Intrathecal Administration of Cebsulfase Alfa in Pediatric Patients with Late Infantile Metachromatic Leukodystrophy: A Single-Arm, Matched External Control Study

Trial ID: 2024-514402-31-00
Protocol: SHP611-201
Sponsor: Shire Human Genetic Therapies Inc.

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Diseases & Conditions

Metachromatic leukodystrophy

Objectives

The primary objective of this study is to evaluate the effects of **intrathecal** (IT) administration of SHP611 on the time to loss of locomotion in children with late infantile **Metachromatic Leukodystrophy** (MLD). This is assessed by observing a category 5 or higher in the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) and comparing it with external control group data. This objective is clinically relevant as it aims to determine the potential of SHP611 to delay the progression of motor function decline, which is a critical aspect of disease management in MLD.

Secondary objectives include:

Evaluating the effects of IT administration of SHP611 on subjects experiencing a decline in gross motor function, as indicated by GMFC-MLD category 5 or higher, compared with matched external control group data.
Assessing the effects on the decline in gross motor function, measured by an unreversed decline in GMFC-MLD of more than 2 categories, the time course of declining gross motor function, and change from baseline using the GMFC-MLD.
Evaluating the effects on cerebrospinal fluid (CSF) sulfatides as a pharmacodynamic biomarker.
Assessing the effects on gross motor function using the Gross Motor Function Measure 88 (GMFM-88) total score in children with MLD.

Participants

The clinical trial involves a total of **16 participants** diagnosed with **Late Metachromatic Leukodystrophy (MLD)**. The study population includes both male and female subjects, with an age range spanning from 6 months to 72 months, depending on the specific group classification within the trial. Participants were selected based on a documented diagnosis of MLD, characterized by low arylsulfatase A (ASA) activity in leukocytes and elevated sulfatides in urine. The trial does not involve a vulnerable population. Participants exhibit varying degrees of locomotion impairment, as classified by the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD). The selection criteria also consider the presence of gait disorders due to spastic ataxia or weakness attributable to MLD, with symptoms documented by healthcare professionals. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The ability to comply with the clinical protocol and the provision of informed consent by the subject's parent or legally authorized representative are essential for participation.

Plans and Procedures

The clinical trial is designed to evaluate the effects of **intrathecal** administration of SHP611 on the time to loss of locomotion in children with late infantile **Metachromatic Leukodystrophy** (MLD). This is a global, multicenter, single-arm study with a matched external control group. The trial is set to run from May 2019 to March 2025, with a total duration of approximately 106 weeks for each participant. The primary objective is to assess the time to progression to a Gross Motor Function Classification in MLD (GMFC-MLD) category 5 or higher, or death, whichever occurs first. Secondary endpoints include maintenance of gross motor function and changes in cerebrospinal fluid sulfatides levels.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as documented diagnosis of MLD and age-specific requirements. Following the screening, participants will receive the investigational product, **cebsulfase alfa**, administered via the SOPH-A-PORT Mini S device for long-term, intermittent access to the intrathecal space. Regular follow-up visits will be conducted to monitor safety, efficacy, and any adverse events. The end-of-study visit will occur at Week 106, where final assessments will be made.

The expected length of participant involvement is up to 106 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must comply with the clinical protocol, and their parent or legally authorized representative must provide written informed consent prior to any study-related activities. The trial is not categorized as low intervention and is classified as a Phase 4 study. The investigational product, rhASA, is a solution for injection and is not a pediatric formulation. The study aims to provide valuable insights into the treatment of late infantile MLD, with the potential to improve patient outcomes through the maintenance of motor function.

Treatment

The clinical trial involves the administration of the experimental medication **rhASA**, which contains the active substance **cebsulfase alfa**. This medication is provided in the form of a **solution for injection** and is specifically designed for **intrathecal use**. The pharmaceutical formulation is developed by Shire Human Genetic Therapies, Inc. The administration of rhASA is facilitated through the SOPH-A-PORT Mini S IDDD device, which is intended for long-term, intermittent access to the intrathecal space for the delivery of the investigational drug. The maximum treatment period for rhASA is 105 days. The dosage is expressed in milligrams per milliliter (mg/ml), although specific daily and total dose amounts are not provided in the trial data.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the effects of the investigational drug rhASA in subjects with late infantile Metachromatic Leukodystrophy. Participant compliance with the dosing schedule is monitored through the use of the SOPH-A-PORT Mini S IDDD device, ensuring accurate and consistent delivery of the medication. The trial aims to evaluate the impact of intrathecal administration of SHP611 on the time to loss of locomotion in affected children, as compared to external control group data.

Efficacy

The efficacy of the investigational drug, **cebsulfase alfa**, administered intrathecally as SHP611, will be assessed in a clinical trial involving subjects with late infantile Metachromatic Leukodystrophy (MLD). The primary efficacy endpoint is the time to loss of locomotion, which is measured by progression to category 5 or higher in the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) or death, whichever occurs first, up to Week 106. This will be evaluated in subjects in Group A.

Secondary efficacy endpoints include several measures: maintenance of gross motor function at Week 106, defined as subjects who do not experience any event within Week 106, where an event is a decline in GMFC-MLD to category 5 or higher, or death; change from baseline at Week 106 and end-of-study (EOS) in gross motor function using GMFC-MLD; time to unreversed decline from baseline in GMFC-MLD of more than 2 categories; change from baseline at Week 106 and EOS in cerebrospinal fluid (CSF) sulfatides levels; maintenance of gross motor function at Week 106, defined as a GMFM-88 total score ≥40; time to unreversed decline from baseline at Week 106 and EOS in GMFM-88 total score decrease of >20 points or unreversed decline to a score <40 points; and change from baseline at Week 106 and EOS in expressive language using the ELFC-MLD.

Inclusion and Exclusion Criteria

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Inclusion Criteria

The subject must have a documented diagnosis of MLD (Groups A-F) • Low ASA activity in leukocytes (compared to laboratory normal range) AND • Elevated sulfatides in urine
The subject must have a gait disorder due to spastic ataxia or weakness attributable to MLD by the investigator and documented by a primary care physician or a specialist physician by 30 months of age (Groups A-C, and F), or be minimally symptomatic and ≥6 to <18 months of age (Group D); or be early symptomatic and ≥12 to <18 months of age (Group E). Subjects in Group E must have neurological symptoms documented by either a primary care physician or a specialist physician.
The subject's age at the time of informed consent, must be: • Group A: 18 to 48 months of age • Group B: 18 to 72 months of age • Group C: 18 to 72 months of age • Group D: ≥6 to <18 months of age • Group E: ≥12 to <18 months of age • Group F: 18 to 72 months of age
The subject's GMFC-MLD category at screening must be: • Group A: GMFC-MLD category of 1 or 2 • Group B: GMFC-MLD category of 3 • Group C: GMFC-MLD category of 4 • Group D: minimally symptomatic, and has the same ASA allelic constitution as an older sibling with confirmed late infantile or juvenile onset MLD • Group E: early symptomatic, ≥12 to <18 months of age with a GMFCMLD category of 1 or 2, and with a history of achieving stable walking (defined as at least 1 month of independent walking) • Group F: GMFC-MLD category of 5 or 6
The subject and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
Subject's parent or legally authorized representative(s) must provide written informed consent prior to performing any study-related activities. Study-related activities are any procedures that would not have been performed during normal management of the subject.

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Exclusion Criteria

Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase (based upon the reference laboratory's normal range) or a known genetic disorder other than MLD
History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT), or gene therapy or undergoes BMT, HSCT, or gene therapy at any point during the study
Primary presentation of MLD was behavioral or cognitive symptoms (per investigator's clinical judgment); behavioral symptoms that are secondary to motor deficits (eg: tantrums in response to loss of motor skills) are not exclusionary.
The subject has any known or suspected hypersensitivity to agents used for anesthesia or has history of difficult airway or potential for airway compromise
Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study
Subjects with laboratory, ECG, or vital sign abnormalities reflecting intercurrent illness that may compromise their safety during the trial should not be enrolled. Abnormal laboratory, vital sign and ECG results at screening should be reviewed with the Takeda medical monitor.
The subject is enrolled in another clinical study that involves use of any investigational product (drug or device) within 30 days or 5 halflives (whichever is longer) prior to study enrollment or at any time during the study
The subject has had prior exposure to SHP611
The subject must weight > 11lbs (5kg)
The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use a. The subject has had, or may have, an allergic reaction to the materials of construction b. The subject has shown an intolerance to an implanted device c. The subject's body size is too small to support the size of the SOPH-APORT Mini S Access Port d. The subject's drug therapy requires substances known to be incompatible with the materials of construction e. The subject has a known or suspected local or general infection f. The subject is at risk of abnormal bleeding due to a medical condition or therapy g. The subject has one or more spinal abnormalities that could complicate safe implantation or fixation h. The subject has a functioning CSF shunt device

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	13 May 2019	2
France	Not Recruiting	13 May 2019	2
Germany	Not Recruiting	13 May 2019	2
Greece	Not Recruiting	13 May 2019	1
Italy	Not Recruiting	13 May 2019	1
Spain	Not Recruiting	13 May 2019	2