Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study

Abstract

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

Patients’ Perceptions of Nusinersen Effects According to Their Responder Status

“…HFMSE was the most used scale, and trunk strength and upper limb function were captured by several items (e.g., sitting items without support, rolling items, four-point kneeling items) in the total score. Patients across the three groups reporting difficulties at the baseline perceived their upper limb function to be improved, which aligns with existing findings highlighted by patients treated with nusinersen [ 34 , 35 ]. Patients assigned to the NR group and who experienced significant improvements in upper limb function could possibly have been identified as responders by the RULM, which is more sensitive to positive upper limb function changes than HFMSE.…”

Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA)

“…Published natural history studies in untreated patients with types 2 and 3 SMA (ambulant and non-ambulant) have reported decline in RULM total score over 12 months (– 0.4 points in patients aged 2.7–49.7 years) [ 25 ] and 24 months (– 0.79 points in patients aged 5–56 years) [ 26 ] and HFMSE total score over 12 months (– 0.54 points in children and adults aged ≥ 2 years with a diagnosis before 19 years of age) [ 24 ], and significant decline over 24 months in MFM32 total score (– 2.08 points in patients aged 2–30 years) [ 21 ]. Although a 2-point (RULM [ 27 ]) or 3-point (HFMSE [ 27 ], MFM32 [ 28 ]) change in these functional motor scales has been highlighted as a clinically meaningful change, stabilization in motor function is an important goal identified by patients with types 2 and 3 SMA [ 29 , 30 ] and is, thus, considered a clinically meaningful outcome in this population.…”

Study on the efficacy, safety, and biomarkers of nusinersen in type II and III spinal muscular atrophy in children

“…A study showed that the RULM scores of SMA in children with types II and III continue to improve, especially in older and more severe phenotypes, where improvement in HFMSE scores may be limited due to scoliosis or contracture. The RULM score seems to be more inclined to monitor changes in motor function than in patients who cannot walk alone ( 19 ). There was no significant improvement in the CHOP score in our research results, which may be related to our shorter monitoring time and smaller number of cases.…”