Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study
Nathalie M Goemans, Már Tulinius, Marleen van den Hauwe, Anna-Karin Kroksmark, Gunnar Buyse, Rosamund J Wilson, Judith C van Deutekom, Sjef J de Kimpe, Afrodite Lourbakos, Giles Campion, Nathalie M Goemans, Már Tulinius, Marleen van den Hauwe, Anna-Karin Kroksmark, Gunnar Buyse, Rosamund J Wilson, Judith C van Deutekom, Sjef J de Kimpe, Afrodite Lourbakos, Giles Campion
Abstract
Background: Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations.
Methods: This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73-80), followed by intermittent dosing (weeks 81-188).
Results: Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored "zero". When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking ≥330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary α1-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72.
Conclusion: Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable cohort.
Trial registration: ClinicalTrials.gov NCT01910649.
Conflict of interest statement
Competing Interests: Nathalie M. Goemans has received funding for trials from Prosensa Therapeutics BV limited to the study costs. Rosamund J. Wilson was an employee of Spica Consultants Ltd, Marlborough, UK, and had a consultancy contract with Prosensa Therapeutics BV. Judith C. van Deutekom, Sjef J. de Kimpe, Afrodite Lourbakos and Giles V. Campion were employees (which includes contribution to patent [applications] and participation in stock-option plans) of Prosensa Therapeutics BV. Judith C. van Deutekom, Sjef J. de Kimpe, Afrodite Lourbakos and Giles V. Campion are employees (which includes participation in stock-option plans) of BioMarin Pharamaceutical Inc. None of the contributing authors listed on this paper were affiliated with GlaxoSmithKline at the time of the study. Már Tulinius, Marleen van den Hauwe, Anna-Karin Kroksmark, and Gunnar Buyse have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Figures
![Fig 1. Patient flow diagram.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010191/bin/pone.0161955.g001.jpg)
![Fig 2. Change from extension study baseline…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010191/bin/pone.0161955.g002.jpg)
Fig 3. α 1 -Microglobulin levels over…
Fig 3. α 1 -Microglobulin levels over 177 weeks.
Subjects 1, 2, 5, 6, 7, 9, and…
Fig 4. Individual drisapersen trough concentrations from…
Fig 4. Individual drisapersen trough concentrations from weeks 72 to 184.
Subject 5 had an…
Fig 5. Comparison of change from baseline…
Fig 5. Comparison of change from baseline in 6MWD from drisapersen-treated subjects with natural history…
- Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study.Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N, Campion G, De Kimpe SJ, Eagle M, Guglieri M, Hood S, Liefaard L, Lourbakos A, Morgan A, Nakielny J, Quarcoo N, Ricotti V, Rolfe K, Servais L, Wardell C, Wilson R, Wright P, Kraus JE. Voit T, et al. Lancet Neurol. 2014 Oct;13(10):987-96. doi: 10.1016/S1474-4422(14)70195-4. Epub 2014 Sep 7. Lancet Neurol. 2014. PMID: 25209738 Clinical Trial.
- Comparison of ambulatory capacity and disease progression of Duchenne muscular dystrophy subjects enrolled in the drisapersen DMD114673 study with a matched natural history cohort of subjects on daily corticosteroids.Goemans N, Tulinius M, Kroksmark AK, Wilson R, van den Hauwe M, Campion G. Goemans N, et al. Neuromuscul Disord. 2017 Mar;27(3):203-213. doi: 10.1016/j.nmd.2016.11.013. Epub 2016 Nov 25. Neuromuscul Disord. 2017. PMID: 28169120
- Systemic administration of PRO051 in Duchenne's muscular dystrophy.Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC. Goemans NM, et al. N Engl J Med. 2011 Apr 21;364(16):1513-22. doi: 10.1056/NEJMoa1011367. Epub 2011 Mar 23. N Engl J Med. 2011. PMID: 21428760 Clinical Trial.
- Exon skipping therapy for Duchenne muscular dystrophy.Kole R, Krieg AM. Kole R, et al. Adv Drug Deliv Rev. 2015 Jun 29;87:104-7. doi: 10.1016/j.addr.2015.05.008. Epub 2015 May 14. Adv Drug Deliv Rev. 2015. PMID: 25980936 Review.
- Corticosteroids for the treatment of Duchenne muscular dystrophy.Matthews E, Brassington R, Kuntzer T, Jichi F, Manzur AY. Matthews E, et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4. Cochrane Database Syst Rev. 2016. PMID: 27149418 Free PMC article. Review.
- Development of Therapeutic RNA Manipulation for Muscular Dystrophy.Saifullah, Motohashi N, Tsukahara T, Aoki Y. Saifullah, et al. Front Genome Ed. 2022 May 10;4:863651. doi: 10.3389/fgeed.2022.863651. eCollection 2022. Front Genome Ed. 2022. PMID: 35620642 Free PMC article. Review.
- Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy.Siemionow M, Langa P, Brodowska S, Kozlowska K, Zalants K, Budzynska K, Heydemann A. Siemionow M, et al. Stem Cell Rev Rep. 2022 Dec;18(8):2872-2892. doi: 10.1007/s12015-022-10384-2. Epub 2022 May 19. Stem Cell Rev Rep. 2022. PMID: 35590083 Free PMC article.
- In vivo and in vitro studies of antisense oligonucleotides - a review.Kilanowska A, Studzińska S. Kilanowska A, et al. RSC Adv. 2020 Sep 17;10(57):34501-34516. doi: 10.1039/d0ra04978f. eCollection 2020 Sep 16. RSC Adv. 2020. PMID: 35514414 Free PMC article. Review.
- Antisense Oligonucleotides Conjugated with Lipophilic Compounds: Synthesis and In Vitro Evaluation of Exon Skipping in Duchenne Muscular Dystrophy.Marchesi E, Cortesi R, Preti L, Rimessi P, Sguizzato M, Bovolenta M, Perrone D. Marchesi E, et al. Int J Mol Sci. 2022 Apr 12;23(8):4270. doi: 10.3390/ijms23084270. Int J Mol Sci. 2022. PMID: 35457088 Free PMC article.
- Prognostic indicators of disease progression in Duchenne muscular dystrophy: A literature review and evidence synthesis.Ferizovic N, Summers J, de Zárate IBO, Werner C, Jiang J, Landfeldt E, Buesch K. Ferizovic N, et al. PLoS One. 2022 Mar 25;17(3):e0265879. doi: 10.1371/journal.pone.0265879. eCollection 2022. PLoS One. 2022. PMID: 35333888 Free PMC article. Review.
-
- Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul.Disord. 1991;1:19–29. - PubMed
-
- Henricson E, Abresch R, Han JJ, Nicorici A, Goude Keller E, de Bie E et al. The 6-minute walk test and person-reported outcomes in boys with duchenne muscular dystrophy and typically developing controls: longitudinal comparisons and clinically-meaningful changes over one year. PLoS.Curr. 2013;5: - PMC - PubMed
- Clinical Trial, Phase I
- Clinical Trial, Phase II
- Adolescent
- Child
- Child, Preschool
- Dystrophin / genetics
- Dystrophin / metabolism
- Exercise Test
- Humans
- Male
- Muscle, Skeletal / metabolism
- Muscular Dystrophy, Duchenne / drug therapy*
- Muscular Dystrophy, Duchenne / genetics
- Muscular Dystrophy, Duchenne / metabolism
- Oligonucleotides / adverse effects
- Oligonucleotides / pharmacokinetics
- Oligonucleotides / therapeutic use*
- Treatment Outcome
- Walking / physiology
- Dystrophin
- Oligonucleotides
- PRO051
- ClinicalTrials.gov/NCT01910649
- Full Text Sources
- Other Literature Sources
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![Fig 3. α 1 -Microglobulin levels over…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010191/bin/pone.0161955.g003.jpg)
Fig 4. Individual drisapersen trough concentrations from…
Fig 4. Individual drisapersen trough concentrations from weeks 72 to 184.
Subject 5 had an…
Fig 5. Comparison of change from baseline…
Fig 5. Comparison of change from baseline in 6MWD from drisapersen-treated subjects with natural history…
- Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study.Voit T, Topaloglu H, Straub V, Muntoni F, Deconinck N, Campion G, De Kimpe SJ, Eagle M, Guglieri M, Hood S, Liefaard L, Lourbakos A, Morgan A, Nakielny J, Quarcoo N, Ricotti V, Rolfe K, Servais L, Wardell C, Wilson R, Wright P, Kraus JE. Voit T, et al. Lancet Neurol. 2014 Oct;13(10):987-96. doi: 10.1016/S1474-4422(14)70195-4. Epub 2014 Sep 7. Lancet Neurol. 2014. PMID: 25209738 Clinical Trial.
- Comparison of ambulatory capacity and disease progression of Duchenne muscular dystrophy subjects enrolled in the drisapersen DMD114673 study with a matched natural history cohort of subjects on daily corticosteroids.Goemans N, Tulinius M, Kroksmark AK, Wilson R, van den Hauwe M, Campion G. Goemans N, et al. Neuromuscul Disord. 2017 Mar;27(3):203-213. doi: 10.1016/j.nmd.2016.11.013. Epub 2016 Nov 25. Neuromuscul Disord. 2017. PMID: 28169120
- Systemic administration of PRO051 in Duchenne's muscular dystrophy.Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC. Goemans NM, et al. N Engl J Med. 2011 Apr 21;364(16):1513-22. doi: 10.1056/NEJMoa1011367. Epub 2011 Mar 23. N Engl J Med. 2011. PMID: 21428760 Clinical Trial.
- Exon skipping therapy for Duchenne muscular dystrophy.Kole R, Krieg AM. Kole R, et al. Adv Drug Deliv Rev. 2015 Jun 29;87:104-7. doi: 10.1016/j.addr.2015.05.008. Epub 2015 May 14. Adv Drug Deliv Rev. 2015. PMID: 25980936 Review.
- Corticosteroids for the treatment of Duchenne muscular dystrophy.Matthews E, Brassington R, Kuntzer T, Jichi F, Manzur AY. Matthews E, et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4. Cochrane Database Syst Rev. 2016. PMID: 27149418 Free PMC article. Review.
- Development of Therapeutic RNA Manipulation for Muscular Dystrophy.Saifullah, Motohashi N, Tsukahara T, Aoki Y. Saifullah, et al. Front Genome Ed. 2022 May 10;4:863651. doi: 10.3389/fgeed.2022.863651. eCollection 2022. Front Genome Ed. 2022. PMID: 35620642 Free PMC article. Review.
- Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy.Siemionow M, Langa P, Brodowska S, Kozlowska K, Zalants K, Budzynska K, Heydemann A. Siemionow M, et al. Stem Cell Rev Rep. 2022 Dec;18(8):2872-2892. doi: 10.1007/s12015-022-10384-2. Epub 2022 May 19. Stem Cell Rev Rep. 2022. PMID: 35590083 Free PMC article.
- In vivo and in vitro studies of antisense oligonucleotides - a review.Kilanowska A, Studzińska S. Kilanowska A, et al. RSC Adv. 2020 Sep 17;10(57):34501-34516. doi: 10.1039/d0ra04978f. eCollection 2020 Sep 16. RSC Adv. 2020. PMID: 35514414 Free PMC article. Review.
- Antisense Oligonucleotides Conjugated with Lipophilic Compounds: Synthesis and In Vitro Evaluation of Exon Skipping in Duchenne Muscular Dystrophy.Marchesi E, Cortesi R, Preti L, Rimessi P, Sguizzato M, Bovolenta M, Perrone D. Marchesi E, et al. Int J Mol Sci. 2022 Apr 12;23(8):4270. doi: 10.3390/ijms23084270. Int J Mol Sci. 2022. PMID: 35457088 Free PMC article.
- Prognostic indicators of disease progression in Duchenne muscular dystrophy: A literature review and evidence synthesis.Ferizovic N, Summers J, de Zárate IBO, Werner C, Jiang J, Landfeldt E, Buesch K. Ferizovic N, et al. PLoS One. 2022 Mar 25;17(3):e0265879. doi: 10.1371/journal.pone.0265879. eCollection 2022. PLoS One. 2022. PMID: 35333888 Free PMC article. Review.
-
- Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul.Disord. 1991;1:19–29. - PubMed
-
- Henricson E, Abresch R, Han JJ, Nicorici A, Goude Keller E, de Bie E et al. The 6-minute walk test and person-reported outcomes in boys with duchenne muscular dystrophy and typically developing controls: longitudinal comparisons and clinically-meaningful changes over one year. PLoS.Curr. 2013;5: - PMC - PubMed
- Clinical Trial, Phase I
- Clinical Trial, Phase II
- Adolescent
- Child
- Child, Preschool
- Dystrophin / genetics
- Dystrophin / metabolism
- Exercise Test
- Humans
- Male
- Muscle, Skeletal / metabolism
- Muscular Dystrophy, Duchenne / drug therapy*
- Muscular Dystrophy, Duchenne / genetics
- Muscular Dystrophy, Duchenne / metabolism
- Oligonucleotides / adverse effects
- Oligonucleotides / pharmacokinetics
- Oligonucleotides / therapeutic use*
- Treatment Outcome
- Walking / physiology
- Dystrophin
- Oligonucleotides
- PRO051
- ClinicalTrials.gov/NCT01910649
- Full Text Sources
- Other Literature Sources
- Medical
![Fig 4. Individual drisapersen trough concentrations from…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010191/bin/pone.0161955.g004.jpg)
Fig 5. Comparison of change from baseline…
Fig 5. Comparison of change from baseline in 6MWD from drisapersen-treated subjects with natural history…
![Fig 5. Comparison of change from baseline…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5010191/bin/pone.0161955.g005.jpg)
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Source: PubMed