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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Spastic Paraplegia Type 50

Intervention / Treatment
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* Biological: MELPIDA


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 4 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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. |