Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy. The drug is given intrathecally at 12 mg, beginning with 3 loading doses at 2-week intervals, a fourth loading dose 30 days thereafter, and maintenance doses at 4-month intervals. This population pharmacokinetic model was developed to clarify how to maintain targeted nusinersen exposure after an unforeseen one-time delay or missed dose. Simulations demonstrated that the impact of a one-time delay in dosing or a missed dose on median cerebrospinal fluid exposures depended on duration of interruption and the regimen phase in which it occurred. Delays in loading doses delayed reaching the peak trough concentration by approximately the duration of the interruption. Resumption of the regimen as soon as possible resulted in achieving steady state trough concentration upon completion of the loading phase. A short delay (30-90 days) during the maintenance phase led to prolonged lower median cerebrospinal fluid concentration if all subsequent doses were shifted by the same 4-month interval. However, administration of the delayed dose, followed by the subsequent dose as originally scheduled, rapidly restored trough concentration. If a dose must be delayed, patients should return to the original dosing schedule as soon as possible.

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).

Background Nusinersen is approved for the treatment of spinal muscular atrophy. The most common approved dosing regimen is four intrathecal loading doses of nusinersen 12 mg; the first three are administered at 14-day intervals followed by a fourth dose 30 days later, and then 12-mg maintenance doses are administered every 4 months thereafter. Interruption of nusinersen treatment in the maintenance dosing phase might occur for a number of clinical reasons. Objective The objective of this report is to describe dosing regimens that allow for the most rapid restoration of steady-state concentrations of nusinersen in the cerebrospinal fluid (CSF) following a treatment interruption during maintenance dosing. Methods Population pharmacokinetic models using integrated pharmacokinetic data from ten nusinersen clinical trials that included a broad range of participants with spinal muscular atrophy treated with intrathecal nusinersen were used to investigate different durations of treatment interruptions during maintenance treatment. Potential dosing regimens for re-initiation of nusinersen were evaluated, with the goal of achieving the quickest restoration of steady-state nusinersen CSF concentrations without exceeding maximal CSF exposures observed during the initial loading period. Results Our pharmacokinetic modeling indicates the following regimen will lead to optimal restoration of nusinersen CSF levels after treatment interruption: two doses of nusinersen should be administered at 14-day intervals following treatment interruptions of ≥ 8 to < 16 months since the last dose, and three doses of nusinersen at 14-day intervals for treatment interruptions of ≥ 16 to < 40 months since the last maintenance dose, with subsequent maintenance dosing every 4 months in both instances. After treatment interruptions of ≥ 40 months, the full loading regimen will rapidly restore nusinersen CSF levels. Conclusions Prolonged treatment interruptions lead to suboptimal CSF levels of nusinersen. The optimal regimen to restore nusinersen CSF levels depends on the interval since the last maintenance dose was administered.

Phosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing the SMA pediatric scenario in the age range of 0-20 years with and without treatment with the antisense oligonucleotide nusinersen.

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