AVXS-101 and nusinersen for spinal muscular atrophy type 1

For spinal muscular atrophy (SMA), nusinersen is currently the only registered therapy. Another very promising therapy in late-stage development is onasemnogene abeparvovec (AVXS-101) gene-replacement therapy.

AVXS-101 for non-ambulatory patients with SMA was feasible, well tolerated, and might improve motor functions, as concluded from interim data analysis of the phase 1/2a STRONG study. In this open-label study, SMA patients of ≥6 to <60 months of age who could not stand or walk, received one of 3 doses intrathecal AVXS-101 (dose A: 6.0x10¹³; B: 1.2x10¹⁴; C: 2.4x1014 vector genomes [vg]). As of 24 March 2019, 31 patients from 11 sites were enrolled. All participants experienced treatment-emergent adverse events (AEs) but none were fatal. In 4 patients, 7 serious treatment-emergent AEs occurred, which were all resolved. Patients aged ≥24 to <60 months showed rapid improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE). Half of the patients had at least a 3-point increase from baseline 1 month after treatment. Patients aged ≥6 to <24 and ≥24 to <60 months averaged a 4.2-point increase from baseline HFMSE score at last follow-up. Ten patients achieved 22 additional motor milestones.

In a post-hoc analysis of two trials, AVXS-101 was compared to nusinersen in the treatment of SMA type 1. The results showed that AVXS-101 led to improved survival and motor function, lower use of pulmonary support, as well as decreased hospitalisation and associated direct medical costs. The analysed trials were CL-101 (cohort 2, n=12) and ENDEAR (n=80). In CL-101, patients were treated with AVXS-101 at a dose of 2.0x10¹⁴ vg/kg; in ENDEAR, patients were treated with nusinersen [1]. In nusinersen-treated patients, 66% were alive without permanent ventilation, in AVXS-101-treated patients this occurred in 100%. In the nusinersen cohort, 19% required permanent assisted ventilation, in the AVXS-101 cohort 0%. In nusinersen-treated patients, 8% sat independently and 1% stood; in AVXS-101-treated patients 92% sat unassisted, 17% stood with assistance, and 17% walked independently. The mean unadjusted annualised rate of hospitalisations was 4.5 and 2.1 for nusinersen- and AVXS-101-treated patients, respectively.

In a case series (CS2/CS12), 5 teenagers who were treated with nusinersen demonstrated stable or improved outcomes in terms of motor function and health-related quality of life measures [2]. The participants (SMA type 2, n=1; type 3, n=4) were 14 or 15 years at treatment initiation in CS2 (phase 1b/2a). They received intrathecal nusinersen 12 mg in the open-label extension CS12. At the last visit (day 715) they were 17 or 19 years old and had transitioned to the long-term extension SHINE study. At CS2 baseline, 3 participants were ambulatory. The participants with SMA type 2 achieved improvement on the HFMSE to CS12 day 715. In the other 4 participants, HFMSE scores remained stable or improved slightly. 6-minute walking test distance increased from CS2 baseline to day 715 in 2 participants; another walked independently for short distances without support in CS2, and walked unaided during CS12 visits (23–74 m).

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   1. Arjunji R, et al. EAN 2019, EPR1049.
   2. Deconinck N, et al. EAN 2019, EPR1055.

Posted on 27 August, 201918 March, 2021