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 (Ctrough ) 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 Ctrough . PK/pharmacodynamic (PK/PD) models used nusinersen CSF Ctrough 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).

Conflict of interest statement

These analyses were sponsored by Biogen (Cambridge, MA, USA). Biogen provided funding for medical writing support in the development of this report; Nancy Niguidula from Excel Scientific Solutions provided writing assistance in the development of the first and subsequent drafts based on input from authors, and Cara Dickinson and Jackie Parker from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. The authors had full editorial control of the paper and provided their final approval of all content.

R.S.F. served as a consultant for AveXis/Novartis Gene Therapies, Biogen, Neurogene, and Roche/Genentech; received honoraria for speaking from AveXis, Biogen, Elsevier, Excerpta Medica, and Roche; received travel support from Cure SMA, SMA Europe, and the SMA Foundation; received grants from Biogen to St Jude Children's Hospital for conduct of the DEVOTE study; received grants paid to his prior institution, Nemours Children's Health System, for the conduct of clinical trials from AveXis, Cytokinetics, Roche, and Scholar Rock; received research funding from Cure SMA to support an SMA study group; served in an advisory capacity for nonprofit organizations: Cure SMA, EveryLife Foundation, and n‐Lorem Foundation with no payments received; and received royalty payments from Children's Hospital of Philadelphia for licensing fees for co‐invention of the CHOP INTEND motor function scale.

M.M.R. has participated in advisory boards for nonprofit organizations: FSHD Global Research Foundation, Muscular Dystrophy Foundation, and Save Our Sons Duchenne Foundation; received honoraria from Biogen, BioMarin, and Novartis; and received research funding from Biogen, FSHD Global Research Foundation, Genzyme, MD NSW, and Save Our Sons Duchenne Foundation paid to her institution.

S.I.P.P. has participated in advisory boards for SMA studies for AveXis, Biogen, Ionis, Novartis, and Roche; and has served as a Principal Investigator for Biogen/Ionis and Roche clinical trials.

J.W.D. has served as a consultant for Shift Therapeutics; has participated on an advisory board or data safety monitoring board for AveXis/Novartis Gene Therapies, Biogen, Cytokinetics, Epirium Bio, Ionis, Pfizer, Roche, and Scholar Rock; received research support from AveXis/Novartis Gene Therapies, Biogen, Cytokinetics, Ionis, Roche/Genentech, and Scholar Rock; and is an inventor on patents related to genetic testing of myotonic dystrophy type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931) assigned to Regents of the University of Minnesota and licensed to Athena Diagnostics and has received royalty payments from Athena Diagnostics.

E.M. has participated in advisory boards for SMA studies for AveXis, Biogen, Ionis, Novartis, and Roche; has been a Principal Investigator for ongoing Biogen and Roche clinical trials; and received research grants from Famiglie SMA Italy, Italian Telethon, Novartis, Scholar Rock, and SMA Europe.

D.C.D. has served as an advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis, METAFORA, Roche, Sanofi, Sarepta, Scholar Rock, SMA Foundation, and Ultragenyx, with no financial interests in these companies; received grants from Cure SMA, Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, National Institutes of Health, and SMA Foundation; received research funding from Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, iSMAC initiative (Biogen), National Institutes of Health, Sanofi, and SMA Foundation; received clinical trial funding from Ionis, Mallinckrodt, PTC, Santhera, Sarepta, Scholar Rock, and Ultragenyx; serves as the Data Safety Monitoring Committee Chair for Aspa Therapeutics; and is an inventor on a patent on gene therapy for Glut1DS.

J.M. has participated in advisory boards for Biogen, Roche, and Scholar Rock; has served as a consultant for Biogen, Genentech, Sarepta, and Scholar Rock; and received research support paid to her institution from Cure SMA, Eunice Kennedy Shriver National Institute for Child Health and Human Development (K01HD084690), Genentech Independent Medical Education Grant (G‐88736), and Muscular Dystrophy Association (575870 and 629259).

J.G.‐G. has participated in advisory boards for Astellas, AveXis/Novartis Gene Therapies, Biogen, BioMarin, Novartis, PTC, Roche, and Sarepta; received research support paid to Hospital das Clínicas (UFMG) from PTC, Roche, and Sarepta; and has received research funding paid to Universidade Federal de Minas Gerais (UFMG) from FAPEMIG (Brazil).

R.F., D.M., and Z.B. are employees of and hold stock/stock options in Biogen.

© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1

Higher nusinersen CSF levels are associated with greater reduction in plasma pNF‐H levels. (A) Summary table showing median nusinersen CSF Ctrough, median plasma pNF‐H levels, and percentage reduction in plasma pNF‐H levels in each treatment group. (B) Higher Nusinersen CSF Ctrough levels were observed with higher and/or more frequent doses, as expected. (C) Greater percentage decreases in plasma pNF‐H levels were seen in groups with higher nusinersen levels. (D) Similar results were observed with absolute plasma values. CSF = cerebrospinal fluid; Ctrough = trough concentration; LD = loading dose; pNF‐H = phosphorylated neurofilament heavy chain; SE = standard error.

Figure 2

PK/PD modeling indicates that higher nusinersen CSF levels are associated with higher efficacy, and that higher dose may lead to clinically meaningful increase in efficacy above that seen with 12‐mg approved dose. PK/PD modeling using CS3A and ENDEAR data from participants with two SMN2 copies shows higher nusinersen CSF levels are associated with higher efficacy as measured by change from baseline in the CHOP INTEND score. This model indicates that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy (~5 points in CHOP INTEND) above that seen with the 12‐mg approved dose of nusinersen. CHOP INTEND change from baseline estimated with exposure at 12 mg is 7.5 points, whereas the exposure at the higher dose is expected to lead to CHOP INTEND change from baseline of 12.7 points (incremental gain of 5.2 points above 12 mg). Exposures are based on steady‐state concentrations calculated using population PK model – 12‐mg approved dose of nusinersen leads to 5 ng/mL nusinersen CSF levels and higher dose of nusinersen is expected to lead to 12 ng/mL nusinersen CSF levels. Both observed and predicted mean PK/PD values per decile (10% of values) are similar, indicating this model is representative of the observed values. Each box represents one decile of the data, shown as a standard box plot (whiskers 90% CI, box 50% CI, line in box represents median value, outliers are shown as single points outside of the box). CHOP INTEND = Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; CI = confidence interval; CSF = cerebrospinal fluid; Ctrough = trough concentration; PD = pharmacodynamic; PK = pharmacokinetic.

Figure 3

Higher dose of nusinersen is expected to lead to ~2.4‐fold increase in nusinersen levels in CSF compared with the approved 12‐mg dose. (A) Schematic illustrating higher‐dose regimen (two loading doses 2 weeks apart of 50 mg and maintenance dose 28 mg every 4 months) and the 12‐mg approved dose of nusinersen (four loading doses of 12 mg and maintenance dose 12 mg every 4 months). (B) Population PK model estimates steady‐state CSF concentration of nusinersen of 5 ng/mL with the 12‐mg approved dose of nusinersen and 12 ng/mL with the higher nusinersen dosing regimen. Steady state is predicted to be achieved after six maintenance doses, or 24 months after the final loading dose. Median values are shown; the confidence intervals for 12‐mg dose were previously described in MacCannell et al. Data for the higher dose will be obtained from the DEVOTE study. CSF = cerebrospinal fluid; D = day, PK = pharmacokinetic.

Figure 4

Age at first dose of nusinersen does not meaningfully impact the predicted increase in CHOP INTEND score with a higher dose of nusinersen compared with 12 mg. (A) In younger participants with age at first dose ≤150 days (at or below median in this data set), a higher nusinersen CSF concentration was associated with higher CHOP INTEND change from baseline. (B) In older participants with age at first dose >150 days (above median in this data set), higher nusinersen CSF concentration was also associated with higher CHOP INTEND change from baseline, albeit with a flatter curve. (C) As expected, the change from baseline in CHOP INTEND scores was greater in younger participants at exposures associated with the steady state of 12 mg and higher dose of nusinersen (28 mg). Importantly, the additional improvement in CHOP INTEND score expected with the higher dose of nusinersen compared with 12 mg was similar in each population (~5 points). (D) No clear relationship between CSF Ctrough and age was observed when patients were stratified into four different quartiles according to their age at first dose. As expected, younger participants (first quartile) have greater change from baseline in CHOP INTEND scores, consistent with Figure 3C and results from the ENDEAR study. (E) A similar PK/PD relationship indicating 5.0‐point increase in CHOP INTEND above 12 mg at exposures expected with the higher dose of nusinersen was observed using only data from the time of first maintenance dose administration (day 183 for ENDEAR study and day 253 for CS3A study). The Emax value in this model could not be determined, likely due to the limited a data set. CHOP INTEND = Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; CSF = cerebrospinal fluid; Ctrough = trough concentration; Emax = maximum effect.

Figure 5

Nusinersen CSF levels are similar as participants age and grow. Body weight is predicted to have minimal impact upon the Ctrough either at the 12‐mg or 28‐mg dose of nusinersen. Steady‐state trough concentrations were simulated over a wide range of body weights (9.0–114.5 kg). Despite an over 10‐fold change in body weight, the volume of the CNS is predicted not to change significantly over a wide range of body weights, leading to consistent exposure within the CNS. The total simulated patient population was divided into weight deciles (the range of body weights is presented on the x‐axis). The boxes represent 50% of the simulated population, bisected by the median value. The whiskers represent the predicted range for 95% of the simulated population. CNS = central nervous system; CSF = cerebrospinal fluid; Ctrough = trough concentration.