A novel indwelling subcutaneous intrathecal catheter circumvented the complex spine anatomy of patients with spinal muscular atrophy (SMA), a challenge when giving nusinersen via intrathecal injection.
Spine deformities and fusions are common in patients with advanced neuromuscular disease, including spinal muscular atrophy (SMA). In patients with SMA, this can make the intrathecal administration of nusinersen a challenge. A prospective study published in Muscle & Nerve assessed the safety and efficacy of nusinersen administered via an indwelling subcutaneous intrathecal catheter (SIC) and found that the SIC was a reliable outpatient method of delivery.
SMA is caused by mutations or deletions of the SMN1 gene, which produces survival motor neuron (SMN) proteins. SMN2 is also capable of producing SMN, but not enough to compensate for mutated or deleted SMN1. Nusinersen, an antisense oligonucleotide, alters pre-mRNA splicing of the homologous SMN2 gene to increase the SMN output of a patient’s SMN2 copies. This partially compensates for SMN1 loss and improves motor outcomes in patients with SMA.
Nusinersen is typically administered via intrathecal injections for an initial loading phase and every 4 months thereafter. But as many as 80% of SMA patients with 2 or 3 copies of SMN2 develop spinal deformities or fusions that complicate lumbar puncture by late childhood, the study authors noted. Therefore, novel methods of administration are warranted to address this challenge. The efficacy of nusinersen in symptomatic adolescent and adult patients with 2 or 3 copies of SMN2—especially those with complex spine anatomy, which complicates intrathecal dosing—is also less certain compared with its efficacy in infants and young children with any type of SMA.
The prospective study, which was conducted between June 2, 2017, and June 10, 2020, combined an intrathecal catheter and power injectable infusion port, both FDA-approved devices, to create the novel SIC system that would allow the investigators to repeatedly access cerebrospinal fluid (CSF) more easily in patients with complex spine anatomy.
A cohort of 10 pediatric and adult patients with SMA were first treated with the novel SIC in a study focused on implantation procedure and safety during the nusinersen loading phase. The cohort for the current analysis includes 17 patients. Two-thirds of those patients have complex spinal anatomy in the form of significant scoliosis and/or spine fusions.
Researchers aimed to (1) evaluate longer-term safety and tolerability of the SIC in all patients and (2) assess the efficacy of nusinersen in a subgroup of 11 patients with symptomatic type 2 SMA with complex spine anatomy (9 with spine fusion and 2 with scoliosis with a Cobb angle greater than 40º).
Implantation during the loading phase was done under general anesthesia and took 2 hours or less for the initial 10-patient cohort. It also eliminated the need for systemic analgesia, radiological guidance, respiratory precautions, or sedation for subsequent administration.
In the overall cohort, 12 study participants experienced a total of 26 recorded adverse events (AEs). All of the treatment-related AEs were caused by the SIC device, not the drug itself. There were 5 outpatient surgical interventions caused by SIC complications such as wound dehiscence, mechanical malfunction, and CSF leak. Device malfunctions, including 4 intrathecal catheter occlusions and 1 catheter fracture at the point of connection to the injection port, affected 2.5% of outpatient doses. Elevated red blood cells (RBCs) in CSF were seen in half of all samples, but all participants were asymptomatic.
The entire efficacy cohort of 11 patients with symptomatic type 2 SMA reported subjective speech, neck and head control, arm strength, endurance, and hand use improvements. Fifteen percent of the patients in this cohort showed improvement in the nine hole peg test (NHPT), which gauges upper-limb speed and dexterity, in the dominant and nondominant hands (15.9% and 19.0%, respectively). Average grip strength also improved.
All of the patients in this cohort reported 1 or more subjective improvements, including with speech, neck and head control, arm strength, physical endurance, and/or activities like handwriting or using a power wheelchair.
Overall, the SIC allowed for reliable nusinersen administration in the outpatient setting, and patients saw meaningful improvement in upper-limb function. Although the study was small, its findings suggest that the SIC is effective despite carrying malfunction and infection risks that any indwelling device would.
“The SIC device circumvents complex spine anatomy and allows nusinersen to be administered in the outpatient setting without sedation or radiological guidance,” the authors concluded, noting that mechanical failures and infection are risks when using this method. “For SMA patients with advanced disease, these various risks can be balanced against an expectation of small but functionally meaningful improvements of upper limb and hand function.”
Carson V, Young M, Brigatti K, et al. Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy. Muscle Nerve. Published online October 4, 2021. doi:10.1002/mus.27425