Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1
Condition: SMA - Spinal Muscular Atrophy; Gene Therapy
MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy
Intervention: Onasemnogene Abeparvovec-xioi
Intervention description: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: One-time intravenous administration of onasemnogene abeparvovec-xioi.
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Maximum age: 180 Days
Healthy volunteers: No

Summary:

      Phase 3 pivotal US trial studying open-label intravenous administration of onasemnogene
      abeparvovec-xioi in spinal muscular atrophy (SMA) Type 1 participants.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants with SMA Type 1 as determined by the following features: a. Diagnosis of
             SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point
             mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier
             mutation (c.859G>C))2

          -  The first 3 participants enrolled must meet the criteria for the Intent-To-Treat
             Population

          -  Participants must be < 6 months (< 180 days) of age at the time of onasemnogene
             abeparvovec-xioi infusion

          -  Participants must have a swallowing evaluation test performed prior to administration
             of gene replacement therapy

          -  Up-to-date on childhood vaccinations. Seasonal vaccinations that include palivizumab
             prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV)
             infections are also recommended in accordance with American Academy of Pediatrics

          -  Parent(s)/legal guardian(s) willing and able to complete the informed consent process
             and comply with study procedures and visit schedule

        Exclusion Criteria:

          -  Previous, planned or expected scoliosis repair surgery/procedure during the study
             assessment period

          -  Pulse oximetry < 96% saturation at screening while the participant is awake or asleep
             without any supplemental oxygen or respiratory support, or for altitudes > 1000 m,
             oxygen saturation < 92% awake or asleep without any supplemental oxygen or respiratory
             support Pulse oximetry saturation may decrease to < 96% after screening provided that
             the saturation does not decrease by ≥ 4 percentage points

          -  Tracheostomy or current use or requirement of non-invasive ventilatory support
             averaging ≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6
             hours/day on average during the screening period or requiring ventilatory support
             while awake over the 7 days prior to screening or at any point during the screening
             period prior to dosing

          -  Participants with signs of aspiration/inability to tolerate non-thickened- liquids
             based on a formal swallowing test performed as part of screening. Participants with a
             gastrostomy tube who pass the swallowing test will be allowed to enroll in the study

          -  Participants whose weight-for-age is below the third percentile based on World Health
             Organization (WHO) Child Growth Standards

          -  Active viral infection (includes human immunodeficiency virus [HIV] or positive
             serology for hepatitis B or C, or Zika virus)

          -  Serious non-respiratory tract illness requiring systemic treatment and/or
             hospitalization within 2 weeks prior to screening

          -  Upper or lower respiratory infection requiring medical attention, medical
             intervention, or increase in supportive care of any manner within 4 weeks prior to
             screening

          -  Severe non-pulmonary/respiratory tract infection within 4 weeks before administration
             of gene replacement therapy or concomitant illness that creates unnecessary risks for
             gene replacement therapy such as: a. Major renal or hepatic impairment b. Known
             seizure disorder c. Diabetes mellitus d. Idiopathic hypocalcuria e. Symptomatic
             cardiomyopathy

          -  Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or
             their excipients

          -  Concomitant use of any of the following: drugs for treatment of myopathy or
             neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive
             therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive
             therapy within 3 months prior to gene replacement therapy

          -  Anti-adeno-associated virus serotype 9 (AAV9) antibody titer > 1:50 as determined by
             Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential
             participant demonstrate Anti-AAV9 antibody titer > 1:50, he or she may receive
             retesting within 30 days of the screening period and will be eligible to participate
             if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50

          -  Clinically significant abnormal laboratory values (gamma glutamyl- transpeptidase
             [GGT], ALT, and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL,
             hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to
             gene replacement therapy

          -  Participation in recent SMA treatment clinical study (with the exception of
             observational Cohort studies or non-interventional studies) or receipt of an
             investigational or commercial compound, product, or therapy administered with the
             intent to treat SMA at any time prior to screening for this study. Oral β-agonists
             must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol
             specifically prescribed for the purposes of respiratory (bronchodilator) management is
             acceptable and not a contraindication at any time prior to screening for this study

          -  Expectation of major surgical procedures during the study assessment period

          -  Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or
             inability to travel for repeat visits

          -  Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential
             or to refrain from posting confidential study results/observations on social media
             sites

          -  Parent(s)/legal guardian(s) refuses to sign consent form

          -  Gestational age at birth < 35 weeks (245 days)