Single-Dose Gene Replacement Therapy Using for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies
Condition: Spinal Muscular Atrophy Type I
MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Spinal Muscular Atrophies of Childhood; Atrophy
Intervention: Onasemnogene Abeparvovec-xioi
Intervention description: Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the human survival motor neuron (SMN) gene under the control of the cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB). Onasemnogene abeparvovec-xioi will be administered as a one-time intravenous infusion over approximately 60 minutes. Dosage will be determined by the participants weight.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 0 Days
Maximum age: 6 Months
Healthy volunteers: No
Keywords: Spinal Muscular Atrophy; SMN2; Onasemnogene Abeparvovec-xioi; Gene replacement therapy

Summary:

      This is a Phase 3, open-label, single-arm, single-dose, trial of onasemnogene
      abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy
      (SMA) Type 1 and who are genetically defined by a biallelic pathogenic mutation of the
      survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene
      (SMN2). The primary objective of the study is to evaluate the efficacy of onasemnogene
      abeparvovec-xioi by assessing the proportion of symptomatic SMA Type 1 participants who
      achieve the ability to sit unaided for at least 10 seconds up to and including the 18 months
      of age trial visit. At least 6 participants aged < 6 months (< 180 days) at the time of gene
      replacement therapy (Day 1) will be enrolled.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants with SMA Type 1 as determined by diagnosis of SMA based on gene mutation
             analysis with biallelic SMN1 mutations (deletion or point mutations) and one or 2
             copies of SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G>C)]

          -  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 as per local health authorities.

          -  Parent(s)/legal guardian(s) willing and able to complete the informed consent process
             and comply with trial procedures and visit schedule

        Exclusion Criteria:

          -  Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of
             age

          -  Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse
             oximetry < 95% saturation at screening:

               1. Pulse oximetry saturation must not decrease ≥ 4 percentage points between
                  screening and dosing with confirmatory oximetry reading

               2. Participants may be put on non-invasive ventilatory support for less than 12
                  hours per day at the discretion of their physician or trial staff

          -  Use or requirement of non-invasive ventilatory support for greater than or equal to 12
             hours daily in the two weeks prior to dosing

          -  Participant with signs of aspiration based on a swallowing test or whose
             weight-for-age falls below the 3rd percentile based on World Health Organization (WHO)
             Child Growth Standards and unwilling to use an alternative method to oral feeding

          -  Active viral infection (includes human immunodeficiency virus [HIV] or positive
             serology for hepatitis B, C, or E, or known Zika virus infection)

          -  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 (eg, pyelonephritis, or meningitis)
             within 4 weeks before administration of gene replacement therapy or concomitant
             illness that, in the opinion of the Principal Investigator, creates unnecessary risks
             for gene replacement such as:

               1. Major renal or hepatic impairment

               2. Known seizure disorder

               3. Diabetes mellitus

               4. Idiopathic hypocalcuria

               5. Symptomatic cardiomyopathy

          -  Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or
             their excipients, or human, animal biological raw materials (human transferrin, human
             insulin, trypsin derived from porcine spleen, bovine derived protein (FBS, bovine
             milk-derived Benzonase, casamino acid, bovine pancreas), HEK 293 cells, Cosmic Calf
             Serum, HyQtase) used in manufacturing of onasemnogene abeparvovec-xioi product

          -  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, or immunosuppressive
             therapy within 3 months prior to gene replacement therapy (e.g., corticosteroids,
             cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin,
             rituximab)

          -  Anti-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, AST, total bilirubin > 2x the ULN, 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. Patients with an elevated bilirubin level that is unequivocally
             the result of neonatal jaundice shall not be excluded

          -  Participation in recent SMA treatment clinical trial (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 (e.g., nusinersen, valproic acid) at any time prior to screening
             for this trial. Oral beta-agonists must be discontinued at least 30 days prior to
             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 trial

          -  Expectation of major surgical procedures during the trial assessment period (e.g.,
             spinal surgery or tracheostomy)

          -  Parent(s)/legal guardian(s) unable or unwilling to comply with trial procedures or
             inability to travel for repeat visits

          -  Parent(s)/legal guardian(s) unwilling to keep trial results/observations confidential
             or to refrain from posting confidential trial results/observations on social media
             sites

          -  Parent(s)/legal guardian(s) refuses to sign consent form

          -  Participants < 35 weeks gestational age at time of birth