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Results from the Phase 1 and 2 Studies for Later-Onset SMA Type 2 and 3

Results from the Phase 1 and 2 Studies for Later-Onset SMA Type 2 and 3

Page last checked: 14th December 2022
Last updated: 19th May 2019

 

The results of a follow-up study of the longer-term effects of nusinersen treatment for patients with later-onset SMA were published in 2019¹. This was of children age 2 – 15 years who had initially received nusinersen as part of the first, early phase 1 and 2 studies into nusinersen. Though none of these children were included in the CHERISH (Type 2) phase 3 trial (results above) and ENDEAR (Type 1) trial that resulted in nusinersen being approved for SMA, these phase 1 and 2 studies were vital to the development of these two trials.

The trial and follow-up study were conducted to assess how the motor function of patients treated with nusinersen changed over time compared to measures from a different study that followed up untreated children with SMA (natural history study). Motor function was assessed using the Hammersmith Functional Motor Scale expanded (HFMSE), the 6-minute walk test (how far you can walk in six minutes on the flat), and the Upper Limb Module (which assesses only the function of the arms):

This started in October 2012, there were 28 children:

  • 11 with SMA Type 2
  • 17 with SMA Type 3

Of the children with SMA Type 3:

  • 4 could no longer walk unaided
  • 13 were still able to walk unaided.

All participants received three nusinersen injections into the spine (intrathecal) – at days 1, 29 and 85. As safety was the primary concern in this early testing of nusinersen, the medication was given in different dosages to ensure it was safe, before all participants in Phase 2 were given the highest dose (12mg) for each injection.

Of these original 28 children, 24 went on to have all doses in the longer follow-up part of the study, where participants received treatment after 1 year (from the beginning of the trial), then at six monthly intervals – 4 doses in total on days 1, 169, 351 and 533. The date of the last child’s last treatment was January 24th 2017, and participants were followed up after this.

The main findings from the follow-up study were:

  • HFSME Results

An increase of 3 points or more from the time of an initial assessment in the HFSME is considered clinically significant for Type 2 and Type 3, no matter what the timeframe is for this increase.

    • 9 out of 11 children with SMA Type 2 showed a clinically significant improvement as they had an increase of 3 or more points from their initial assessment in the HFMSE. Overall, the average improvement for these children was 10.8 points which is clinically significant
    • 4 out of the 11 children with Type 3 showed a clinically significant improvement as they had an increase of 3 or more points from their initial assessment in the HFMSE. This included one child who was non ambulant. Overall, the average improvement for these children was 1.8 points which is not regarded as clinically significant.
  • Six-minute walk test (6MWT) Results
    • Infants with SMA Type 2 are not expected to walk. One infant with SMA Type 2 age 2.1 years at first dose, gained the ability to walk. They first completed the 6MWT at the day 650 visit (total distance walked 25.5 metres) and demonstrated continuous improvements over time; by day 1,150 visit, their 6MWT was 180 metres.
    • Children with SMA Type 3 showed clinically meaningful progressive improvements from their baseline in the 6MWT with an average improvement in walking distance of 92 metres by day 1,150.
    • 2 of the 4 children who were previously able to walk but had lost that ability before the baseline assessment regained the ability to walk independently during the course of the studies. In addition, 6 of the 12 children (50%) assessed at the day 253 visit demonstrated clinically meaningful improvements in 6MWT distance (previously defined as ≥ (greater or equal to) 30-metre increase from their baseline) and 8 of 8 (100%) demonstrated clinically meaningful improvements by day 1,050.
  • Upper Limb Module Results
    • The children with SMA Type 2 were seen to progressively improve in their upper limb scores; all those with SMA Type 3 achieving the maximum score by the end of the study.

The findings of this study suggest that in treatment of SMA Types 2 and 3 with nusinersen, there may be long-term (2-3 years) positive effects on muscle function.

1. Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, Xia S, Bennett CF, Bishop KM, Shefner JM, Green AM, Sun P, Bhan I, Gheuens S, Schneider E, Farwell W, De Vivo DC; ISIS-396443-CS2/ISIS-396443-CS12 Study Groups (2019) Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies. Neurology 92: e2492-e2506.