Preliminary Safety and Tolerability of a Novel Subcutaneous Intrathecal Catheter System for Repeated Outpatient Dosing of Nusinersen to Children and Adults With Spinal Muscular Atrophy

Abstract

Background: Many patients with spinal muscular atrophy (SMA) who might benefit from intrathecal antisense oligonucleotide (nusinersen) therapy have scoliosis or spinal fusion that precludes safe drug delivery. To circumvent spinal pathology, we designed a novel subcutaneous intrathecal catheter (SIC) system by connecting an intrathecal catheter to an implantable infusion port.

Methods: Device safety and tolerability were tested in 10 SMA patients (age, 5.4 to 30.5 y; 80% with 3 copies of SMN2); each received 3 sequential doses of nusinersen (n=30 doses). Pretreatment disease burden was evaluated using the Revised Hammersmith Scale, dynamometry, National Institutes of Health pegboard, pulmonary function testing, electromyography, and 2 health-related quality of life tools.

Results: Device implantation took ≤2 hours and was well tolerated. All outpatient nusinersen doses were successfully administered via SIC within 20 minutes on the first attempt, and required no regional or systemic analgesia, cognitive distraction, ultrasound guidance, respiratory precautions, or sedation. Cerebrospinal fluid withdrawn from the SIC had normal levels of glucose and protein; cerebrospinal fluid white blood cells were slightly elevated in 2 (22%) of 9 specimens (median, 1 cell/µL; range, 0 to 12 cells/µL) and red blood cells were detected in 7 (78%) specimens (median, 4; range, 0 to 2930 cells/µL).

Discussion: Preliminary observations reveal the SIC to be relatively safe and well tolerated in SMA patients with advanced disease and spinal fusion. The SIC warrants further study and, if proven effective in larger trials of longer duration, could double the number of patients able to receive nusinersen worldwide while reducing administration costs 5- to 10-fold.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1

SIC system. A, The interlocked intrathecal catheter and subcutaneous infusion port used to construct the hybrid nusinersen delivery system. B, Distortions of spinal and pulmonary anatomy, commonly observed among older SMA patients, that inspired design of the SIC system. C, The SIC system in situ, with the infusion port and intrathecal catheter tip marked by a yellow arrow and arrowhead, respectively. D, The SIC allows for safe, low-cost, repeated outpatient nusinersen dosing. SIC indicates subcutaneous intrathecal catheter; SMA, spinal muscular atrophy.

FIGURE 2

Multidomain baseline assessments. Among SMA patients with 3 copies of SMN2 and below 16 years of age (blue circles), we found strong inverse Pearson correlations between age and Revised Hammersmith Functional Motor Scale (A), weight-adjusted SFI (B), and forced vital capacity. This association broke down after age 16 (gray circles). C, MEP as compared with inspiratory pressure (corrected for age and sex) was low for all patients, reflecting weakness of intercostal muscles relative to the diaphragm. Gray shaded area indicates normal z-scores ranging from −2 to +2. D, Baseline mean CMAP, averaged from 4 separate recordings, varied by SMN2 copy number (white triangle, 4 copies; blue circles, 3 copies; purple diamond, 2 copies) but did not vary as a function of age among patients with 3 SMN2 copies. Gray shaded area represents the range of CMAP amplitude observed in ambulatory (as compared with nonambulatory) SMA patients (Lewelt et al23). E, Independent PedsQL responses of participants and their caregivers were generally in good agreement (blue-dashed line represents unity) but there was a tendency for parents to overrate their child’s well-being. F, The overall burden of disease on family functioning (PedsQL family impact module) was strongly associated with patient age. CMAP indicates compound muscle action potential; SMA, spinal muscular atrophy; PedsQL, Pediatric Quality of Life.

FIGURE 3

Administration economics. Projected nusinersen administration costs (not including drug) for 10 participants were plotted over 10 years, assuming a 1-time SIC implantation cost of $22,000 and an annual medical inflation rate of 6%. The SIC (blue line) yields average savings of $24,000 per child per year (2.4 million dollars for the cohort over 10 y) as compared with repeated lumbar puncture (gray shaded area, bounded by upper and lower limits of projected interlaminar administration costs). SIC indicates subcutaneous intrathecal catheter.