Novel Nusinersen Delivery System Shows Success for Patients with SMA

August 28, 2018

A subcutaneous intrathecal catheter delivery system has proven safe and tolerable in a preliminary investigation in patients with SMA.

Kevin A. Strauss, MD

A novel, subcutaneous intrathecal catheter delivery system for nusinersen (Spinraza, Biogen) has proven to be relatively safe and well tolerated in preliminary observations, highlighting the potential to improve the quality of life for patients with spinal muscular atrophy (SMA).

Overall, the device was implanted in an average of 1.4 hours (range, 1.1 to 2.0), and all outpatient doses of nusinersen were successfully administered via subcutaneous intrathecal catheter within 20 minutes of the first attempt.1

Led by Kevin A. Strauss, MD, the medical director of the Clinic for Special Children, in Strasburg, Pennsylvania, the group of investigators crafted a hybrid infusion device from 2 FDA-approved devices: a catheter utilized for continuous or repeated intrathecal infusion from Medtronic, and a power injectable implantable infusion port from Med-Comp, designed for repetitive blood sampling or chemotherapy.

These patients with SMA, who require antisense oligonucleotide therapy for life, can often also have scoliosis or spinal fusion that can prove difficult for safe drug delivery. Additionally, repeated lumbar puncture in younger patients has shown to result in a high rate of traumatic complications.2-3 The implications of the new process, the authors wrote, extend beyond possible patient preference, as the comparative costs of treatment—not including the cost of the therapy—yield an average savings of $24,000 per child per year, assuming a cost of $22,000 for the catheter and an annual medical inflation rate of 6%.

The novel delivery method was tested in 10 patients with SMA (age range, 5.4 to 30.5 years) of which 80% had 3 copies of the SMN2 gene. All patients received 3 sequential doses of nusinersen.

The results revealed no instances of necessary regional or systemic analgesia, cognitive distraction, ultrasound guidance, respiratory precautions, or sedation for patients. When examining cerebral spinal fluid (CSF) from the subcutaneous intrathecal catheter, the levels of glucose and protein were normal. Of the 9 specimens taken, CSF white blood cells were shown to be slightly elevated in 22% (n = 2; median, 1 cell/μL; range, 0 to 12 cells/μL) and red blood cells were detected in 78% (n = 7; median, 4; range, 0 to 2930 cells/μL).

Strauss and colleagues noted that a phenomenon similar to that observed with the presence of red blood cells in the CSF was seen in newborn patients with an intrathecal reservoir or ventriculoperitoneal shunt.4 This, they noted, raised the possibility that indwelling CSF catheter tips could potentially cause issues when suction is applied. “To safeguard against this, we added an initial 0.2 mL saline flush to the administration protocol to gently dislodge the catheter tip from surrounding thecal membranes before withdrawal of CSF.”

A total of 3 adverse events (AEs) occurred in as many participants. One patient experienced a urinary tract infection, 1 experienced back pain secondary to a protruding spinal rod, and 1 showed an inability to withdraw CSF from the catheter’s port. Although, the therapy could still be administered via this port, implying a dynamic suction-induced catheter obstruction in this patient. This was the only AE deemed related to the device.

At baseline, mean compound muscle action potential (CMAP) varied by SMN2 copy number: Those with 4 (n = 1), 3 (n = 8), and 2 (n = 1) copies of SMN2 recorded CMAP amplitudes of 6.6 ± 0.8 mV, 1.3 ±0.7 mV, and 0.2 ±0.1 mV, respectively. Strauss and colleagues noted that motor nerve amplitude was not varied as a function of age for the patients with 3 copies of SMN2.

Notably, the authors acknowledged that the “parents of the 4 youngest study participants [aged 5.4 to 10.4 years] who had no anatomic or pulmonary contraindications to interlaminar dosing—elected [subcutaneous intrathecal catheter] implantation as potentially safer, more convenient, and less costly than repeated lumbar puncture."

“Although the [subcutaneous intrathecal catheter] was designed for SMA patients with advanced disease and attendant spinal pathology, our preliminary observations have implications for younger, less severely affected patients,” Strauss and colleagues wrote. “As private and government insurers adapt to the extraordinary costs associated with new disease-modifying precision therapies, they will likely seek practical innovations like the [subcutaneous intrathecal catheter], which have the potential to safely control administration costs while preserving therapeutic value.”

REFERENCES

1. Strauss KA, Carson VJ, Brigatti KW, et al. 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. J Pediatr Orthoped. Epub August 21, 2018. doi: 10.1097/BPO.0000000000001247.

2. Carter GT, Abresch RT, Fowler WM Jr, et al. Profiles of neuromuscular diseases. Spinal muscular atrophy. Am J Phys Med Rehabil. 1995;74:S150—S159.

3. Glatstein MM, Zucker-Toledano M, Arik A, et al. Incidence of traumatic lumbar puncture: experience of a large, tertiary care pediatric hospital. Clin Pediatr (Phila). 2011;50:1005—1009.