A Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

The study is an open-label, single-arm, multicenter clinical study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants aged from birth to 6 weeks who have been genetically diagnosed with SMA but are not yet presenting with symptoms. There will be a screening, treatment, open-label extension (OLE) and a follow-up. All participants will receive risdiplam orally once daily for 2 years followed by an OLE phase of at least 3 years and a follow-up (if applicable), for a total treatment duration of at least 5 years for each participant enrolled.

Inclusion criteria

• Males and females aged from birth (1 day) to 6 weeks (42 days) of age at the time of first dose (Day 1); a minimum age of 7 days at first dose is required for the first infant to be enrolled
• Gestational age of 37-42 weeks for singleton births; gestational age of 34-42 weeks for twins
• Body weight >= 3rd percentile for age, using appropriate country-specific guidelines
• Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene
• Absence of clinical signs or symptoms at screening (Day -42 to Day -2) or at baseline (Day -1) that are, in the opinion of the investigator, strongly suggestive of SMA
• Receiving adequate nutrition and hydration at the time of screening, in the opinion of the investigator
• Adequately recovered from any acute illness at baseline and considered well enough to participate in the study, in the opinion of the investigator
• Able and expected to be able to safely travel to the study site for the entire duration of the study and in accordance to the frequency of required study visits, in the opinion of the investigator
• Able to complete all study procedures, measurements, and visits, and the parent (or caregiver), in the opinion of the investigator, has adequately supportive psychosocial circumstances
• Parent (or caregiver) is willing to consider nasogastric, naso-jejunal, or gastrostomy tube placement during the study to maintain safe hydration, nutrition, and treatment delivery, if recommended by the investigator
• Parent (or caregiver) is willing to consider the use of non-invasive ventilation during the study, if recommended by the investigator

Exclusion criteria

• Concomitant or previous participation in any investigational drug or device study at any time
• Concomitant or previous administration of an SMN2-targeting antisense oligonucleotide, SMN2-splicing modifier, or gene therapy either in a clinical study or as part of medical care
• Presence of significant concurrent syndromes or diseases
• In the opinion of the investigator, inadequate venous or capillary blood access for the study procedures
• Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation
• Awake hypoxemia (SaO2 < 95%) with or without ventilator support
• Multiple or fixed contractures and/or hip subluxation or dislocation at birth
• Systolic blood pressure or diastolic blood pressure or heart rate considered to be clinically significant by the investigator
• Presence of clinically relevant ECG abnormalities before study drug administration; corrected QT interval using Bazett's method > 460 ms; personal or family history (first degree relatives) of congenital long QT syndrome indicating a safety risk for patients as determined by the investigator. First-degree atrioventricular block or isolated right bundle branch block are allowed
• The infant (and the mother, if breastfeeding the infant) taking any inhibitor of CYP3A4 taken within 2 weeks, any inducer of CYP3A4 taken within 4 weeks, any OCT 2 and MATE substrates within 2 weeks and known FMO1 or FMO3 inhibitors or substrates
• Clinically significant abnormalities in laboratory test results
• Ascertained or presumptive hypersensitivity to risdiplam or to the constituents of its formulation
• Treatment with oral salbutamol or another beta-2 adrenergic agonist taken orally for SMA is not allowed. Use of inhaled beta-2 adrenergic agonists is allowed
• Infants exposed to drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled. Anticipated need for drugs known to cause retinal toxicity during the study.
• Diagnosis of ophthalmic diseases