Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)

Shire24 enrolled

Overview

The purpose of this study is to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks (20 injections) in children with metachromatic leukodystrophy (MLD).

Metachromatic leukodystrophy (MLD) is an inherited, autosomal recessive disorder of lipid metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA). MLD is a rare disease that occurs in most parts of the world. The estimated overall incidence of the disease in the western world is approximately 1 in 100,000 live births that varies by geographic location. There are no approved therapies for MLD. This is a multicenter, open-label, dose-escalation study designed to evaluate the safety of up to 3 dose levels (10, 30, or 100 mg) of HGT-1110 administered via an intrathecal drug delivery device (IDDD) every other week (EOW) for a total of 38 weeks (20 injections, Weeks 0 to 38) to children with MLD. The study also includes the assessment of HGT-1110 drug product produced with a revised drug substance manufacturing process (referred to as Process B) in a fourth cohort (Cohort 4). Approximately 24 patients will be enrolled and will receive treatment of HGT-1110. Patients will be sequentially enrolled into 4 dose cohorts, approximately 6 patients each. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring per dose cohort.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metachromatic Leukodystrophy (MLD)

Interventions

Recombinant human arylsulfatase ABIOLOGICAL

6 patients treated with HGT-1110 EOW by IT injection

Eligibility

Sex: ALLMax age: 12 Years

Medical Language ↔ Plain English

Inclusion For Cohorts 1-4: 1. Confirmed diagnosis of metachromatic leukodystrophy by both: * Arylsulfatase A (ASA) deficiency by assay in leukocytes AND * Elevated sulfatide in urine 2. Appearance of the first symptoms of disease at or before 30 months of age. For Cohorts 1-3 only: 3. Ambulatory at the time of screening. The minimum level of function required to meet this criterion is defined as the ability to walk forward 10 steps with one hand held. 4. The patient is less than 12 years of age at the time of screening. For Cohort 4 only: 3.1 Minimum motor function requirements: 1. A total GMFM-88 (percent) score ≥40 at the screening examination and a total GMFM-88 (percent) score ≥35 at the baseline examination, AND 2. GMFM-88 Dimension E: Walking, Running \& Jumping, item 68 ("walk forward 10 steps with one hand held") score of at least 1 "initiates" at the screening and baseline examinations (if applicable). 4.1 The patient is less than 8 years of age at the time of screening. For Cohorts 1-4: 5. Neurological signs of MLD must be present at the screening examination. 6. The patient and his/her parent/representative(s) must have the ability to comply with the clinical protocol. 7. Patient's parent(s) 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 patient. Exclusion Criteria: Patients will be excluded from the study if there is evidence or history of any of the following criteria at screening: For Cohorts 1-4: 1. History of hematopoietic stem cell transplantation (HSCT). 2. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions. 3. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial. 4. The patient is enrolled in another clinical study that involves the use of any investigational product (drug or device) other than HGT-1110 or the IDDD used in this study within 30 days prior to study enrollment or at any time during the study. 5. The patient is pregnant or breastfeeding. 6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU), including: 1. The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device. 2. The patient's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator. 3. The patient has a known or suspected local or general infection. 4. The patient is at risk of abnormal bleeding due to a medical condition or therapy. 5. The patient has one or more spinal abnormalities that could complicate safe implantation or fixation. 6. The patient has a functioning CSF shunt device. 7. The patient has shown an intolerance to an implanted device.

Locations (5)

The Children's Hospital at Westmead

Westmead, Australia

Rigshospitalet

Copenhagen, Denmark

Hopital de Bicetre

Le Kremlin-Bicêtre, Île-de-France Region, France

Center for Pediatric Clinical Studies

Tübingen, Baden-Wurttemberg, Germany

Outcomes

Primary Outcomes

Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Drug-related and device-related types of TEAEs were analyzed and reported. The severity of AEs was assessed by the investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 grading scale. Severity of all AEs or SAEs was recorded as grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or fatal. Here SDI refers to surgical device implantation.

Time frame: From start of study treatment up to Week 42

Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

Clinical laboratory test included serum chemistry, hematology and urinalysis. Clinical laboratory abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

Time frame: From start of study treatment up to Week 40

Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

Vital sign assessments included blood pressure, heart rate, respiratory rate and body temperature. Vital sign abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Vital sign abnormalities included pyrexia which was considered as TEAE and was reported.

Data from ClinicalTrials.gov

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Secondary Outcomes

Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40

The GMFM-88 was used to measure motor function. The GMFM-88 item scores were used to calculate domain-specific percent score for each of the 5 GMFM-88 dimensions (lying and rolling; sitting; crawling and kneeling; standing; walking, running, and jumping), and a total GMFM-88 (percent) score was calculated based on each dimension score. Each of the 88 items was rated on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. The GMFM-88 total scores ranged from 0% (no mobility) to a score of 100%, that is (i.e,) the score that can be obtained by an average 5-year-old or older child with normal motor abilities.

Time frame: Baseline, Week 40

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40

Time frame: Week 40

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for laryngeal penetration was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

Time frame: Week 40

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. Feeding assessment for aspiration through vocal cords were assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

Time frame: Week 40

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for dose residue clear after subsequent swallowing was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture.

Time frame: Week 40

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40

The FEES assessment was performed to evaluate the structure and function of the upper throat during swallowing and for an assessment of aspiration risk. Each participant had this assessment performed at the clinical site using transnasal flexible laryngoscopy. FEES for aspiration risk was assessed. Data was presented only for the shifts observed. Here TL refers to thin liquids, THL refers to thickened liquids, PT refers to puree texture, WCC refers to with cough and clearance and WCNC refers to with cough and no clearance.

Time frame: Week 40

Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40

Time frame: Baseline, Week 40

Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40

Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized nerve conduction velocity values were assessed. Data was presented only for number of participants who reported change in nerve conduction velocity \> 0. Here MME refers to median motor elbow, WCV for wrist conduction velocity, PMA for peroneal motor ankle, FHCV to fibular head conduction velocity, TMA for tibial motor ankle, KCV for knee conduction velocity and UME for ulnar motor elbow,

Time frame: Baseline, Week 40

Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40

Evaluation of peripheral nerve function by ENG studies was performed to measure nerve conduction velocity (NCV), amplitude (AMP),distal latency (DL), and F-wave latency. Categorized amplitude values were assessed. Data was presented only for number of participants who reported change in distal latency \> 0. Here MMW refers to median motor wrist, APB for abductor pollicis brevis, MSW for median sensory wrist, DDL for digit distal latency, PMA for peroneal motor ankle, EDB for extensor digitorum brevis, SSB-point DL for sural sensory B-point distal latency, TMA for tibial motor ankle, abductor hallucis for AH distal latency and, UMW for ulnar motor wrist.

Time frame: Baseline, Week 40

Change From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40

The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 4 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (ABC) (a composite of the other 4 domain). Items in each domain are rated as either 0 (does not), 1(sometimes) or 2(independently) performs a given behavior or skill. The 4 domain standard scores range from 20-160 and higher scores indicate a higher level of functioning. ABC scores have a mean of 100 and a standard deviation of 15 (range = 20 to 160) and higher scores indicate a higher level of functioning. A positive change value indicates improvement in adaptive functioning.

Time frame: Baseline, Week 40

Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40

COMFORT questionnaire was used to assess health status and the impact of disease on the ability of participants with MLD to carry out activities of daily life. The questionnaire was organized by 8 domains (ie, personal care; positioning, transfer, or mobility; eating; pain and discomfort during the day; sleep; emotions; communication; and play and leisure activities). The COMFORT scores range from 0 to 100, with higher scores indicating a decline in the functioning.

Time frame: Baseline, Week 40

Maximum Observed Serum Concentration (Cmax) of SHP611

Cmax is the maximum observed serum concentration of SHP611.