Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50

A Phase 1 Open-label Intrathecal Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50 (SPG50) Caused by a Mutation in the AP4M1 Gene

This will be a first-in-human Phase I, open-label, single dose clinical study of MELPIDA administered intrathecally (IT) through a lumbar puncture (LP) to a single subject with confirmed pathogenic mutations in the Adaptor Related Protein Complex 4 Subunit Mu 1 (AP4M1) gene. The primary outcome will be the determination of the safety and tolerability of MELPIDA in patients with SPG50, based on development of toxicity.

The secondary outcome will be a preliminary exploration of efficacy of the treatment.

MELPIDA, is a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene and will be administer to the patient via a single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg.

The total study duration is 5 years post dosing and the participant will be tested at screening/baseline (-28 to -7 days), return for dosing, and then follow-up visits post-dosing on Days 7 (+/-2), 30 (+/-2), 60 (+/-2), 90 (+/-14), 180 (+/-14), 270 (+/-14), 360 (+/-14), 540 (+/-14), and 720 (+/-14) days, then annually for the last 3 years.

Study Overview

• Status: Active, not recruiting
• Conditions: Spastic Paraplegia Type 50
• Intervention / Treatment: Biological: MELPIDA

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age < 5 years old
• Confirmed diagnosis of SPG50 disease by:
• Genomic DNA mutation analysis demonstrating homozygous or compound heterozygous, pathogenic and/or potentially pathogenic variants in the AP4M1 gene
• Clinical history or examination features consistent with SPG50 and that include neurologic dysfunction
• Parent/legal guardian willing to provide written informed consent for their child prior to participation in the study
• Subject able to comply with all protocol requirements and procedures

Exclusion Criteria:

• Inability to participate in study procedures (as determined by the site investigator)
• Presence of a concomitant medical condition that precludes lumbar puncture (LP) or use of anesthetics
• History of bleeding disorder or any other medical condition or circumstance in which lumbar puncture is contraindicated according to local institutional policy
• Inability to be safely sedated in the opinion of the clinical anesthesiologist
• Active infection, at the time of dosing, based on clinical observations
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
• Inability of the patient to undergo MRI according to local institutional policy
• Inability of the patient to undergo any other procedure required in this study
• The presence of significant non-SPG50 related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
• Have received an investigational drug within 30 days prior to screening or plan to receive an investigational drug (other than gene therapy) during the study.
• Enrollment and participation in another interventional clinical trial
• Contraindication to MELPIDA or any of its ingredients
• Contraindication to any of the immune suppression medications used in this study
• Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total bilirubin > 3 × Upper Limit of Normal (ULN), creatinine ≥ 1.5 mg/dL, hemoglobin [Hgb] < 6 or > 20 g/dL; white blood cell (WBC) > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MELPIDA; A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg (open-label)	Biological: MELPIDA; A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of unanticipated anticipated treatment-related toxicities, Grade 3 or higher	collection of occurrence and severity of serious adverse events. Incidence of serious adverse events and adverse events throughout the study, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Higher grade values indicated greater severity. Grade 1 - Grade 5.	through study completion, an average of 5 years
Change from baseline in nerve conduction velocity	Nerve conduction studies will be used to determine nerve conduction velocity. Nerve conduction studies involve providing a small electrical stimulus to either a motor or sensor nerve and then measuring the resulting action potential at distal point of that nerve (for sensory nerve studies) or at the muscle that the nerve innervates (motor nerve studies). Velocity of conduction (measured between the two points and represented in m/s) will be obtained. The value is compared to standard reference values for age.	Screening, Day 21, and Month 3, 6, 12, 24, 36, 48 and 60
Determination of liver safety	Changes in Liver Ultrasound findings from baseline. Incidence of serious adverse events and adverse events throughout the study, as assessed by CTCAE v5.0	Screening, Month 6, 12, 24, 36, 48 and 60
Determination of liver safety	Liver laboratory test: alanine transaminase (ALT) in U/L	Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Determination of liver safety	Liver laboratory test: aspartate aminotransferase (AST) in U/L	Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
determination of liver safety	Liver laboratory test: Total bilirubins in umol/L	Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Determination of liver safety	Liver laboratory test: direct bilirubins in umol/L	Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Determination of liver safety	Liver laboratory test: alkaline phosphatase (ALP) in U/L	Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Determination of liver safety	Liver laboratory test: gamma-glutamyl transferase (GGT) in U/L	Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Change from baseline in nerve conduction amplitude	Nerve conduction study will be done to assess nerve conduction amplitude. Nerve conduction studies involve providing a small electrical stimulus to either a motor or sensor nerve and then measuring the resulting action potential at distal point of that nerve (for sensory nerve studies) or at the muscle that the nerve innervates (motor nerve studies). Amplitude of the action potential (measured at the distal site and represented in uV for sensory amplitudes and mV for motor amplitudes) will be obtained. The value is compared to standard reference values for age.	Screening, Day 21, and Month 3, 6, 12, 24, 36, 48 and 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stability or improvement in spasticity	Modified Ashworth scale (0-4). 0: no increase in muscle tone; 1: slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension; 1+: slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the range of motion; 2: more marked increase in muscle tone through most of the range of motion, but affected part(s) easily moved; 3: considerable increase in muscle tone, passive movement difficult; 4: affected part(s) rigid in flexion or extension. Values reported separately for right and left upper and lower limbs.	Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Stability or improvement in spasticity	Tardieu scale (0-5). 0: no resistance throughout passive movement; 1: slight resistance throughout with no clear catch at a precise angle; 2: clear catch at a precise angle, followed by release; 3: fatiguable clonus (<10 seconds) occurring at a precise angle; 4: unfatiguable clonus (>10 seconds) occurring at a precise angle; 5: joint immobile. Values reported separately for right and left upper and lower limbs.	Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor function, neuropsychological, and disease burden assessments	Bayley 4 (Fine Motor, Gross Motor, Cognitive & Language). Scores are aggregated for each domain into a scaled score. The highest possible score on a subtest or subdomain is 19, and the lowest possible score is 1. Scores from 8 to 12 are considered average.	Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Number of seizures per day (numerical value)	Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Type of seizures, if applicable	Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Seizure triggers, if applicable. Trigger will be defined by any observer or the participant. An open answer format will be collected.	Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Seizure rescue medication used, if applicable	Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Clinical Global Impression of Overall Change by Physician (1-7); 1: very much improved to 7: very much worse. Single value reported.	Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Vineland (Comprehensive Parent/Caregiver Form). The domain scores are expressed as standard scores with a mean of 100 and standard deviation of 15; domains: communication, daily living skills, socialization and motor skills.	Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
motor function, neuropsychological, and disease burden assessments	Number of falls per day	Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Causes of any falls reported, as applicable	Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Motor function, neuropsychological, and disease burden assessments	Clinical Severity of Illness by Physician (1-7); 1: normal, shows no sign of illness to 7: among the most extremely ill of patients. Single value reported.	Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2022
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: August 17, 2023
• First Submitted That Met QC Criteria: October 2, 2023
• First Posted (Actual): October 6, 2023

Study Record Updates

• Last Update Posted (Actual): May 14, 2025
• Last Update Submitted That Met QC Criteria: May 9, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Paralysis; Muscle Spasticity; Paraplegia
• Other Study ID Numbers: 1000079110

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No