A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy

Nathalie Goemans, Eugenio Mercuri, Elena Belousova, Hirofumi Komaki, Alberto Dubrovsky, Craig M McDonald, John E. Kraus, Afrodite Lourbakos, Zhengning Lin, Giles Campion, Susanne X. Wang, Craig Campbell

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

Original languageEnglish (US)
JournalNeuromuscular Disorders
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Duchenne Muscular Dystrophy
Antisense Oligonucleotides
Placebos
Exons
PRO051
Kidney
Safety
Mutation
Injections
Population

Keywords

  • Antisense oligonucleotide
  • Drisapersen
  • Duchenne muscular dystrophy
  • Dystrophin
  • Exon skipping
  • Six-minute walking distance

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Clinical Neurology
  • Genetics(clinical)

Cite this

A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. / Goemans, Nathalie; Mercuri, Eugenio; Belousova, Elena; Komaki, Hirofumi; Dubrovsky, Alberto; McDonald, Craig M; Kraus, John E.; Lourbakos, Afrodite; Lin, Zhengning; Campion, Giles; Wang, Susanne X.; Campbell, Craig.

In: Neuromuscular Disorders, 01.01.2017.

Research output: Contribution to journalArticle

Goemans, N, Mercuri, E, Belousova, E, Komaki, H, Dubrovsky, A, McDonald, CM, Kraus, JE, Lourbakos, A, Lin, Z, Campion, G, Wang, SX & Campbell, C 2017, 'A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy', Neuromuscular Disorders. https://doi.org/10.1016/j.nmd.2017.10.004
Goemans, Nathalie ; Mercuri, Eugenio ; Belousova, Elena ; Komaki, Hirofumi ; Dubrovsky, Alberto ; McDonald, Craig M ; Kraus, John E. ; Lourbakos, Afrodite ; Lin, Zhengning ; Campion, Giles ; Wang, Susanne X. ; Campbell, Craig. / A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. In: Neuromuscular Disorders. 2017.
@article{130324c62c9e46f692523341cd4040f8,
title = "A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy",
abstract = "This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90{\%} to actual 53{\%}. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.",
keywords = "Antisense oligonucleotide, Drisapersen, Duchenne muscular dystrophy, Dystrophin, Exon skipping, Six-minute walking distance",
author = "Nathalie Goemans and Eugenio Mercuri and Elena Belousova and Hirofumi Komaki and Alberto Dubrovsky and McDonald, {Craig M} and Kraus, {John E.} and Afrodite Lourbakos and Zhengning Lin and Giles Campion and Wang, {Susanne X.} and Craig Campbell",
year = "2017",
month = "1",
day = "1",
doi = "10.1016/j.nmd.2017.10.004",
language = "English (US)",
journal = "Neuromuscular Disorders",
issn = "0960-8966",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy

AU - Goemans, Nathalie

AU - Mercuri, Eugenio

AU - Belousova, Elena

AU - Komaki, Hirofumi

AU - Dubrovsky, Alberto

AU - McDonald, Craig M

AU - Kraus, John E.

AU - Lourbakos, Afrodite

AU - Lin, Zhengning

AU - Campion, Giles

AU - Wang, Susanne X.

AU - Campbell, Craig

PY - 2017/1/1

Y1 - 2017/1/1

N2 - This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

AB - This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

KW - Antisense oligonucleotide

KW - Drisapersen

KW - Duchenne muscular dystrophy

KW - Dystrophin

KW - Exon skipping

KW - Six-minute walking distance

UR - http://www.scopus.com/inward/record.url?scp=85035316347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85035316347&partnerID=8YFLogxK

U2 - 10.1016/j.nmd.2017.10.004

DO - 10.1016/j.nmd.2017.10.004

M3 - Article

C2 - 29203355

AN - SCOPUS:85035316347

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

SN - 0960-8966

ER -