Dr Darras BasilDarras Basil, MD
The use of nusinersen (Spinraza, Biogen) over the course of roughly 3 years in 2- to 15-year-old children with spinal muscular atrophy (SMA) has been shown to result in improvements never before seen in the natural history of the disease—most importantly, in older children treated early in life.1

The integrated analysis of the phase 1/2 CS2 (NCT01703988) and CS12 (NCT02052791) studies provided Class IV evidence that nusinersen improves motor function in children with later-onset SMA. The average age at symptom onset in the cohort was 17.7 months (standard deviation [SD], 11.9; range, 3 to 60), with the mean onset for SMA type 2 and type 3 being 11 months (SD, 3.4; range, 3 to 15) and 22 months (SD, 13.5; range, 6 to 60), respectively. As the median age of survival is 8 to 14 months with SMA, the study results are certainly encouraging.

The data ultimately showed improvements in average Hammersmith Functional Motor Scale-Expanded (HFMSE) and Upper Limb Module (ULM) scores, and 6-Minute Walk Test (6MWT) distances by day 1150. The use of the FDA-approved treatment was assessed in patients with SMA type 2 (n = 11) and type 3 (n = 17).

“This study involved kids up to age 15 years at enrollment with SMA types II and III, and they were followed for approximately three years, so we were excited to see that the drug can show benefit for these older kids too and that the benefit can extend for this period of time,” said study author Basil T. Darras, MD, associate neurologist-in-chief; chief, division of clinical neurology; director, neuromuscular center and spinal muscular atrophy program; professor of neurology, Harvard Medical School, in a statement.2

Nusinersen has previously shown a suggested ability to improve the status of patients with SMA at a later stage of the disease, with data from Aragon-Gawinska et al., published in Neurology last year, showing significant 6-month improvements in the Hammersmith Infant Neurologic Examination Part 2 (HINE-2; <.001), as well as granting 16.6% of patients the ability to achieve a support-free sitting position for >30 seconds.3

The improvements experienced by this most recent, 28-patient cohort were notable, with day 1150 scores improving by 10.8 points and 4 points for those with SMA type 2 in the HFMSE and ULM, respectively, and by 1.8 points and 92 meters for those with SMA type 3 in the HFMSE and 6MWT, respectively. ULM scores were not recorded for those with type 3 and 6MWT scores were not recorded for those with type 2.

Among those with SMA type 3, 19% (n = 3) demonstrated a clinically meaningful improvement in HFMSE score by day 253—including a nonambulant child. All told, 36% (n = 4) showed meaningful improvement by day 1050. For the 13 patients with SMA type 3 who were nonambulant, mean HFMSE scores were improved by 2.6 points while 17% (n = 2) and 44% (n = 4) showed meaningful increases by day 253 and Day 1050, respectively.

For ULM scores, those with SMA type 3 who were nonambulant had achieved the maximum score of 18 points by day 350 and maintained it through Day 1150. Of those 11 patients with SMA type 2, 45% (n = 5) showed an improvement of ≥2 points by day 253 and 56% (n = 5 of 9) by Day 1050. Darras and colleagues noted that there was a strong correlation between change in baseline HFMSE score and change in ULM score (r = .87) at Day 1050.

“These results also suggest that treatment with nusinersen may not just prevent motor function deterioration but could also allow for continued motor function improvement and even reversal of motor function loss,” the investigators wrote. Although they acknowledged that the biological basis for the demonstrated time-dependent effect of the therapy is unknown and unstudied, it may be related to a number of processes— continued axonal growth and reinnervation of muscle fibers, improved neuronal/axonal function, maturation of abnormal synapses, and/or transneuromuscular junction effects on muscles—possibly induced by an increased SMN protein production.

6MWT scores were significantly improved by ≥30 meters from baseline in 50% of patients with SMA type 3 by day 253. By day 1050, 100% of the 8 children showed clinically meaningful improvements. Of the 4 children who had lost the ability to walk, 2 regained the ability to walk independently during the study period.

As for safety, all 28 children experienced ≥1 adverse event (AE), though most were mild or moderate and unrelated to nusinersen treatment. The most common (occurring in ≥20%) were post-lumbar puncture syndrome (n = 16; 57%), headache (n = 13; 46%), nasopharyngitis (n = 12; 43%), upper respiratory tract infection (n = 12; 43%), puncture site pain (n = 11; 39%), back pain (n = 9; 32%), scoliosis (n = 8; 29%), pyrexia (n = 7; 25%), joint contracture (n = 6; 21%), rhinorrhea (n = 6; 21%), and vomiting (n = 6; 21%).

Serious AEs were reported by 5 patients (18%), though none led to discontinuation and none were deemed related to the study drug. “No clinically relevant changes in laboratory values or neurologic examinations considered related to nusinersen treatment were observed,” Darras and colleagues wrote.
REFERENCES
1. Darras BT, Chiriboga CA, Iannaccone ST, et al. Nusinersen in later-onset spinal muscular atrophy. Neurology. 2019;92:1-15. doi: 10.1212/WNL.0000000000007527.
2. Spinal muscular atrophy drug may help kids with later-onset disease [press release]. Minneapolis, MN: American Academy of Neurology; Published April 24, 2019. eurekalert.org/pub_releases/2019-04/aaon-sma041919.php. Accessed April 24, 2019.
3. Aragon-Gawinska K, Seferian A, Daron A, et al. Nusinersen in spinal muscular atrophy type 1 patients older than 7 months. Neurology. 2018;91:1-7. doi:10.1212/WNL.0000000000006281.