A quantitative systems pharmacology model representing the scenario of spinal muscular atrophy (SMA) in people who are 0 to 20 years of age successfully reproduced phosphorylated neurofilament heavy (pNfH) subunit levels in both presence and absence of treatment with nusinersen, according to a recently published study in CPT: Pharmacometrics and Systems Pharmacology.

pNfH is released into cerebrospinal fluid and blood due to axonal damage; therefore, it has been proposed as a biomarker for disease progression in several neurodegenerative diseases, including SMA. Evidence shows that pNfH levels tend to be significantly higher in patients with SMA than in healthy individuals.

Furthermore, patients treated with nusinersen have significantly lower pNfH levels than untreated patients, thus making it a disease-sensitive pharmacodynamic response biomarker in SMA.

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The authors aimed to build a mathematical model capable of predicting the trafficking of pNfH levels in pediatric patients. The model was an extension of a previously developed model studying SMA trafficking in healthy adult subjects.

Researchers used data from previous clinical trials that enrolled patients with SMA being treated with nusinersen for the development and parametrization of the model. Data regarding pNfH plasma and cerebrospinal fluid levels were available in the majority of cases. The authors noted that nusinersen dosing, as well as pNfH data sampling varied greatly among patients.

Because neurofilament concentrations depend on compartment volumes, the mathematical model took into consideration the effect of the volume growth of the tissues during the pediatric age. The model also reproduced the development of the central nervous system at 0 to 20 years of age, accounting for the process of synaptogenesis and pruning.

The contribution of SMA to pNfH trafficking was included in the model as additional neural leakage, and the impact of nusinersen was calculated by multiplying the effect of SMA by a factor proportional to an effective time-dependent drug profile.

Finally, the results from the final model were validated by comparing its predictions to data obtained from a real cohort of patients with SMA. The final model successfully reproduced the pNfH concentration in treated and untreated patients with SMA, particularly during the 0 to 7 interval.

“The performance of the model makes it a valuable tool for investigating pNfH as a biomarker of disease severity and treatment response in SMA and for in silico evaluation of novel treatment protocols,” the authors concluded.


Paris A, Bora P, Parolo S, et al. A pediatric quantitative systems pharmacology model of neurofilament trafficking in spinal muscular atrophy treated with the antisense oligonucleotide nusinersen. CPT: Pharmacomet Syst Pharmacol. Published online December 5, 2022. doi:10.1002/psp4.12890