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Infants (210 days or younger) with SMA and two SMN2 copies 2014–2016 Percentage of motor milestone responders and time to death or permanent ventilation Overall survival and probability of event-free survival were significantly higher in the treated group. The treated group had a lower risk of death (63%) than the sham-procedure control group. Nusinersen-treated infants (53%) achieved more HINE motor milestones (i.e., 22% achieved head control, 10% were able to roll, 8% were able to sit without assistance, and 1% were able to stand). Control group infants did not gain any milestones (53). SMA types II and III CHERISH (NCT02292537) Phase 3, randomized, sham-procedure controlled Assess the clinical efficacy and safety of intrathecaladministered nusinersen SMA patients aged 2–12 years with onset of clinical symptoms after six months of age 2014–2017 Change from baseline in HFMSE score at month 15 of treatment Interim evaluation: Nusinersen treatment increased HFMSE score by a mean of 4 points, whereas the sham-procedure control group had a decline of 1.9 points. Final trial analyses: Children treated with nusinersen showed definite motor improvement and higher survival likelihood than the control group (116). CS12 (NCT02052791), including CS2 (NCT01703988) and CS10 (NCT01780246) Phase 1, open label, single group assignment Assess the safety and tolerability of nusinersen in patients from the CS2 and CS10 studies CS12: children, adults, and older adults with SMA CS2 and CS10: SMA patients aged 2–15 years with an estimated life expectancy of more than two years from screening 2014–2017 Adverse events and/or serious adverse events based on neurological and physical examination, laboratory and cerebrospinal fluid laboratory assessment, and weight and ECG abnormalities Nusinersen treatment over approximately three years led to motor function improvements and disease stabilization not observed in historical SMA cohorts. Nusinersen showed long-term benefit in later-onset (type III) SMA. Abbreviations: ECG, electrocardiogram; HFMSE, Hammersmith Functional Motor Scale–Expanded (≥3 points indicates an improvement in at least two motor skills); HINE, Hammersmith Infant Neurological Examination; SMA, spinal muscular atrophy. aEstimated end of ongoing trial. www.annualreviews.org • 25 Years of Spinal Muscular Atrophy Research 247 Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. By contrast, the second Hoffmann–La Roche molecule, RG7916 (risdiplam), managed to reach phase 2 clinical studies and Priority Medicines (PRIME) designation by the European Medicines Agency after the successful completion of the phase 1 study (NCT02633709). Currently, risdiplam is under evaluation in three ongoing clinical trials in Europe: one in 1–7-month-old infants with severe SMA (FIREFISH, NCT02913482), one in 2–25-year-old patients with SMA type II or III (SUNFISH, NCT02908685), and one in children and adults with SMA type II or III who had already received daily doses of risdiplam for two years ( JEWELFISH, NCT03032172). Interim analyses of the FIREFISH study reported improved motor function and event-free survival in infants with SMA type I compared with the infants from historical cohorts. In addition, interim analyses of the SUNFISH study reported that risdiplam has led to a sustained increase of SMN with no drug-related safety issues leading to study withdrawal (119; E. Mercuri, unpublished results presented at the 23rd International SMA Researcher Meeting, Anaheim, California, USA, June 27–30, 2019). Another small molecule promoting exon 7 inclusion in SMN2 is LMI070 (branaplam), developed by Novartis Pharmaceuticals. Preclinical analyses of branaplam in severe SMA mice showed not only an increase in SMN levels but also an extended life span in orally treated animals (131). Phase 1–2 clinical trials of branaplam administration in SMA type I patients (NCT02268552) were discontinued after more than a year due to evidence of toxicity to blood
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