A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)

Key Inclusion Criteria:

• Parent or guardian has signed informed consent and, if indicated per participant's ageand institutional guidelines, participant has signed informed assent
• Be medically diagnosed with Spinal Muscular Atrophy (SMA)
• Have onset of clinical signs and symptoms consistent with SMA at greater than 6 monthsof age
• Be able to sit independently, but has never had the ability to walk independently
• Have Motor Function Score (Hammersmith Functional Motor Scale - Expanded) greater thanor equal to 10 and less than or equal to 54 at Screening
• Be able to complete all study procedures, measurements and visits and parent orguardian and subject has adequately supportive psychosocial circumstances, in theopinion of the Investigator
• Have an estimated life expectancy of greater than 2 years from Screening, in theopinion of the Investigator
• Meet age-appropriate institutional criteria for use of anesthesia and sedation, if useis planned for study procedures
• For subjects who have reached reproductive maturity, satisfy study contraceptiverequirements

Key Exclusion Criteria:

• Respiratory insufficiency, defined by the medical necessity for invasive ornon-invasive ventilation for greater than 6 hours during a 24 hour period, atScreening
• Medical necessity for a gastric feeding tube, where the majority of feeds are given bythis route, as assessed by the Site Investigator
• Severe contractures or severe scoliosis evident on X-ray examination at Screening
• Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event,or nutritional support within 2 months of Screening or planned during the duration ofthe study
• Presence of an untreated or inadequately treated active infection requiring systemicantiviral or antimicrobial therapy at any time during the screening period
• History of brain or spinal cord disease, including tumors, or abnormalities bymagnetic resonance imaging (MRI) or computed tomography (CT) that would interfere withthe LP procedures or cerebrospinal fluid (CSF) circulation
• Presence of an implanted shunt for the drainage of CSF or an implanted central nervoussystem (CNS) catheter
• History of bacterial meningitis
• Dosing with IONIS-SMN Rx in any previous clinical study
• Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impactsthe subject's ability to perform any of the outcome measure testing required in theprotocol and from which the subject has not fully recovered or achieved a stablebaseline
• Clinically significant abnormalities in hematology or clinical chemistry parameters orelectrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visitthat would render the subject unsuitable for inclusion
• Treatment with another investigational drug (e.g., oral albuterol or salbutamol,riluzole, carnitine, creatine, sodium phenylbutyrate, et.c), biological agent, ordevice within 1-month of Screening or 5 half-lives of study agent, whichever islonger. Treatment with valproate or hydroxyurea within 3-months of Screening. Anyhistory of gene therapy, antisense oligonucleotide therapy, or cell transplantation.
• Ongoing medical condition that according to the Site Investigator would interfere withthe conduct and assessments of the study. Examples are medical disability (e.g.,wasting or cachexia, severe anemia, etc.) that would interfere with the assessment ofsafety or would compromise the ability of the subject to undergo study procedures. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.