For spinal muscular atrophy (SMA) patients with spinal deformities, administration of Spinraza (nusinersen) by a novel subcutaneous intrathecal catheter system improved upper limb function, a small study reports.
This delivery technique, however, increased the risk of mechanical malfunction and infections, the researchers noted.
The study, “Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy,” was published in the journal Muscle & Nerve.
Spinraza is a disease-modifying therapy approved to treat SMA; it is designed to increase the levels of SMN, a protein essential for the health of motor nerve cells. People with SMA lack SMN protein, leading to progressive muscle weakness and atrophy (shrinkage), breathing problems, and skeletal complications.
Spinraza is administered by intrathecal injection — directly into the cerebrospinal fluid (CSF) surrounding the spinal cord. Treatment takes place in hospitals or clinics by staff trained in performing the procedure. However, in advanced cases, skeletal complications and spinal deformities can complicate Spinraza administration.
Clinicians based at the Clinic for Special Children in Pennsylvania recently developed a subcutaneous intrathecal catheter (SIC) system that combines an intrathecal catheter tube with an implanted infusion port for SMA patients with complex spine anatomy.
For the first 10 patients, the surgical implantation of SIC took no more than two hours, allowed Spinraza to be administered in the outpatient setting, and eliminated the need for pain medications, breathing precautions, or sedation.
SIC now has been used in a total of 17 pediatric and adult SMA patients, with two-thirds having significant scoliosis (curvature of the spine) and/or fusion surgery to correct spinal deformities.
The goal of this study, partially funded by a grant from the therapy’s manufacturer Biogen, was to evaluate the safety and tolerability of SIC and assess the effectiveness of Spinraza in a subgroup of symptomatic SMA patients with complex spine anatomy due to long-term muscle weakness.
The 17 participants began Spinraza therapy from about 3 to 32 years old and received nine to 12 doses by SIC. Of these, one was diagnosed with SMA type 1 (infantile-onset SMA), 14 participants had SMA type 2 (intermediate SMA), and the remaining two had SMA type 3 (juvenile SMA).
The team recorded 26 adverse events (AEs) among 12 participants who received a total of 203 doses of Spinraza. The SIC device (not Spinraza) caused all 14 AEs that were related to treatment.
Mechanical malfunction accounted for five AEs, one wound failed to heal correctly, and two AEs were a CSF leak, leading to five outpatient surgical revisions among four participants. One patient experienced a headache and low-grade fever after 12 doses, and the CSF reservoir became infected with Staphylococcus epidermidis resulting in its permanent removal.
From an analysis of 138 CSF samples withdrawn for testing (average eight per patient), half had elevated red blood cells, but patients did not experience symptoms.
A subset of 11 patients was included in the efficacy analysis, in which Spinraza began at a mean age of 18 and who received a mean of 11 doses over about two to three years.
The mean pre-treatment Revised Hammersmith Scale (RHS) score for motor function was 7.6. The maximum RHS score is 69, with higher scores reflecting better motor function.
Of these 11 patients, nine had spinal fusion, and two had scoliosis.
The mean performance of the Nine Hole Peg Test to measure manual dexterity increased in the dominant hand by 15.9% and in the non-dominant hand by 19%. The mean grip strength improved by 44.9%, but strength in other muscle groups was unaffected. There was no change in RHS or lung function.
All of these patients reported one or more subjective improvements in speech (25%), head and neck control (42%), arm strength (42%), physical endurance (58%), and the use of hands for handwriting, typing, or maneuvering a power wheelchair (75%).
Pediatric quality of life (PedsQLTM) scores comparing physical to emotional disability did not change in response to therapy, except for the National Institute of Health (NIH) Toolbox Emotion Domain, with a small but significant increase of 8%.
Before treatment, the Sum Total Force, a combined measure of muscle strength by dynamometry in various body parts, showed a strong correlation with the compound muscle action potential (CMAP), which assesses electrical impulses in muscle function. Sum Total Force also moderately correlated with phosphorylated neurofilament heavy chain (pNF-H) in the CSF, a marker for motor neuron degeneration. However, these parameters did not change with Spinraza treatment.
The levels of pNF-H in blood samples of SMA patients were similar to values collected from a control group of 55 healthy family members. They did not correlate with CSF pNF-H or any other measurement of motor function.
“For SMA patients with complex spine anatomy, the SIC allows for reliable outpatient administration of [Spinraza] that results in meaningful improvements of upper limb function, but introduces risks of technical malfunction and [treatment-related] infection,” the authors wrote.
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