Rationale for Higher Dose of Nusinersen for Spinal Muscular Atrophy Suggested

A pharmacokinetic/pharmacodynamic (PK/PD) modeling study published in the Annals of Clinical and Translational Neurology, suggest there may be greater efficacy of a higher dose of nusinersen (Spinraza; Biogen, Cambridge MA) than has been approved by the Food and Drug Administration (FDA). 

The PK/PD study is based on analysis of data from the CS3A (NCT01839656) and ENDEAR (NCT02193074) studies, which indicate a dose-response relationship of plasma levls of phosphorylated neurofilament heavy chain (pNF-H), a biomarker of axonal degeneration. An increased dose of nusinersen led to greater decreases in pNF-H levels and higher efficacy of treatment as measured with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale. 

PK/PD modelling suggest the higher dose of nusinersen may result in a 2.4-fold increase in nusinersen CSF levels with fewer loading doses. The PK/PD modeling also predicts a 5-point increase in the CHOP INTEND score with a higher dose vs the approved 12-mg dose.

Potentially greater efficacy of higher doses of nusinersen is being evaluated clinically in the DEVOTE study (NCT04089566) in children with infantile-onset spinal muscular atrophy (SMA).