: RISK OF ANAPHYLAXIS

Life-threatening anaphylactic reactions have occurred in some patients during and up to 24 hours after ELAPRASE infusions. Anaphylaxis, presenting as respiratory distress, hypoxia, hypotension, urticaria and/or angioedema of throat or tongue have been reported to occur during and after ELAPRASE infusions, regardless of duration of the course of treatment. Closely observe patients during and after ELAPRASE administration and be prepared to manage anaphylaxis.

Important Safety Information

WARNING: RISK OF ANAPHYLAXIS

Life-threatening anaphylactic reactions have occurred in some patients during and up to 24 hours after ELAPRASE infusions. Anaphylaxis, presenting as respiratory distress, hypoxia, hypotension, urticaria and/or angioedema of throat or tongue have been reported to occur during and after ELAPRASE infusions, regardless of duration of the course of treatment. Closely observe patients during and after ELAPRASE administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring.

Hypersensitivity Reactions Including Anaphylaxis:

Ensure that personnel administering product are adequately trained in cardiopulmonary resuscitative measures, and have ready access to emergency medical services (EMS).

If anaphylactic or other acute reactions occur, immediately discontinue the infusion of ELAPRASE and initiate appropriate medical treatment. Observe patients closely for an appropriate period of time after administration of ELAPRASE, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. When severe reactions have occurred during clinical trials, subsequent infusions were managed with antihistamine and/or corticosteroids prior to or during infusions, a slower rate of ELAPRASE infusion, and/or early discontinuation of the ELAPRASE infusion.

Risk of Hypersensitivity, Serious Adverse Reactions, and Antibody Development in Hunter Syndrome Patients with Severe Genetic Mutations:

Hunter syndrome patients aged 7 years and younger with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations experienced a higher incidence of hypersensitivity reactions, serious adverse reactions and anti-idursulfase antibody development.

Risk of Acute Respiratory Complications:

Patients with compromised respiratory function or acute febrile or respiratory illness may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient’s clinical status prior to administration of ELAPRASE and consider delaying the ELAPRASE infusion.

Risk of Acute Cardiorespiratory Failure:

Caution should be exercised when administering ELAPRASE to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ELAPRASE infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.

Adverse Reactions:

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.

The most common adverse reactions occurring in at least three patients (≥9%) aged five years and older were headache, pruritus, musculoskeletal pain, urticaria, diarrhea, and cough. The most common adverse reactions occurring in at least three patients (≥10%) aged seven years and younger were pyrexia, rash, vomiting, and urticaria. In all clinical trials, the most common adverse reactions requiring medical intervention were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and headache.

Immunogenicity:

In clinical trials in patients 5 years and older, 32 of 63 (51%) patients tested positive for anti-idursulfase IgG antibodies (Ab) at least one time. Of the 32 Ab-positive patients, 23 of 32 (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 (neutralizing antibodies, NAb) or enzymatic activity 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, with 16 of 19 (84%) having persistent Ab. In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) having persistent NAb.

Postmarketing 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.

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

To report SUSPECTED ADVERSE REACTIONS, contact Takeda at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
For additional safety information, please click here for Full Prescribing Information, including Boxed Warning.

1. ELAPRASE Prescribing Information.

2. Muenzer J et al. Genet Med. 2006; 8(8): 465–473.

3. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. Am J Respir Crit Care Med. 2002; 166(1): 111–117.

4. Giugliani R et al. Genet Med. 2014; 16(6): 435–441.

5. de Jong JG et al. Clin Chem. 1989; 35(7): 1472–1477.

6. Muenzer J et al. Genet Med. 2011; 13(2): 102–109.

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