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. 2023;10(5):813-823.
doi: 10.3233/JND-221667.

DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results

Richard S Finkel  1 , John W Day  2 , Samuel Ignacio Pascual Pascual  3 , Monique M Ryan  4 , Eugenio Mercuri  5 , Darryl C De Vivo  6 , Jacqueline Montes  7 , Juliana Gurgel-Giannetti  8 , Michael Monine  9 , Giulia Gambino  10 , Corinne Makepeace  10 , Richard Foster  10 , Zdenek Berger  9 ; DEVOTE Study Group
Affiliations

DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results

Richard S Finkel et al. J Neuromuscul Dis. 2023.

Abstract

Background: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose.

Objective: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A.

Methods: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses.

Results: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1-12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing.

Conclusions: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

Keywords: Spinal muscular atrophy; nusinersen; pharmacokinetics; safety.

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Conflict of interest statement

RSF: is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review; consultant to AveXis, Biogen, Capricor, Cytokinetics, Genentech, Novartis, Roche, and Scholar Rock on SMA related topics and with no financial interests in these companies; received SMA clinical trial funding from Biogen/Ionis, AveXis/Novartis, Genentech/Roche, Cytokinetics, and Scholar Rock; research funding from Biogen, Cure SMA, Genentech, SMA Foundation, Muscular Dystrophy Association, National Institutes of Health; data safety monitoring boards for the AveXis AVXS-101 START study, Roche MOONFISH study, and Ionis Angelman HALOS study; received royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale.

JWD: is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review; consultant for Avidity Biosciences; Biogen; BioMarin; Cytokinetics; Epirium Bio; Ionis Pharmaceuticals; Kate Therapeutics; Novartis Gene Therapies; PepGen; Roche/Genentech Pharmaceuticals; Sarepta Therapeutics; Scholar Rock; Shift Therapeutics; Vertex Pharmaceuticals, with no financial interest in these companies; research grant support from AMO Pharma; Avidity Biosciences; Biogen; Cure SMA; Cytokinetics; Genentech; Ionis Pharmaceuticals; Muscular Dystrophy Association; Novartis Gene Therapies; Roche Pharmaceuticals; Sanofi-Genzyme; Sarepta Therapeutics; Scholar Rock; SMA Foundation. He receives royalties and licensing fees from Athena Diagnostics for 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.

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

MMR: advisory boards for nonprofit organizations: FSHD Global Research Foundation, Muscular Dystrophy Foundation, and Save Our Sons Duchenne Foundation; honoraria from Biogen and BioMarin; research funding from FSHD Global Research Foundation and Save Our Sons Duchenne Foundation; grants/advisor fees from Biogen and Genzyme.

EM: advisory boards for SMA studies for AveXis, Biogen, Ionis, Novartis, and Roche; Principal Investigator for ongoing Biogen/Ionis and Roche clinical trials; funding from Famiglie SMA Italy, Italian Telethon, and SMA Europe.

DCD: advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis, METAFORA, Roche, Sanofi, Sarepta, Scholar Rock, SMA Foundation, and Ultragenyx, with no financial interests in these companies; grants from Cure SMA, Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, National Institutes of Health, and SMA Foundation; 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; clinical trial funding from Biogen, Ionis, Mallinckrodt, PTC, Santhera, Sarepta, Scholar Rock, and Ultragenyx.

JM: advisory boards for Biogen, Roche, and Scholar Rock; consultant for Biogen and Scholar Rock; research support from Eunice Kennedy Shriver National Institute for Child Health and Human Development (K01HD084690) and Muscular Dystrophy Association (575870 and 629259).

JG-G: advisory boards for AveXis/Novartis, Biogen, BioMarin, PTC, Roche, and Sarepta; Principal Investigator for ongoing clinical PTC and Sarepta trials; research funding from CAPES, CNPq, and FAPEMIG (Brazil).

MM, GG, CM, RF, and ZB: employees of and hold stock/stock options in Biogen.

Figures

Fig. 1
Fig. 1
Study design. aParticipants who meet the protocol criteria for contraception use will complete additional visit (Day 399 in Part B, Day 361 in Part C). D, day. mo, months. SMA, spinal muscular atrophy. y, years.
Fig. 2
Fig. 2
Nusinersen levels in the CSF in DEVOTE Part A are greater than those with the 12-mg dose, as predicted by the population PK model. Individual level DEVOTE Part A data of nusinersen concentrations in the CSF (Ctrough) show steady increase through the loading dose period and reaching median concentration of 8.7 ng/mL on Day 29. On Day 269, the last measurement in Part A, the observed median pre-dose CSF Ctrough was 10.2 ng/mL. The predicted CSF Ctrough for the 12-mg dose regimen are 6.1 ng/mL on Day 29 and 5.6 ng/mL on Day 269. CSF levels of nusinersen increased during loading. CSF, cerebrospinal fluid.
Fig. 3
Fig. 3
Individual level data for HMFSE and RULM from Day 1 to Day 302 in Part A with x-axis showing age of participants. A: HFMSE total score. B: RULM total score. Most participants in Part A showed improvement or stabilization in motor function after treatment with nusinersen 28 mg. *Participant 2 reported a fall and fractured femur as treatment-emergent adverse events on Day 287, prior to the end of study visit; this participant had a 7-point decrease in HMFSE score from baseline to end of study, likely due to these adverse events. HFMSE, Hammersmith Functional Motor Scale –Expanded. RULM, Revised Upper Limb Module.
See this image and copyright information in PMC

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