Objective: To evaluate plasma phosphorylated neurofilament heavy chain (pNF-H) as a biomarker in spinal muscular atrophy (SMA). Methods: Levels of pNF-H were measured using the ProteinSimple® platform in plasma samples from infants with SMA enrolled in ENDEAR (NCT02193074) and infants/children without neurological disease. Results: Median pNF-H plasma level was 167.0 pg/mL (7.46-7,030; n = 34) in children without SMA (aged 7 weeks-18 years) and was higher in those aged < 1 versus 1-18 years (P = 0.0002). In ENDEAR participants with infantile-onset SMA, median baseline pNF-H level (15,400 pg/mL; 2390-50,100; n = 117) was ~10-fold higher than that of age-matched infants without SMA (P < 0.0001) and ~90-fold higher than children without SMA (P < 0.0001). Higher pretreatment pNF-H levels in infants with SMA were associated with younger age at symptom onset, diagnosis, and first dose; lower baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders score; and lower peroneal compound muscle potential amplitude. Nusinersen treatment was associated with a rapid and greater decline in pNF-H levels: nusinersen-treated infants experienced a steep 71.9% decline at 2 months to 90.1% decline at 10 months; sham control-treated infants declined steadily by 16.2% at 2 months and 60.3% at 10 months. Interpretation: Plasma pNF-H levels are elevated in infants with SMA. Levels inversely correlate with age at first dose and several markers of disease severity. Nusinersen treatment is associated with a significant decline in pNF-H levels followed by relative stabilization. Together these data suggest plasma pNF-H is a promising marker of disease activity/treatment response in infants with SMA
