phase 3, open-label study to assess the efficacy and safety of a single lumbar intrathecal administration of melpida in individuals with hereditary spastic paraplegia type 50 (spg50) versus matched prospective concurrent controls.

Conditions: Hereditary Spastic Paraplegia Type 50

Summary: phase 3, open-label study to assess the efficacy and safety of a single lumbar intrathecal administration of melpida in individuals with hereditary spastic paraplegia type 50 (spg50).

melpida is an aav9-based gene therapy vector that expresses the fully functional form of ap4m1 under the control of a synthetic promoter. melpida will be delivered intrathecally and is designed to achieve stable, potentially life-long expression of ap4m1 in non-dividing cells. this clinical study is a pivotal open-label phase 3 study designed to assess safety and efficacy of melpida in individuals with spg50.

Eligibility criteria:
inclusion criteria: for the treatment group * male and females between the ages of 23 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 1) bi-allelic pathogenic and/or likely pathogenic variants in the ap4m1 gene, or 2) bi-allelic variants with one pathogenic and/or likely pathogenic variant in trans with a variant of uncertain significance if laboratory evidence of loss of ap-4 function exists. * ability to sit independently for 3 seconds (item 24 of the gmfm-88). * 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. * two custodial parents with legal capacity (legally acceptable representatives) to execute an irb approved consent for medical research must be able to participate in the consent process. if only one parent has sole custody to consent for medical research, then that parent must be able to actively participate in the consent process. * legally acceptable representatives must be able to attend all scheduled study visits and provide feedback regarding the subject's symptoms and performance as described in the protocol. * subjects and caregivers must demonstrate ability to travel to the study center. for the 30 days post treatment subjects must reside within 100 miles of the clinical site. for the control group * male and females between the ages of 21 to 78 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 1) bi-allelic pathogenic and/or likely pathogenic variants in the ap4b1, ap4m1, or ap4s1 gene, or 2) bi-allelic variants with one pathogenic and/or likely pathogenic variant in trans with a variant of uncertain significance if laboratory evidence of loss of ap-4 function exists. * ability to sit independently for 3 seconds (item 24 of the gmfm-88). * subjects must have features of neurologic dysfunction by clinical history and physical examination. * two custodial parents with legal capacity (legally acceptable representatives) to execute an irb approved consent for medical research must be able to participate in the consent process. if only one parent has sole custody to consent for medical research, then that parent must be able to actively participate in the consent process. * legally acceptable representatives must be able to attend all scheduled study visits and provide feedback regarding the subject's symptoms and performance as described in the protocol. * subjects and caregivers must demonstrate the ability to travel to the study center. exclusion criteria: for the treatment group * inability to participate in the clinical evaluation as determined by the principal investigators. * clinically significant abnormal laboratory values (hemoglobin \ 20 g/dl; white blood cell \> 20,000 per cmm, platelets count \ 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 that precludes a lumbar puncture or use of anesthetics for sedated procedures. * bleeding disorder or any other medical condition or circumstance in which a lumbar puncture is contraindicated according to local institutional policy. * documented cardiomyopathy or significant congenital heart abnormalities. * inability to be safely sedated in the opinion of the clinical anesthesiologist. * 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. * concomitant chronic drug treatment that would cause clinically significant interactions with immunosuppressive agents used in the study. * any item which would exclude the subject from being able to undergo mri according to local institutional policy. * 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. * abnormal laboratory values that are considered to be potentially clinically significant. * 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 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. for the control group * 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 during the study. * enrollment and participation in another interventional clinical trial 90 days before first visit.

Keywords: spg50 spastic paraplegia gene therapy phase 3