Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Infants Diagnosed with Spinal Muscular Atrophy and 4 SMN2 Copies through Newborn Screening – Opportunity or Burden?1

“…Based on the mechanism of SMN2splicing modifiers like nusinersen, it is likely that patients with a high number of SMN2 copies profit most from therapy. The NURTURE study demonstrated that children with 3 copies of SMN2 have a better outcome than those with 2 SMN2 copies [30]. This gives hope that treatment in patients with 4 and more SMN2 copies will produce enough SMNprotein to live a normal life.…”

“…With the availability of new treatments for SMA and the technical feasibility of a population based newborn screening program, presymptomatic treat-ment of children with SMA has become a realistic option. As with many genetic disorders, a growing amount of data suggests presymptomatic treatment leading to far better outcomes than post-symptomatic therapy [30] does. However, in contrast to nearly all children with 2 or 3 copies of the SMN2 gene who develop the severe or intermediate phenotypes of SMA type 1 or type 2, the situation in patients with 4 and more copies is less clear.…”

“…Since a number of SMN-dependent and SMNindependent therapies are available [11], the timing of treatment is crucial for a good outcome [12,13] and available data show that presymptomatic treatment is superior to treatment after onset of symptoms [14] experts agree that newborn screening should be established [15,[16][17][18][19][20][21][22][23]. Currently first pilot projects for a genetic NBS in SMA are underway [18,[24][25][26][27][28].…”

“…Currently first pilot projects for a genetic NBS in SMA are underway [18,[24][25][26][27][28]. It has been shown that children with less than 4 SMN2 copies clearly have a benefit from an early presymptomatic treatment [14,24].…”

Limitations of 6‐minute walk test reference values for spinal muscular atrophy

“…The currently approved treatments for SMA provide optimal benefit if administered presymptomatically . As treated infants with SMA grow and develop, new phenotypes in SMA are emerging.…”