Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

SKIP-NMD Study Group; Diane E Frank; Frederick J Schnell; Cody Akana; Saleh H El-Husayni; Cody A Desjardins; Jennifer Morgan; Jay S Charleston; Valentina Sardone; Joana Domingos; George Dickson; Volker Straub; Michela Guglieri; Eugenio Mercuri; Laurent Servais; Francesco Muntoni; Linda Popplewell

doi:10.1212/WNL.0000000000009233

Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

SKIP-NMD Study Group, Diane E Frank, Frederick J Schnell, Cody Akana, Saleh H El-Husayni, Cody A Desjardins, Jennifer Morgan, Jay S Charleston, Valentina Sardone, Joana Domingos, George Dickson, Volker Straub, Michela Guglieri, Eugenio Mercuri, Laurent Servais, Francesco Muntoni, Linda Popplewell

SHLS Allied Health Professions

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.

METHODS: Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.

RESULTS: Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.

CONCLUSION: Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.

CLINICALTRIALSGOV IDENTIFIER: NCT02310906.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

Original language	English
Pages (from-to)	e2270-e2282
Journal	Neurology
Volume	94
Issue number	21
DOIs	https://doi.org/10.1212/WNL.0000000000009233
Publication status	Published - 5 Mar 2020

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SKIP-NMD Study Group, Frank, D. E., Schnell, F. J., Akana, C., El-Husayni, S. H., Desjardins, C. A., Morgan, J., Charleston, J. S., Sardone, V., Domingos, J., Dickson, G., Straub, V., Guglieri, M., Mercuri, E., Servais, L., Muntoni, F., & Popplewell, L. (2020). Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology, 94(21), e2270-e2282. https://doi.org/10.1212/WNL.0000000000009233

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title = "Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy",

abstract = "OBJECTIVE: To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.METHODS: Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.RESULTS: Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.CONCLUSION: Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.CLINICALTRIALSGOV IDENTIFIER: NCT02310906.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.",

author = "{SKIP-NMD Study Group} and Frank, {Diane E} and Schnell, {Frederick J} and Cody Akana and El-Husayni, {Saleh H} and Desjardins, {Cody A} and Jennifer Morgan and Charleston, {Jay S} and Valentina Sardone and Joana Domingos and George Dickson and Volker Straub and Michela Guglieri and Eugenio Mercuri and Laurent Servais and Francesco Muntoni and Linda Popplewell",

note = "Copyright {\textcopyright} 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",

year = "2020",

month = mar,

day = "5",

doi = "10.1212/WNL.0000000000009233",

language = "English",

volume = "94",

pages = "e2270--e2282",

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SKIP-NMD Study Group, Frank, DE, Schnell, FJ, Akana, C, El-Husayni, SH, Desjardins, CA, Morgan, J, Charleston, JS, Sardone, V, Domingos, J, Dickson, G, Straub, V, Guglieri, M, Mercuri, E, Servais, L, Muntoni, F & Popplewell, L 2020, 'Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy', Neurology, vol. 94, no. 21, pp. e2270-e2282. https://doi.org/10.1212/WNL.0000000000009233

TY - JOUR

T1 - Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

AU - SKIP-NMD Study Group

AU - Frank, Diane E

AU - Schnell, Frederick J

AU - Akana, Cody

AU - El-Husayni, Saleh H

AU - Desjardins, Cody A

AU - Morgan, Jennifer

AU - Charleston, Jay S

AU - Sardone, Valentina

AU - Domingos, Joana

AU - Dickson, George

AU - Straub, Volker

AU - Guglieri, Michela

AU - Mercuri, Eugenio

AU - Servais, Laurent

AU - Muntoni, Francesco

AU - Popplewell, Linda

PY - 2020/3/5

Y1 - 2020/3/5

N2 - OBJECTIVE: To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.METHODS: Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.RESULTS: Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.CONCLUSION: Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.CLINICALTRIALSGOV IDENTIFIER: NCT02310906.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

AB - OBJECTIVE: To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.METHODS: Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.RESULTS: Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.CONCLUSION: Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.CLINICALTRIALSGOV IDENTIFIER: NCT02310906.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

U2 - 10.1212/WNL.0000000000009233

DO - 10.1212/WNL.0000000000009233

M3 - Article

C2 - 32139505

SN - 0028-3878

VL - 94

SP - e2270-e2282

JO - Neurology

JF - Neurology

IS - 21

ER -

Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

Abstract

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