New Delivery System for Nusinersen Safe in SMA

Deborah Brauser

September 25, 2018

A subcutaneous intrathecal catheter (SIC) system is a safe, more cost-effective, and at least for some adult and child patients, a more convenient way to deliver nusinersen (Spinraza, Biogen) for the treatment of spinal muscular atrophy (SMA), new research suggests.

The drug was the first to be approved by the US Food and Drug Administration (FDA), back in 2016, for treating this rare and often fatal genetic disease. However, it needed to be administered into cerebrospinal fluid (CSF) by repeat puncture every 4 months — a difficulty for the many patients with SMA who have scoliosis or spinal fusion.

After searching for alternative dosing strategies, investigators created a new system that connects an intrathecal catheter to an implantable infusion port.

Interim safety results from a pilot study of 10 individuals between the ages of 5 and 30 years showed that all doses of the drug were administered successfully and without any "systemic analgesia, cognitive distraction, ultrasound guidance, respiratory precautions, or sedation," the researchers report.

Although glucose and protein levels in CSF withdrawn from the SIC were normal, two of nine specimens showed "slightly elevated" white blood cells, and red blood cells were detected in seven specimens.

Dr Kevin A. Strauss

The investigators note that further study into this delivery method is needed. However, if larger and longer-duration trials show efficacy, it "could double the number of patients able to receive nusinersen worldwide while reducing administration costs 5- to 10-fold," they write.

"If the safety is equivalent to lumbar puncture and there's less trauma involved, we may find that people are electing to do it even if they don't have spinal pathology simply because it represents a much more convenient way to give the drug," lead author Kevin A. Strauss, MD, medical director at the Clinic for Special Children, Strasburg, Pennsylvania, told Medscape Medical News.

"It remains to be seen if that will be true broadly, but that has been our preliminary experience," said Strauss.

The findings were recently published online in the Journal of Pediatric Orthopedics

1 in 11,000 Births Affected

SMA affects approximately 1 in 11,000 births, is a progressive motor neuron disorder, and causes muscle weakness and difficulties with breathing and eating. The most severe form, infantile-onset type 1, affects about 60% of patients with SMA; less than 25% of these infants survive past 2 years of age without being dependent on ventilators.

The antisense oligonucleotide nusinersen was created to increase concentrations of stable survival motor neuron (SMN) protein, which is underexpressed in patients with SMA. It does this by alter splicing SMN2, an encoding gene that produces a rapidly degraded and unstable protein fragment.

Now commercially available, the drug has had the high price of $750,000 during the first year of loading doses; the cost is cut in half during subsequent years.

In addition to cost worries, there have been concerns about the delivery system, which leaves out many patients who might otherwise benefit from the treatment.

"Even among SMA patients without advanced neuromuscular disease or spinal pathology, repeated interlaminar dosing of nusinersen poses challenges. The overall incidence of traumatic lumbar punctures in children ranges from 20% to 50%," note the investigators.

Strauss reported that the genesis of the current study came about because of one child. In March 2017, an 11-year-old boy with advanced SMA was denied access to intrathecal nusinersen because of his spinal fusion.

"We were faced with a conundrum in a single child, and as it turns out, that child was representative of a large number of children with a similar problem," said Strauss.

Fruitful Collaboration

The boy was almost helpless, could barely move the fingers on one hand, could only speak in a whisper, was fed through a tube, and used a breathing machine at night, Strauss reported.

Although the child's parents didn't have health insurance, "through the generosity of the company, they were able to get the medication at no cost." However, two different academic medical centers refused to administer him the drug.

"They basically said, 'it's just too difficult and too dangerous to try to do lumbar puncture through the spinal hardware,' " said Strauss.

After talking with the parents, he reached out to a former colleague, senior author Freeman Miller, MD, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, Delaware, and Department of Orthopedics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.

Miller "has been a leader in orthopedics for cerebral palsy and a real pioneer in developing innovative orthopedic procedures and assessment tools for children with motor disabilities," Strauss said.

After working together on possible solutions, the two physicians met with the family to show their preferred device and discuss risks — and subsequently went forward with the procedure.

"It went so smoothly and worked so well, we thought: there are a lot of other children with SMA with this same exact problem. Why couldn't we do this electively?" Strauss reported.

After meeting with the drug manufacturer, "who was on board with the plan," the investigators designed a prospective study to evaluate 20 patients with SMA. Each participant was to be given seven SIC-delivered doses of the study drug (four loading and three maintenance doses) over 14 months.

The current article reports on the first 10 participants (80% with three copies of SMN2) who each received three loading doses via the SIC system over 4 weeks. Among these patients, five were between the ages of 5 and 12 years, two were teens, and three were between the ages of 20 and 30 years.

Although the six eldest patients had spinal fusion, the others did not. The parents of the younger patients "elected the SIC based on its perceived administration safety, convenience, and cost," the investigators write.

"Pretreatment disease burden" was assessed using several measures, including the Revised Hammersmith Scale, National Institutes of Health Toolbox pegboard, dynamometry and electromyography, pulmonary function, and quality of life determinants.

Interim Feasibility, Safety Results

Implantation for all patients took 2 hours or less (average, 1.4 hours) and was followed by a 50- to 55-hour hospital stay.

"There were no perioperative or postoperative complications and all wounds were clean and dry by postoperative week 2," the investigators report.

All nusinersen doses, which were administered on an out-patient basis, were successfully given within 20 minutes of the first attempt.

There were three reports of adverse events in three patients during the interim study period. One boy had a urinary tract infection and one woman reported "back pain secondary to a protruding spinal rod," write the researchers. Although CSF could not be withdrawn from the SIC port in another woman, the study drug was "freely administered through this same port, implicating dynamic suction-induced catheter obstruction."

This left nine patients who had CSF specimens for assessments. Levels of glucose (median, 53 mg/dL) and protein (median, 25 mg/dL) in these patients were considered to be normal.

In two of the specimens (22%), white blood cells were elevated at a median of 1 cell/µL (range, 0 to 12 cells/µL). Seven specimens showed the presence of red blood cells (median, 4 cells/µL; range, 0 to 2930 cells/µL).

The researchers note that these findings suggest that "indwelling CSF catheter tips, when not continuously infusing, can adhere to pial or arachnoid membranes to become dynamically obstructed and/or cause microvascular injury when suction is applied."

They add that CSF withdrawal and assessment were only used as a way to measure "patency and safety" in this particular trial, but does not need to be routinely used in long-term administration protocols.

Raises Other Opportunities

Overall, preliminary study observations "reveal SIC to be relatively safe and well tolerated in SMA patients with advanced disease and spinal fusion," the investigators write.

They stress that efficacy was not the endpoint in this interim report and expect that effects in this particular cohort "will be relatively modest, slow to emerge, and observed primarily as an arrest of disease progression."

That could be because of the need for different measures for adolescents and adults with SMA, they write, adding that "conventional endpoints of motor function used for infants and young children lose their informative value after age 16 years."

Strauss reported that, although the main study was to last about 14 months and through seven total doses per patient, the investigators have decided to extend it long-term for those who would like to continue.

"This is based on the fact that it does appear to be safe," he said. "The second phase will be looking at effectiveness and tolerability over a longer period of time."

When the FDA first approved the drug, they recommended doses of 12 mg for each loading dose, followed by maintenance doses every 4 months thereafter. Asked about this regimen for the SIC system, Strauss said it raises interesting questions.

"Now that the catheters are in place, it creates opportunities to examine other dosing regimens and strategies — both in terms of the amount of medicine given and frequency of administration." He added that those issues are part of the ongoing discussions the investigators are having with the manufacturer.

"Very Promising"

Asked to comment by Medscape Medical News, Alejandro Tobon, MD, neurology section chief at South Texas Veterans Healthcare System and associate professor of neurology at the University of Texas Health Science Center at San Antonio, said the interim results looked "very good," especially for patients where lumbar punctures would be quite difficult.

Dr Alejandro Tobon

"Using this device in the way the investigators describe it is probably simple because they're just combining two already FDA-approved devices," said Tobon, who was not involved with the research.

"We need to look at it long-term, in terms of making sure there are no problems with malfunctioning of the device or other complications such as displacement. But overall, I think it seems very promising," he added.

"I know what these kids go through every time they go for a lumbar puncture. If this makes their lives easier, after one big procedure it's probably simple to just give the medications, as long as the system works, I think for everybody involved it's a win."

The study was funded in part by a grant from Biogen. The study authors have reported no relevant financial relationships.

J Pediatr Orthop. Published online August 21, 2018. Abstract

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