Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2
Condition: Spinal Muscular Atrophy
MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy
Intervention: onasemnogene abeparvovec-xioi
Intervention description: A non-replicating recombinant 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: Open-label, single arm
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Maximum age: 42 Days
Healthy volunteers: No
Keywords: gene therapy

Summary:

      To evaluate the safety and efficacy of intravenous onasemnogene abeparvovec-xioi in
      pre-symptomatic patients with SMA and 2 or 3 copies SMN2
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age ≤6 weeks (≤42 days) at time of dose

          -  Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing
             test

          -  Compound muscle action potential (CMAP) ≥2mV at Baseline; centralized review of CMAP
             data will be conducted

          -  Gestational age of 35 to 42 weeks

          -  Parent(s)/legal guardian(s) willing and able to complete the informed consent process
             and comply with study procedures and visit schedule

               -  Patients with pre-symptomatic SMA Type 1 as determined by the following features:

                  a. 2 copies of SMN2 (n ≥14)

               -  Patients with pre-symptomatic SMA Type 2 as determined by the following features:

                    1. 3 copies of SMN2 (n ≥12)

        Exclusion Criteria:

          -  Weight at screening visit <2 kg

          -  Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or
             respiratory support) at the screening visit or for altitudes >1000 m, oxygen
             saturation <92% awake or asleep without any supplemental oxygen or respiratory support
             at the screening visit

          -  Any clinical signs or symptoms at screening or immediately prior to dosing that are,
             in the opinion of the Investigator, strongly suggestive of SMA

          -  Tracheostomy or current prophylactic use or requirement of noninvasive ventilatory
             support at any time and for any duration prior to screening or during the screening
             period

          -  Patients with signs of aspiration/inability to tolerate nonthickened liquids based on
             a formal swallowing test performed as part of screening or patients receiving any
             non-oral feeding method

          -  Clinically significant abnormal laboratory values (gamma-glutamyl transferase [GGT],
             Alanine transaminase [ALT], and aspartate aminotransferase [AST], or total bilirubin >
             2 × the upper limit of normal [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

          -  Treatment with an investigational or commercial product, including nusinersen, given
             for the treatment of SMA. This includes any history of gene therapy, prior antisense
             oligonucleotide treatment, or cell transplantation.

          -  Patients whose weight-for-age is below the third percentile based on World Health
             Organization (WHO) Child Growth Standards

          -  Biological mother with active viral infection as determined by screening laboratory
             samples (includes human immunodeficiency virus [HIV] or positive serology for
             hepatitis B or C)

             • Biological mothers with clinical suspicion of Zika virus that meet Centers for
             Disease Control and Prevention (CDC) Zika virus epidemiological criteria including
             history of residence in or travel to a geographic region with active Zika transmission
             at the time of travel will be tested for Zika virus RNA. Positive results warrant
             confirmed negative Zika virus RNA testing in the patient prior to enrollment.

          -  Serious nonrespiratory 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
             dosing

          -  Severe nonpulmonary/respiratory tract infection within 4 Weeks before administration
             of gene replacement therapy or concomitant illness that, in the opinion of the
             Investigator or Sponsor medical monitor, creates unnecessary risks for gene
             replacement therapy such as:

               -  Major renal or hepatic impairment

               -  Known seizure disorder

               -  Diabetes mellitus

               -  Idiopathic hypocalciuria

               -  Symptomatic cardiomyopathy

          -  Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or
             their excipients

          -  Previous, planned or expected major surgical procedure including scoliosis repair
             surgery/procedure during the study assessment period

          -  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 4 Weeks prior to gene replacement therapy

          -  AntiAAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay
             (ELISA) binding immunoassay

             • Should a potential patient demonstrate AntiAAV9 antibody titer >1:50, he or she may
             receive retesting inside the 30-Day screening period and will be eligible to
             participate if the AntiAAV9 antibody titer upon retesting is ≤1:50, provided the <6
             Week age requirement at the time of dosing is still met

          -  Biological mother involved with the care of the child refuses anti-AAV9 antibody
             testing prior to dosing