Hunterase ICV

Hunterase ICV is indicated for patients with Hunter Syndrome as an enzyme replacement therapy administered intracerebroventricularly.

About Hunterase ICV Clinical Trials Safety Information How to Use

About
Hunterase ICV

What is
Hunterase ICV?

#ICV #Intraventricular #CNS #central nervous system #BBB #blood brain barrier

Hunterase ICV is indicated for patients with Hunter Syndrome (Mucopolysaccharidosis II, MPS II) as an enzyme replacement therapy (ERT) administered intracerebroventricularly (ICV).

Reservoir Details

API

Idursulfase beta

Composition
(1 ml/vial)

15mg/mL of idursulfase beta in 150 mM of sodium chloride and 0.005% of polysorbate 20

Indication

Mucopolysaccharidosis type II Administration of Hunterase ICV Injection should be considered for patients with MPS II for which improvement of central nervous system symptoms is necessary.

Dosage and Administration

The usual dosage is 30mg of idursulfase beta (genetic recombination) administered intracerebroventricularly(ICV) once every 4 weeks. Administer Hunterase ICV inj. without dilution over at least 1 min.

Why Should CNS Symptoms Be Considered?

Non-neuronopathic (attenuated) type: Minimal CNS involvement

Common symptoms & signs

Developmental delay
Coarse face
Short stature
Skeletal abnormalities
(dysostosis multiplex)

Joint contracture
Hepatosplenomegaly
Upper airway obstruction
Valvular heart disease

Neuronopathic (severe) type: CNS involvement

Neurobehavioral symptoms

Aggression
Hyperactivity
Sleep disturbances
Progressive neurological decline
Cognitive impairment

Urmet needs in
IV ERT-treated
patients

Symptoms of CNS involvement

Since conventional intravenous enzyme replacement therapy (ERT) does not reach the brain compartment, the abnormal accumulation of glycosaminoglycans in the brain can lead to degeneration of brain tissue and progressive decline in cognitive function. Cognitive development stops at the age of 3-4 years and regression starts at the age of 4-5 years.

Quality of Life

In the neuronopathic type of MPS II, developmental age can be significantly affected by the CNS involvement associated with the disorder. The patients experience intellectual disabilities and delays in speech and language development, which can affect their ability to learn, communicate, and function independently. In addition, the progressive nature of MPS II can lead to a decline in physical abilities over time, including difficulties with fine motor skills and mobility. These factors can further affect an individual's developmental age and overall quality of life.

Life Expectancy

The life expectancy of MPS II patients can depend on the severity of their condition. In severe cases of MPS II, life expectancy is significantly reduced and may be limited to the teenage years or early adulthood compared to a longer the life expectancy until the fifth or sixth decade in the attenuated type. Early diagnosis and intervention are indeed critical in prolonging life expectancy and improving the quality of life as well.

Clinical Trials

Phase I/II
study with
5-year follow-up

Study Design

Multicenter, open-label, phase 1/2 clinical study

Objective

Evaluate efficacy and safety of ICV idursulfase-β (Hunterase ICV)

Treatment

Dose escalation from 1 mg to 30 mg between weeks 0 and 24, followed by a fixed 30 mg dose. Administered intracerebroventricularly (ICV) once every 4 weeks using an implanted cerebrospinal fluid (CSF) reservoir. Intravenous (IV) idursulfase was continued throughout the study.

Comparator

Historical control: 13 Japanese patients with neuronopathic MPS II treated with IV idursulfase only

Outcome Measure

Developmental age (DA) data comparison

Primary endpoint

Heparan sulfate (HS) concentration in the cerebrospinal fluid (CSF).

Change in CSF HS concentration (μg/mL)

Change in HS in the CSF of patients with MPS Il from the start of ICV idursulfase-β treatment up to week 228

Secondary endpoint

Developmental age (DA) determined by the Kyoto Scale of Psychological Development 2001 (KSPD) in the following three areas: postural-motor, cognitive-adaptive and language-social

Change from screening period to final observation (range 196-220 weeks) in DA(all 3 areas) by KSPD (months)

Comparison with the historical control data in patients with MPS II

Change in KSPD DA from screening to final observation

Safety Information

PRECAUTIONS

Precautions concerning indications

Administration of Hunterase (ICV Injection 15 mg) should be considered for patients with MPS II for which improvement of central nervous system symptoms is necessary.

Precautions concerning dosage
and administration

Hunterase ICV should be administered to patients who have received idursulfase (genetic recombination) intravenously and have been confirmed to tolerate it well. (see Section 14.1.1. of the package insert)
To prevent fluctuations in intraventricular pressure, collect cerebrospinal fluid (CSF, 2 mL) in the same volume as HUNTERASE ICV to be injected in advance and administer Hunterase without dilution over at least 1 min.
Hunterase ICV should be administered by a physician with knowledge and experience of intracerebroventricular administration.

Important precautions

As device-related complications, infections that include cerebral ventriculitis and cerebral meningitis, central nervous system events such as excessive intracranial hypotension or hypertension, device failure, etc., may occur. Pay attention to the following. (see Sections 9.1.1, 11.3.2–11.3.3. of the package insert)
- Establish a system to take appropriate actions for device failure etc.
- To reduce the risk of infection, Hunterase ICV should be administered aseptically.
- Confirm that there is no abnormality in the skin around the site of implantation before every administration of Hunterase ICV to check the signs of device failure and infection.
- Take appropriate actions if device-related complication is noted. See also the package inserts of the relevant medical device for device failure etc.
Because Hunterase ICV is a protein product, the possibility of causing anaphylactic shock cannot be ruled out. Therefore, the patient should be adequately monitored, and if any abnormality is noted, treatment with this product should be discontinued, and appropriate therapeutic measures should be taken. In addition, facilities for the treatment of emergencies should be prepared in case of the development of such a symptom. (see Sections 1, 2, 9.1.2 of the package insert)
Periodic testing of IgG antibodies against idursulfase-β (genetic recombination) is recommended, because IgG antibody production is predicted.

Precautions concerning patients with specific backgrounds

Patients with Complication/Medical History
- Patients on ventriculoperitoneal shunt or ventriculoatrial shunt
  Intracerebral Hunterase ICV exposure decreases, and efficacy cannot be expected. (see Section 8.1. of the package insert)
- Patients with a past history of hypersensitivity to the compounds of Hunterase ICV. (see Sections 2, 8.2. of the package insert)
Use during Pregnancy

Hunterase ICV should be used in pregnant women or women who may possibly be pregnant only if it is considered that the expected therapeutic benefits outweigh the possible risks associated with treatment. Impact on pregnancy of dams, embryos, fetuses, and neonates has not been investigated.
Use during Lactation

Consider therapeutic benefits and the benefit of breast-feeding to decide on whether to continue or discontinue breast-feeding. No study on the excretion of Hunterase ICV in breast milk has been conducted.
Pediatric Use

No clinical study in pediatric patients under 1 year old has been conducted.
Use in the Elderly

Hunterase ICV should be administered with care while observing the patients' condition. Elderly patients have generally reduced physiological function.

Storage and
Shelf-life

They may depend on the approved conditions in individual countries.

Store at 2 ºC to 8 ºC in a hermetic container.
The shelf-life of this product is 24 months from the date of manufacture.

ENG Official Insert Paper

PDF Download

How to Use

Injection Procedure

Implant a CSF reservoir under the patient’s scalp for i.c.v. administration.
To prevent fluctuations in intraventricular pressure, collect CSF (2 ml) of the same volume with Hunterase ICV (usually 30 mg) to be injected in advance.
Administer Hunterase ICV without dilution over at least 1 min.

Injection Schedule

Hunterase ICV is intracerebroventricularly administered once every 4 weeks (Hunterase ICV: 15 mg per vial).
Please note that in the Phase I/II trial, intravenous administration of idursulfase (0.5 mg/
kg/week) was also continued throughout the study; an interval of ≥24 hours was set between intravenous idursulfase and Hunterase ICV.

Example

IV : Once a week

ICV : Once a month

A minimum 24-hour interval is recommended between IV and ICV injections.

≥24 H

References

Orphanet J Rare Dis. 2013;8:42
Mol Ther Methods Clin Dev. 2021;21:67-75
Mol Genet Metab. 2015;114(2):156-60