Nusinersen May Improve Fatiguability in SMA, but More Research Is Needed

Following treatment with nusinersen (Spinraza), adult patients with spinal muscular atrophy (SMA) type III improved their 6-minute walk test (6MWT) performance; however, nusinersen was generally unsuccessful in improving fatigue measures, according to a study published in Muscle & Nerve.¹

The 6-Minute Walking Test is a common tool for measuring fatiguability in SMA | image credit: Antonioguillem - stock.adobe.com

When researchers talk about fatigue in SMA, they refer to an individual’s subjective perception of the exhaustion or difficulty they experience when carrying out a motor activity. Fatigue has been reported as one of the more disabling symptoms that accompany SMA due to its influence on their ability to perform daily tasks, yet fatigue remains an underestimated component of clinical practice.² Fatiguability, on the other hand, as the current authors elaborate, can be measured objectively over time to track someone’s progress with motor performance.¹

“To date, there is no consensus on which outcome measure should be used to test fatiguability in SMA patients,” the researchers wrote, pointing to the popularity of the 6MWT for evaluating motor performance and fatiguability in patients with SMA. The 6MWT became an increasingly valuable measure in the wake of nusinersen’s approval, which provided benefits to patients’ motor functions, as demonstrated by multiple prior cohort studies. However, the authors continued, these studies have produced conflicting findings on the impact of nusinersen, in part to the variability of measures used to quantify patients’ fatigue. To add to this body of literature, the researchers conducted a study to assess fatigability with the 6MWT prior to and following nusinersen treatment in adult patients with SMA type III.

Patients (n = 48) were included from 18 secondary or tertiary SMA care centers in Italy, and were eligible for participation if they began nusinersen in adulthood, could walk unassisted by another person for the duration of follow-up, and had 6MWT data available at baseline (prior to initiation of treatment) and 6 months afterwards. Moreover, patients were separated into subgroups based on whether they could walk over 300 m (longer walker) or under 300 m (shorter walker), respectively, at baseline.

Data were collected at baseline (T0), as well as the 6-month (T6), 10-month (T10) and 14-month (T14) marks following the beginning of treatment. Patients were evaluated with the 6MWT, Hammersmith Functional Motor Scale—Expanded (HFMSE), and the Revised Upper Limb Module (RULM). Fatiguability was characterized as a decrease in walking distance of 10% or more between minute 1 and 6 of the 6MWT, with the primary outcome measuring fatiguability changes from baseline over the course of 14 months post nusinersen.

No patients lost their ability to walk throughout the follow-up period. A total of 27 patients’ (56.3%) treatment period lasted the entirety of the 14-month period, whereas 8 (16.7%) had treatment for 10 months, and 13 (27%) for 6 months. On average, baseline scores for 6MWT were 306.4, RULM were 35.2, and HFMSE were 49.

The authors noted that RULM scores and 6MWT distances were not found to be associated with one another; however, a correlation was observed between HFMSE scores and 6MWT distances at baseline, T6, and T10 (P = .02), and even more so at T14 (P = .01). Distances in the 6MWT also significantly increased from baseline to T6 (306.4 m vs 321.5 m; P < .05), T10 (315.7 m; P < .05), and T14 (333.9 m; P < .05). Overall, 85% of patients at T14 (n = 23) notably remained stable or improved in these measures. No noteworthy differences were observed in 6MWT between longer or shorter walkers.

Comparing the differences in walked meters at minute 1 vs minute 6 revealed significant declines, however, indicating degrees of fatiguability throughout the course of the study (P < .05). These measures of fatiguability were not significantly different at T14 compared with baseline.

While their results suggest the possible benefits of nusinersen on the walking ability of patients with SMA, the authors conclude, “Data from literature and our study still fail to define whether nusinersen may be effective in reducing fatiguability in walker SMA patients. Persistence of fatiguability in our SMA patients treated with nusinersen is probably related to multiple factors affecting the [neuromuscular junction] function and involving other pathological mechanisms, such as muscle fiber metabolism and mitochondrial function.” Therefore, conducting further studies about these associations remains imperative.

References

1. Govoni A, Ricci G, Bonanno S, et al. Six-minute walk test as outcome measure of fatigability in adults with spinal muscular atrophy treated with nusinersen. Muscle Nerve. Published online August 2, 2024. doi:10.1002/mus.28225

2. Mongiovi P, Dilek N, Garland C, et al. Patient reported impact of symptoms in spinal muscular atrophy (PRISM-SMA). Neurology. 2018;91(13):e1206-e1214. doi:10.1212/WNL.0000000000006241