Severity of SMA Muscle Impairment Prior to Treatment May Have Implications for Nusinersen Efficacy

A new study has found that the severity of muscle impairment and scoliosis before treatment may help predict response to nusinersen for certain patients with spinal muscular atrophy (SMA).

The retrospective study of patients with SMA type 2 and 3, published in Brain and Development, found that the severity of fatty infiltration and muscle atrophy at the start of treatment had implications for changes in motor function after treatment with nusinersen. The findings, which the researchers say highlight the importance of early diagnosis and initiation of treatment, come amid efforts to determine efficacy trends among the several treatment options for the condition.

“Recent development in the 5q SMA treatment has brought the approval of not only nusinersen but also onasemnogene abeparvovec and risdiplam. Under the presence of multiple treatment choices, many efforts have been made to understand the possible patterns of drug efficacy,” wrote the researchers.

“Further, although data are becoming available for the effect of nusinersen, there still remain questions over the relevant factors that discriminate responders and the non-responders of the treatment, which needs to be addressed.”

The researchers analyzed data from 14 patients who had received treatment for at least 15 months and had available baseline data, finding that changes in Hammersmith Functional Motor Scale-Expanded (HFMSE) after treatment were correlated with the MRI scores at baseline. The researchers noted that MRI was limited to thigh and pelvic muscles and motor function evaluation was limited to HMFSE, a limitation of the study.

They also found that Cobb angle (B = –0.093 [95% CI, –0.171 to –0.014]; P = .024) and age (B = –0.534 [95% CI, –1.065 to –0.03]; P = .049) at baseline had significant correlations with changes in HFMSE, suggesting that the 2 factors give signal to nusinersen efficacy.

Overall, the mean change in HFMSE from baseline to 15 months was 4.4, with half of the patients achieving a minimally clinically important difference (MCID)—characterized by a change of at least 3 points from baseline. These patients had less severe scoliosis at baseline but were also younger and had lower muscle MRI scores, though the differences for the latter 2 findings were statistically nonsignificant. There were no differences in SMN2 gene copy number between patients who achieved MCID and those who did not.

“The magnitude of muscle impairment potentially affects the outcome in gross motor function, and T1-weighted muscle MRI images can be useful to assess muscle involvement,” wrote the researchers, reflecting on their findings.

“In addition, scoliosis may also affect the outcome. These insights may help both patients and clinicians to understand what to expect from the drug in each case. A larger study may confirm the more accurate prediction model for outcome after nusinersen treatment, and in that case, muscle MRI score, Cobb angle, and age are the candidate variables to be explored.”

The researchers noted that the inclusion of younger patients may account for the favorable outcomes seen in their study. There were 5 patients included in the study aged younger than 5 and 7 years—a group of patients who if untreated can experience spontaneous improvement in HFMSE. Among these patients, just 1 had a score of less than 3.

Reference

Shimizu-Motohasi Y, Chiba E, Mizuno K, et al. Muscle impairment in MRI affect variability in treatment response to nusinersen in patients with spinal muscular atrophy type 2 and 3: a retrospective cohort study. Brain Dev. Published online November 29, 2022. doi:10.1016/j.braindev.2022.11.002