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Scientific rationale for a higher dose of nusinersen
Richard S Finkel1, Monique M Ryan2, Samuel Ignacio Pascual Pascual3
1St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Annals of Clinical and Translational Neurology
|May 14, 2022
Summary
Higher doses of nusinersen may improve spinal muscular atrophy (SMA) treatment. Increased cerebrospinal fluid (CSF) exposure correlated with better outcomes, suggesting a dose-response relationship for enhanced efficacy.
Area of Science:
- Neurology
- Pharmacokinetics
- Biomarkers
Background:
- Nusinersen has a favorable long-term safety profile.
- Investigating higher doses of nusinersen is warranted for potential improved efficacy in spinal muscular atrophy (SMA).
Purpose of the Study:
- To explore the relationship between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy.
- To evaluate the potential benefits of a higher nusinersen dose compared to the current 12 mg dose.
Main Methods:
- Utilized data from the CS3A and ENDEAR studies in infantile-onset SMA patients.
- Applied a population pharmacokinetic (PK) model to predict CSF Ctrough levels.
- Used PK/pharmacodynamic (PK/PD) models correlating CSF nusinersen levels with CHOP INTEND scores and pNF-H levels.
Main Results:
- Higher nusinersen CSF exposure was linked to decreased pNF-H levels and improved CHOP INTEND scores.
- Demonstrated a dose-response relationship between CSF nusinersen levels and treatment response.
- Predicted a 2.4-fold increase in CSF levels with a higher dose, potentially leading to an additional 5-point increase in CHOP INTEND score.
Conclusions:
- A higher dose of nusinersen may offer additional clinically meaningful efficacy improvements over the 12 mg dose.
- The safety, efficacy, and PK of a higher nusinersen dose are under investigation in the DEVOTE study.
