Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial
Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading...
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| Published in | Neuromuscular disorders : NMD Vol. 24; no. 1; pp. 16 - 24 |
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| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Elsevier B.V
01.01.2014
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0960-8966 1873-2364 1873-2364 |
| DOI | 10.1016/j.nmd.2013.09.004 |
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| Abstract | Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ⩾9years, in wheelchairs for ⩾1 to ⩽4years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12mg/kg), but study objectives were met with the 9mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6mg/kg range. Single doses of drisapersen at 3 and 6mg/kg did not result in significant safety or tolerability concerns; however, at the 9mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. |
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| AbstractList | Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-
O
-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ≥9 years, in wheelchairs for ≥1 to ≤4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. Abstract Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′- O -methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ⩾9 years, in wheelchairs for ⩾1 to ⩽4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ⩾9years, in wheelchairs for ⩾1 to ⩽4years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12mg/kg), but study objectives were met with the 9mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6mg/kg range. Single doses of drisapersen at 3 and 6mg/kg did not result in significant safety or tolerability concerns; however, at the 9mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged >=9 years, in wheelchairs for >=1 to [el]4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3-9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3-6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ⩾9years, in wheelchairs for ⩾1 to ⩽4years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12mg/kg), but study objectives were met with the 9mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3-9mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3-6mg/kg range. Single doses of drisapersen at 3 and 6mg/kg did not result in significant safety or tolerability concerns; however, at the 9mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population.Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ⩾9years, in wheelchairs for ⩾1 to ⩽4years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12mg/kg), but study objectives were met with the 9mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3-9mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3-6mg/kg range. Single doses of drisapersen at 3 and 6mg/kg did not result in significant safety or tolerability concerns; however, at the 9mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. |
| Author | Kraus, John E. Quarcoo, Naashika Voit, Thomas Liefaard, Lia Dorricott, Susie Campion, Giles Morgan, Allison Drury, Tom Wright, Padraig Nakielny, Joanna Rosales, Xiomara Q. Flanigan, Kevin M. Servais, Laurent Wardell, Claire |
| AuthorAffiliation | g GlaxoSmithKline, London, UK a Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, United States b Institut de Myologie, Université Pierre et Marie Curie Paris 6, UM 76, INSERM U 974, CNRS UMR 7215, France d GlaxoSmithKline, Stockley Park, UK c GlaxoSmithKline, Research Triangle Park, NC, United States f GlaxoSmithKline, Stevenage, UK e Prosensa Therapeutics BV, Leiden, The Netherlands |
| AuthorAffiliation_xml | – name: a Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, United States – name: c GlaxoSmithKline, Research Triangle Park, NC, United States – name: e Prosensa Therapeutics BV, Leiden, The Netherlands – name: d GlaxoSmithKline, Stockley Park, UK – name: b Institut de Myologie, Université Pierre et Marie Curie Paris 6, UM 76, INSERM U 974, CNRS UMR 7215, France – name: f GlaxoSmithKline, Stevenage, UK – name: g GlaxoSmithKline, London, UK |
| Author_xml | – sequence: 1 givenname: Kevin M. surname: Flanigan fullname: Flanigan, Kevin M. organization: Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, United States – sequence: 2 givenname: Thomas surname: Voit fullname: Voit, Thomas organization: Institut de Myologie, Université Pierre et Marie Curie Paris 6, UM 76, INSERM U 974, CNRS UMR 7215, France – sequence: 3 givenname: Xiomara Q. surname: Rosales fullname: Rosales, Xiomara Q. organization: Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, United States – sequence: 4 givenname: Laurent surname: Servais fullname: Servais, Laurent organization: Institut de Myologie, Université Pierre et Marie Curie Paris 6, UM 76, INSERM U 974, CNRS UMR 7215, France – sequence: 5 givenname: John E. surname: Kraus fullname: Kraus, John E. email: john.e.kraus@gsk.com organization: GlaxoSmithKline, Research Triangle Park, NC, United States – sequence: 6 givenname: Claire surname: Wardell fullname: Wardell, Claire organization: GlaxoSmithKline, Stockley Park, UK – sequence: 7 givenname: Allison surname: Morgan fullname: Morgan, Allison organization: Prosensa Therapeutics BV, Leiden, The Netherlands – sequence: 8 givenname: Susie surname: Dorricott fullname: Dorricott, Susie organization: Prosensa Therapeutics BV, Leiden, The Netherlands – sequence: 9 givenname: Joanna surname: Nakielny fullname: Nakielny, Joanna organization: GlaxoSmithKline, Stockley Park, UK – sequence: 10 givenname: Naashika surname: Quarcoo fullname: Quarcoo, Naashika organization: GlaxoSmithKline, Stockley Park, UK – sequence: 11 givenname: Lia surname: Liefaard fullname: Liefaard, Lia organization: GlaxoSmithKline, Stevenage, UK – sequence: 12 givenname: Tom surname: Drury fullname: Drury, Tom organization: GlaxoSmithKline, Stockley Park, UK – sequence: 13 givenname: Giles surname: Campion fullname: Campion, Giles organization: Prosensa Therapeutics BV, Leiden, The Netherlands – sequence: 14 givenname: Padraig surname: Wright fullname: Wright, Padraig organization: GlaxoSmithKline, London, UK |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24321374$$D View this record in MEDLINE/PubMed |
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| Keywords | Drisapersen Duchenne muscular dystrophy Exon 51 DMD Oligonucleotide Safety Dystrophin Non-ambulant Pharmacokinetics |
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| Snippet | Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the... Abstract Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the... |
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| SubjectTerms | Adolescent Biomarkers Child DMD Double-Blind Method Drisapersen Duchenne muscular dystrophy Dystrophin Exon 51 Humans Inflammation Mediators - analysis Male Muscular Dystrophy, Duchenne - drug therapy Muscular Dystrophy, Duchenne - metabolism Neurology Non-ambulant Oligonucleotide Oligonucleotides - administration & dosage Oligonucleotides - adverse effects Oligonucleotides - pharmacokinetics Oligonucleotides - therapeutic use Pharmacokinetics Safety |
| Title | Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial |
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