One-time lumbar injection of MELPIDA gene therapy for young children with SPG50

Intrathecal Administration of MELPIDA (AAV9/AP4M1) For Hereditary Spastic Paraplegia Type 50 (SPG50): A Phase 3, Open-Label Trial With Matched Prospective Concurrent Control Arm

This will test whether a single lumbar intrathecal injection of MELPIDA can safely improve neurologic function in children aged 4–72 months with genetically confirmed SPG50.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 4 Months to 72 Months
• Sex: All
• Sponsor: Elpida Therapeutics SPC (Industry-sponsored)
• Locations: 2 sites (Dallas, Texas and 1 other locations)
• Trial ID: NCT06692712 on ClinicalTrials.gov

What this trial studies

MELPIDA is an AAV9-based gene therapy designed to deliver a functional AP4M1 gene to the central nervous system via a single lumbar intrathecal administration. The open-label, pivotal phase 3 protocol enrolls young children with bi-allelic pathogenic AP4M1 variants and neurologic features of SPG50 and compares treated participants to concurrent controls. Investigators will monitor safety, clinical neurologic endpoints, and relevant biomarkers over follow-up to determine whether treatment produces durable clinical benefit. The therapy aims for stable, long-term AP4M1 expression in non-dividing neural cells after one administration.

Who should consider this trial

Good fit: Ideal candidates are children aged 4 months to 72 months with molecularly confirmed bi-allelic pathogenic or likely pathogenic AP4M1 variants and clinical signs of neurologic dysfunction whose caregivers can provide consent and travel to a study site.

Not a fit: Patients without bi-allelic AP4M1 mutations, older than the enrollment window, with advanced irreversible neurologic injury, or with contraindications to intrathecal procedures are unlikely to benefit from this therapy.

Why it matters

Potential benefit: If successful, MELPIDA could provide durable replacement of AP4M1 and meaningfully improve or stabilize motor and developmental outcomes in affected children.

How similar studies have performed: AAV9-based gene therapies have produced durable benefit in other pediatric neurologic disorders (for example SMA), but use of MELPIDA specifically for SPG50 is a novel application with limited prior human data.

Eligibility criteria

Inclusion:

For the treatment group

* Male and females between the ages of 4 months to 72 months at the time of screening.
* Molecularly-confirmed diagnosis of SPG50 (confirmed by a CLIA certified, CE-marked, or equivalent lab): Genomic DNA mutation analysis demonstrating bi-allelic pathogenic or likely pathogenic variants in the AP4M1 gene.
* Subjects must have features of neurologic dysfunction by clinical history and physical examination.
* Stable doses of concomitant medications such as anti-spasticity medications, anti-seizure medications, behavioral management medications, sleep medications, and special diets, supplements, or nutritional support for at least 3 months prior to Screening. If recent changes (\< 3 months) in medications, the subject may be allowed per Investigator judgement.
* Parent/legal guardian willing to provide written informed consent for their child prior to participation in the study,
* Subjects and caregivers must demonstrate the ability to travel to the study center. For the 30 days post treatment subjects must reside within 100 miles (approximately 160 km) of the clinical site.

For the control group

* Male and females between the ages of 4 to 72 months at the time of screening.
* A molecularly confirmed diagnosis of SPG47, SPG50 or SPG52 (confirmed by a CLIA certified, CE-marked, or equivalent lab). Genomic DNA mutation analysis demonstrating bi-allelic pathogenic variants in the AP4B1, AP4M1, or AP4S1 gene,
* Subjects must have features of neurologic dysfunction by clinical history and physical examination.
* 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.
* Subjects and caregivers must demonstrate the ability to travel to the study center.

Exclusion

For the treatment group

* Loss of one of the 8 major motor milestones within the last 12 months. Milestones defined as:

  * #24: Sit on mat: Maintain, arms free, 3 seconds
  * #44: 4 Point: Crawls or hitches forward 1.8m (6')
  * #53: Standing: Maintains, arms free, 3 seconds
  * #67: Standing: 2 hands held: walks forward 10 steps
  * #69: Standing: Walks forward 10 steps
  * #84: Standing: Holding 1 rail: walks up 4 steps, holding 1 rail, alternating feet
  * #85: Standing: Holding 1 rail: walks down 4 steps, holding 1 rail, alternating feet
  * #88: Standing on 15cm (6") step: Jumps off, both feet simultaneously
* Inability to participate in the clinical evaluation as determined by the principal investigators.
* Clinically significant abnormal laboratory values (hemoglobin \< 6 or \> 20 g/dL; white blood cell \> 20,000 per cmm, platelets count \< 100,000 per cmm; INR \> ULN; GGT, ALT, and AST or total bilirubin \> 1.5 × ULN, creatinine ≥ 1.5 mg/dL) prior to gene replacement therapy.
* Presence of a concomitant medical condition (eg, scoliosis or bleeding disorder) that precludes a lumbar puncture or use of anesthetics for sedated procedures.
* Documented cardiomyopathy or significant congenital heart abnormalities.
* History of severe/life-threatening allergic reaction to sirolimus, tacrolimus, corticosteroids, or gadolinium.
* Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer, or interactions with the immunosuppressive agents.
* Any item which would exclude the subject from being able to undergo MRI according to local institutional policy, or any other procedure.
* The presence of significant AP-4 related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study.
* Recent or planned elective surgical procedures (within 6 months) that would confound the scientific rigor or interpretation of results of the study.
* Failure to obtain appropriate informed consent.
* Reason to believe that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
* 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 90 days before first visit (screening).

For the control group

* Loss of one of the 8 major motor milestones within the last 12 months. Milestones defined as:

  * #24: Sit on mat: Maintain, arms free, 3 seconds
  * #44: 4 Point: Crawls or hitches forward 1.8m (6')
  * #53: Standing: Maintains, arms free, 3 seconds
  * #67: Standing: 2 hands held: walks forward 10 steps
  * #69: Standing: Walks forward 10 steps
  * #84: Standing: Holding 1 rail: walks up 4 steps, holding 1 rail, alternating feet
  * #85: Standing: Holding 1 rail: walks down 4 steps, holding 1 rail, alternating feet
  * #88: Standing on 15cm (6") step: Jumps off, both feet simultaneously
* Inability to participate in the clinical evaluation as determined by the principal investigators.
* Any other situation that would exclude the subject from undergoing any other procedure required in this study.
* The presence of significant AP-4 related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study.
* Recent or planned elective surgical procedures that would confound the scientific rigor or interpretation of results of the study.
* Failure to obtain appropriate informed consent.
* Reason to believe that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
* Have received an investigational drug within 30 days prior to screening or plans to receive an investigational drug (other than gene therapy) during the study.
* Enrollment and participation in another interventional clinical trial 90 days before first visit (screening).

Where this trial is running

Dallas, Texas and 1 other locations

• University of Texas Southwestern Medical Center — Dallas, Texas, United States (Recruiting)
• Sant Joan de Deu — Barcelona, Spain (Active_not_recruiting)

Study contacts

• Study coordinator: Rachel Thomas

Conditions Hereditary Spastic Paraplegia Type 50; SPG50; Spastic Paraplegia; Gene Therapy; Phase 3