Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy

Abstract

Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA).Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1–C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded.Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21–64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable.Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA

“…Therefore, in our study nusinersen increased motor unit function but not number in adults with SMA. In a parallel study in non-ambulatory adults with SMA, we found a similar pattern of increases in CMAP and SMUP and stable MUNE (31). Interestingly, in a recent study that used MscanFit MUNE to estimate motor unit number in children with SMA treated with nusinersen, it was shown that nusinersen induced recovery of smaller motor units (32).…”

Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen

“…This substudy was performed as part of two prospective, open-label studies (clinicaltrials.gov: NCT04139343 and NCT04591678) that were conducted at the Ohio State University Wexner Medical Centre between June 2017 and January 2020. 19 20 Data collection for this substudy was conducted between May 2019 and October 2020. All procedures were approved by the institutional review board, and before enrolment, written informed consent was obtained.…”

Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy

“…Several other motor scales have been used for nonambulatory SMA patients (eg, Hammersmith Functional Rating Scale‐Expanded, Revised Upper Limb Module, Motor Function Measure, etc). These tests can be difficult to perform in debilitated individuals, and all have limitations for detecting subtle but potentially meaningful changes in SMA patients with advanced disease 8,15,40 . This underscores the need for more refined outcome measures in the era of multiple disease‐modifying therapies for SMA 41 …”

“…These tests can be difficult to perform in debilitated individuals, and all have limitations for detecting subtle but potentially meaningful changes in SMA patients with advanced disease. 8,15,40 This underscores the need for more refined outcome measures in the era of multiple disease-modifying therapies for SMA. 41 Plasma pNF-H concentrations and CMAPs, biomarkers used to track SMA disease severity in infants, 26,42,43 were already very low in patients from the older SIC cohort.…”

“…[8][9][10] By late childhood, as many as 80% of SMA patients with two or three copies of SMN2 have spine deformities or instrumentation that complicates lumbar puncture. 11 Investigators have devised a number of methods to administer nusinersen to patients with complex spine anatomy, including the computed tomography (CT)-guided transforaminal approach (TFA), 12,13 translaminar drilling, 14 lateral cervical puncture, 15 and insertion of a subarachnoid catheter with a suboccipital access port. 16 CT-guided TFA has a technical success rate approaching 100%, 17,18 but 4.0% to 14.8% of injections are complicated by an adverse event (AE) and 0.5% to 3.7% of these are serious, including meningitis and subarachnoid hemorrhage.…”