Higher blood levels of phosphorylated neurofilament heavy chain (pNF-H) — a marker of nerve cell damage — before beginning Spinraza (nusinersen) treatment are associated with greater motor improvements in children with spinal muscular atrophy (SMA) types 2 or 3.
Notably, this association increased over time, reaching statistical significance at about three years of treatment.
Those findings come from an analysis of data from the Phase 3 CHERISH clinical trial and the SHINE extension study.
The results support the use of pNF-H levels at treatment start (baseline) to predict future clinical responses in SMA patients. More studies are needed to confirm its predictive value in this patient population, the researchers noted.
The results were presented by Michelle Farrar, PhD, of the Sydney Children’s Hospital and the University of New South Wales Sydney, in an oral presentation at the 2021 virtual American Academy of Neurology Annual Meeting (AANAM), running through April 22.
The presentation was titled “Plasma Phosphorylated Neurofilament Heavy Chain (pNF-H) Level is Associated with Future Motor Function in Nusinersen-treated Individuals with Later-onset Spinal Muscular Atrophy (SMA).”
Neurofilaments are major structural proteins of neurons, and comprise three subunits: heavy, intermediate, and light chains. When neurons are damaged or die, neurofilaments are found “on the loose” in the bloodstream or in the cerebrospinal fluid, which is the liquid that surrounds the brain and spinal cord.
As such, neurofilaments have gained increasing interest as potential biomarkers of nerve cell damage, neurodegenerative conditions, and treatment responses. Higher-than-normal levels of neurofilaments have been detected in people with neurodegenerative disorders, such as SMA and amyotrophic lateral sclerosis (ALS).
A previous study showed that pNF-H levels were higher in SMA patients who participated in the different Spinraza trials than in healthy individuals, and that these levels showed a rapid drop after treatment began, followed by stabilization at lower levels.
Biogen’s Spinraza, the first disease-modifying therapy approved for SMA, works by increasing the levels of SMN, a protein essential for motor neuron and muscle health and whose production is largely absent or insufficient in SMA.
The therapy is administered directly into the spinal canal at a recommended treatment schedule of four doses in the first two months, followed by maintenance treatment every four months.
Now, Biogen and researchers involved in Spinraza trials, including Farrar, evaluated whether baseline pNF-H levels could predict motor function improvements in children with later-onset SMA treated with Spinraza in both the Phase 3 CHERISH Phase 3 trial (NCT02292537) and the SHINE open-label extension study (NCT02594124).
CHERISH tested Spinraza against a sham procedure in 126 children, ages 2 to 12, with type 2 or 3, while SHINE is evaluating the treatment’s long-term safety and effectiveness in participants of Spinraza trials. SHINE is expected to finish in August 2023.
The new analysis included data from 75 children (39 girls and 36 boys) who had their blood pNF-H levels measured at treatment initiation and throughout both studies. Their median age at first Spinraza dose was 4.1 years, and they were treated and followed for a median of 4.1 years.
Changes in children’s motor functions were assessed with the Hammersmith Functional Motor Scale — Expanded (HFMSE) and Revised Upper Limb Module (RULM), in which higher scores indicated better function.
A potential association between pNF-H levels and motor function was assessed at day 450 (more than a year), 690 (nearly two years), 930 (about 2.5 years), 1,170 (more than three years), and day 1,410 (nearly four years).
Results showed that after adjusting for children’s age and motor function at baseline, higher pNF-H levels were associated with greater motor improvements (in both tests) over time, reaching statistical significance at days 1,170 and 1,410.
Particularly, for every threefold increase in pNF-H levels at baseline there was an associated mean increase of four points in the HFMSE score and of two points in the RULM score at these later time points, Farrar noted.
These findings highlighted that, in this patient population, “higher pNF-H levels at baseline are associated on average with greater improvements in Hammersmith and the RULM scores at later visits,” Farrar said.
The data also suggest that “motor function increases and positive benefits to treatment do emerge over time, and that the time period can be up to the course of a year,” she added.
“Pre-treatment phosphorylated neurofilament heavy chain may be a useful indicator of future motor function and warrants further evaluation as a biomarker of treatment response in SMA,” Farrar said.
This may be “very relevant to clinical practice, particularly as you have a patient sitting in front of you and setting expectations regarding therapeutic response,” Farrar concluded.
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