Differences in baseline characteristics and eligible criteria in presymptomatic infants with spinal muscular atrophy led to differential results on motor and nonmotor clinical outcomes.
Results from the ongoing phase 2 NURTURE trial (NCT02386553) investigating nusinersen (Spinraza; Biogen) in presymptomatic infants with spinal muscular atrophy (SMA) showed that both motor and nonmotor clinical outcomes are impacted by small differences in inclusion and exclusion criteria as well as baseline characteristics.1 Thus, these findings suggest that it is critical to consider those characteristics in data interpretation in trials assessing presymptomatic individuals.
A subgroup of 8 patients with 2 SMN2 copies who did not have compound muscle action potential (CMAP) values and were areflexic at baseline were assessed and compared with 15 children with 2 SMN2 copies who had similar age at first nusinsersen dose and similar baseline Hammersmith Infant Neurological Examination Section 2 scores. Considered subgroup 1, this cohort also had higher baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores (median, 45.0 [range, 25-60] vs 54.5 [range, 35-60]).
Findings showed that a higher proportion of patients in subgroup 1 achieved each World Health Organization (WHO) motor milestone in normal timeframe compared with all NURTURE patients with 2 SMN2 copies: sitting without support (88% vs 73%), standing with assistance (100% vs 60%), hands and knees crawling (75% vs 40%), walking with assistance (75% vs 40%), standing alone (50% vs 27%), and walking alone (75% vs 40%).
The results were presented as a late breaking poster at the annual at Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held in Dallas, Texas, March 19-22, 2023, by lead author Thomas O. Crawford, MD, codirector, Muscular Dystrophy Association Clinic, and professor of neurology, Johns Hopkins Medical Institute. In terms of between-group differences, no participant in subgroup 1 required respiratory intervention or gastrostomy tube placement although 1 developed SMA symptoms by age 24 months.
A sensitivity analysis of subgroup 1 plus 3 patients with 2 SMN2 copies with missing values (baseline tendon reflex, n=2; or peroneal CMAP data, n=1) showed that the proportion of infants who achieved WHO motor milestones within normal timeframes was generally higher than all NURTURE children with 2 SMN2 copies and lower than subgroup 1.
Greenlit in December 2016, at the time nusinersen became the first FDA-approved therapy to treat SMA types 1, 2, and 3. Since the approval, several trials have been initiated to study safety and efficacy of the treatment such as the NURTURE trial.
In March 2022, interim results from NURTURE suggested that the treatment is safe and beneficial over long-term use for presymptomatic infants with SMA and 2 or 3 copies of SMN2.2 The data were presented by Crawford at the 2022 MDA Clinical & Scientific Conference, March 13-16, in Nashville, Tennessee. Data were assessed with a mean of 4.9 years (range, 3.9-5.7) of follow-up from the study, with the data cut off of Feb 15, 2021. A total of 25 infants were enrolled in the study (2 SMN2 copies: n = 15; 3 SMN2 copies, n = 10), and at the data cut off all infants were alive, and none required permanent ventilation.
All told, 4 infants—all from the 2 SMN2 copy cohort—required respiratory intervention for ≥6 hours/day continuously for ≥7 days, though investigators noted that all cases were initiated during an acute reversible illness. Every infant in the study cohort achieved the WHO motor milestone of sitting without support, while 96% (n = 24) were able to walk with assistance and 92% (n = 23) were able to walk unassisted.
In June 2020, findings from open-label portion of NURTUREshowed that in infants with genetically diagnosed SMA, treatment with nusinersen resulted in unprecedented survival rates for up to 4.8 years, with patients continuing to maintain and achieve gains in motor function compared to SMA natural history.3 All study participants who were previously able to walk with assistance (92%) and walk independently (88%) maintained that ability over the 11 months since the last data cut.
A year prior, in July 2019, the study revealed that nusinersen had prolonged efficacy and safety in presymptomatic pediatric patients with SMA after 45 months.4 Presented at the Cure SMA Annual SMA Conference, June 28-July 1, in Anaheim, California, and the 5th Congress of the European Academy of Neurology, June 29-July 2, in Oslo, Norway, the findings ultimately showed that 100% of the infants treated with nusinersen were able to sit without support while 88% were able to walk independently.
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