Scientific rationale for a higher dose of nusinersen

Abstract

Objective: The long-term favorable safety profile of nusinersen provides an opportunity to consider a higher dose. We report on the relationships between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy. Methods: The analyses used data from the CS3A and ENDEAR studies of nusinersen in participants with infantile-onset spinal muscular atrophy (SMA). Steady-state CSF trough (C trough ) levels, plasma phosphorylated neurofilament heavy chain (pNF-H) levels, body weight, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores were selected as parameters of interest. A validated population pharmacokinetic (PK) model was applied to predict the nusinersen CSF C trough . PK/pharmacodynamic (PK/PD) models used nusinersen CSF C trough measurements, which were time-matched with CHOP INTEND scores. Results: Higher nusinersen CSF exposure was associated with a greater decrease in pNF-H levels and greater efficacy, as measured by change in the CHOP INTEND score from baseline. These findings indicate a dose-response relationship between CSF nusinersen levels and treatment response. The higher dose is predicted to lead to approximately a 2.4-fold increase in nusinersen CSF levels with fewer loading doses. PK/PD modeling indicates that a higher concentration of nusinersen may predict an additional 5-point increase in CHOP INTEND score beyond that observed with 12 mg. Interpretation: Our data indicate that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy when compared with the currently approved 12-mg dose. The efficacy, safety, and PK of a higher nusinersen dose are currently under investigation in the ongoing phase 2/3 DEVOTE study (NCT04089566).

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“…A higher dose of nusinersen is being tested in patients with early and late-onset SMA (DEVOTE study). 68 In Part A, all six enrolled participants aged 6.1 to 12.6 years have completed the study. Common adverse events (headache, pain, chills, vomiting, and paresthesia) were considered related to the lumbar puncture procedure, and there were no safety concerns regarding clinical or laboratory parameters.…”

“…Most participants showed stabilization or improved motor function. 68 Parts B and C of the DEVOTE are ongoing.…”

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

“…Research has shown that NF is elevated in SMA-affected infants and young children compared to healthy controls, and it rapidly declines with treatment by nusinersen before stabilizing above normal [ 107 , 113 , 118 , 165 ]. For example, Finkel et al (2022) analyzed data from the CS3A and ENDEAR studies and found that in infants with SMA, lower NF-H levels in CSF were associated with increased nusinersen dosage, which in turn correlated with better treatment outcomes [ 165 ]. Studies that have evaluated the effects of nusinersen treatment on NF levels in SMA-affected adolescents and adults have yielded conflicting results, suggesting a need for further, standardized studies on these populations [ 109 , 111 , 115 , 121 , 147 – 149 , 166 , 167 ].…”

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

“…Table 2 demonstrates that NfL and pNfH were used as potential pharmacodynamic (response) biomarkers in the majority of studies that examined the utility of molecular biomarkers for monitoring therapeutic response in SMA. In the majority of studies, a decrease in NfL and pNfH levels was observed following treatment with nusinersen [39,[61][62][63][76][77][78][79][80][81], whereas others observed no change in the levels of these biomarkers [45,56,60,[82][83][84] (Table 2).…”