Trial Outcomes & Findings for A Study of AT132 in Young Children With X-Linked Myotubular Myopathy (XLMTM) (NCT NCT03199469)

Participants diagnosed with X-linked myotubular myopathy (XLMTM) resulting from a genetically confirmed mutation in the myotubular myopathy (MTM) 1 gene as assessed by a Sponsor-approved testing facility were enrolled in this study.

Participants who met all inclusion criteria and none of the exclusion criteria were enrolled in the study. The study is ongoing, and data for efficacy is reported for Part 1 (week 24) of the study only with mortality and safety data being reported up to data cut-off date 30 June 2023 (up to 5 years).

Full Analysis Set (FAS) population (included all randomized and enrolled participants who received resamirigene bilparvovec and had at least 1 post-dose efficacy assessment) with available data was reported.

The hours of ventilation support were based on diary data from participants for whom diary data was collected at baseline and by assessment of time off ventilator questionnaire for all other participants. Weekly scores were the average of ventilation hours needed for at least 5 out of the 7 days leading up to and including the analysis visit day (e.g., Day 168 for Week 24). For cases where the diary or the ventilator assessment indicated the ventilator type = "None", then zero was imputed for the number of hours on ventilator.

Independence to sit is defined as a participant who sits for at least 30 seconds without assistance from another person or object. Data was determined from the motor milestone electronic case report form (eCRF) or the Bayley Scales of Infant and Toddler Development (BSID) subtest performance criteria number 26, used to determine whether the participant achieves (Yes) or doesn't achieve (No) the milestone. If data was not available then they would be included as "missing".

The reduced ventilator time was obtained directly from the daily diary or assessment of the time off ventilator questionnaire. The first instance of time reduction reported as ≤ 16 hours per day was considered as an event. Kaplan- Meier estimate was used for analysis.

The CHOP INTEND is an assessment scale that was originally designed to quantify motor abilities in infants aged 1.4 to 37.9 months, with spinal muscular atrophy type I (SMA-I) and has been validated for X-linked myotubular myopathy (XLMTM). The scale contains 16 questions, each of which is scored on a scale of 0 to 4, with 0 being no response/ability to perform the movement and 4 highest abilities to perform the task, per CHOP INTEND item instructions. The score used for analysis is the total sum of all 16 questions, which will range from 0 to 64. Higher score indicates better neuromuscular function. If an item is missing or scored as "Could Not Test (CNT)" then 0 will be imputed for the item score.

MIP is a quick and non-invasive test to measure strength of inspiratory muscles, primarily diaphragm, and allows for assessment of ventilatory failure, restrictive lung disease and respiratory muscle strength. MIP refers to how much air pressure force an individual creates by inhaling through the mouth as hard as possible.

Myotubularin is a protein, a highly conserved, dual-specific lipid phosphatase that is involved in the development, maturation, and maintenance of skeletal muscle cells. Myotubularin is encoded by an MTM1 gene. The concentration of the sample was normalized such that the equivalent amount of protein was tested per sample.

ACEND was developed to measure impact on lives of parents/legally authorized representatives /caregivers caring for children with severe neuromuscular disorders. ACEND has 41 items which reflected 2 domains (physical impact \[feeding/grooming/dressing {6 items}, sitting/play {5 items}, transfers {5 items} and mobility {7 items}\] and general caregiver impact \[time {4 items}, emotion {9 items}, and finance {5 items}\]). Score for each item was based on 6- or 5-point ordinal scale, and scores for each domain and subdomain were scored on 0 - 100 scale. Higher scores reflected caregivers experiencing less intense care-giving impact. Raw scores for each subdomain was created by computing algebraic mean of items for those respondents who completed one item or more; setting missing for those items with no responses. Then, arithmetic mean of responded items was standardized to 0 to 100 score and transformed scores were from 0 to 100 for each subdomain. Higher score indicated a better outcome.

PedsQL is a tool designed to measure health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. PedsQL measures the core dimensions of health as delineated by the World Health Organization, as well as role (school) functioning. This questionnaire has different modules that are administered depending on the age and condition of the child. Each item of the questionnaire is measured on a 5-point likert scale from - 0 (Never) to 4 (Almost always). The module is composed of 25 items comprising 3 dimensions: About My Neuromuscular Disease (17 items), Communication (3 items), About Our Family Resources (5 items). Items are reversed scored and linearly transformed to a total score of 0-100 scale. Higher scales/scores indicate lower problems.

Motor Developmental Milestones included: head control (holds head erect for at least 15 seconds without support), rolls from back to sides (turns from back to both sides), sits without support (sits alone without support for at least 10 seconds), stands with assistance (supports own weight for at least 2 seconds), crawls (makes forward progress of at least 5 feet by crawling on hands and knees), pulls to stand (raises self to standing position using chair or other convenient object for support), walks with assistance (child walks by making coordinated, alternating stepping movements. May hold on with 1 or 2 hands for support), stands alone (stands alone for at least 3 seconds after you release hands), walks alone (takes at least 3 steps without support, even if gait is stiff-legged and wobbly). Mean percentage of gross motor function milestones attained was reported.

"Full ventilator independence" is defined as: the date of removal from ventilator field on the "Assessment of Ventilator Parameters" eCRF is not blank or "Is subject on a ventilator" = "No" on the same eCRF.

Survival status was assessed at each visit until the participant withdraws consent or completes the study. If the participant missed a visit or withdraws for a reason other than withdrawal of consent or death, the site contacted the parent(s)/legally authorized representatives to ascertain if the participant was alive. For participants who withdrew from the study, the participant was contacted every 6 months for 5 years after administration and to assess for survival. Kaplan- Meier estimate was used for analysis.

An AE is any untoward medical occurrence in a participant administered a study drug not necessarily having a causal relationship with this treatment. An AE can therefore be any unfavorable \& unintended sign, symptom, or disease temporally associated with the use of medicinal product (MP) whether or not considered related to MP. A TEAE is any AEs, regardless of relationship to study drug, that begins or worsens on or after baseline (dosing) visit date.