Phase 1/2a for Safety, PK and PD of SQY51 in Paediatric and Adult Patients Duchenne Muscular Dystrophy

Summary

This is a Phase 1/2a, monocentric, open label study to evaluate the safety, pharmacokinetics, and pharmacodynamics of SQY51 in patients with Duchenne muscular dystrophy

Timeline

Start

2023-04-26

Primary completion

2025-02

Completion

2025-02

Publications

• Background Bladen CL, Rafferty K, Straub V, Monges S, Moresco A, Dawkins H, Roy A, Chamova T, Guergueltcheva V, Korngut L, Campbell C, Dai Y, Barisic N, Kos T, Brabec P, Rahbek J, Lahdetie J, Tuffery-Giraud S, Claustres M, Leturcq F, Ben Yaou R, Walter MC, Schreiber O, Karcagi V, Herczegfalvi A, Viswanathan V, Bayat F, de la Caridad Guerrero Sarmiento I, Ambrosini A, Ceradini F, Kimura E, van den Bergen JC, Rodrigues M, Roxburgh R, Lusakowska A, Oliveira J, Santos R, Neagu E, Butoianu N, Artemieva S, Rasic VM, Posada M, Palau F, Lindvall B, Bloetzer C, Karaduman A, Topaloglu H, Inal S, Oflazer P, Stringer A, Shatillo AV, Martin AS, Peay H, Flanigan KM, Salgado D, von Rekowski B, Lynn S, Heslop E, Gainotti S, Taruscio D, Kirschner J, Verschuuren J, Bushby K, Beroud C, Lochmuller H. The TREAT-NMD Duchenne muscular dystrophy registries: conception, design, and utilization by industry and academia. Hum Mutat. 2013 Nov;34(11):1449-57. doi: 10.1002/humu.22390. Epub 2013 Aug 26.
• Background Ryder S, Leadley RM, Armstrong N, Westwood M, de Kock S, Butt T, Jain M, Kleijnen J. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis. 2017 Apr 26;12(1):79. doi: 10.1186/s13023-017-0631-3.
• Background Mendell JR, Shilling C, Leslie ND, Flanigan KM, al-Dahhak R, Gastier-Foster J, Kneile K, Dunn DM, Duval B, Aoyagi A, Hamil C, Mahmoud M, Roush K, Bird L, Rankin C, Lilly H, Street N, Chandrasekar R, Weiss RB. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012 Mar;71(3):304-13. doi: 10.1002/ana.23528.
• Background Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK). Eur J Hum Genet. 2013 Oct;21(10):1049-53. doi: 10.1038/ejhg.2012.301. Epub 2013 Jan 23.
• Background McDonald CM, Henricson EK, Abresch RT, Han JJ, Escolar DM, Florence JM, Duong T, Arrieta A, Clemens PR, Hoffman EP, Cnaan A; Cinrg Investigators. The cooperative international neuromuscular research group Duchenne natural history study--a longitudinal investigation in the era of glucocorticoid therapy: design of protocol and the methods used. Muscle Nerve. 2013 Jul;48(1):32-54. doi: 10.1002/mus.23807. Epub 2013 May 16.
• Background Li D, Mastaglia FL, Fletcher S, Wilton SD. Precision Medicine through Antisense Oligonucleotide-Mediated Exon Skipping. Trends Pharmacol Sci. 2018 Nov;39(11):982-994. doi: 10.1016/j.tips.2018.09.001. Epub 2018 Sep 30.
• Background Echevarria L, Aupy P, Goyenvalle A. Exon-skipping advances for Duchenne muscular dystrophy. Hum Mol Genet. 2018 Aug 1;27(R2):R163-R172. doi: 10.1093/hmg/ddy171.
• Background Goyenvalle A, Griffith G, Babbs A, El Andaloussi S, Ezzat K, Avril A, Dugovic B, Chaussenot R, Ferry A, Voit T, Amthor H, Buhr C, Schurch S, Wood MJ, Davies KE, Vaillend C, Leumann C, Garcia L. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat Med. 2015 Mar;21(3):270-5. doi: 10.1038/nm.3765. Epub 2015 Feb 2.
• Background Renneberg D, Leumann CJ. Watson-Crick base-pairing properties of tricyclo-DNA. J Am Chem Soc. 2002 May 29;124(21):5993-6002. doi: 10.1021/ja025569+.
• Background Ittig D, Gerber AB, Leumann CJ. Position-dependent effects on stability in tricyclo-DNA modified oligonucleotide duplexes. Nucleic Acids Res. 2011 Jan;39(1):373-80. doi: 10.1093/nar/gkq733. Epub 2010 Aug 17.
• Background Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, Case LE, Clemens PR, Hadjiyannakis S, Pandya S, Street N, Tomezsko J, Wagner KR, Ward LM, Weber DR; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3. Epub 2018 Feb 3.
• Background Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, Case LE, Cripe L, Hadjiyannakis S, Olson AK, Sheehan DW, Bolen J, Weber DR, Ward LM; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5. Epub 2018 Feb 3.
• Background Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK, Cripe L, Herron AR, Kennedy A, Kinnett K, Naprawa J, Noritz G, Poysky J, Street N, Trout CJ, Weber DR, Ward LM; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7. Epub 2018 Feb 2.
• Background McDonald CM, Campbell C, Torricelli RE, Finkel RS, Flanigan KM, Goemans N, Heydemann P, Kaminska A, Kirschner J, Muntoni F, Osorio AN, Schara U, Sejersen T, Shieh PB, Sweeney HL, Topaloglu H, Tulinius M, Vilchez JJ, Voit T, Wong B, Elfring G, Kroger H, Luo X, McIntosh J, Ong T, Riebling P, Souza M, Spiegel RJ, Peltz SW, Mercuri E; Clinical Evaluator Training Group; ACT DMD Study Group. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Sep 23;390(10101):1489-1498. doi: 10.1016/S0140-6736(17)31611-2. Epub 2017 Jul 17.
• Background Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982. Epub 2013 Sep 10.
• Background Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E; Eteplirsen Study Group and Telethon Foundation DMD Italian Network. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016 Feb;79(2):257-71. doi: 10.1002/ana.24555. Epub 2016 Jan 8.
• Background Charleston JS, Schnell FJ, Dworzak J, Donoghue C, Lewis S, Chen L, Young GD, Milici AJ, Voss J, DeAlwis U, Wentworth B, Rodino-Klapac LR, Sahenk Z, Frank D, Mendell JR. Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. Neurology. 2018 Jun 12;90(24):e2146-e2154. doi: 10.1212/WNL.0000000000005680. Epub 2018 May 11.
• Background Kinane TB, Mayer OH, Duda PW, Lowes LP, Moody SL, Mendell JR. Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History. J Neuromuscul Dis. 2018;5(1):47-58. doi: 10.3233/JND-170272.
• Background Alfano LN, Charleston JS, Connolly AM, Cripe L, Donoghue C, Dracker R, Dworzak J, Eliopoulos H, Frank DE, Lewis S, Lucas K, Lynch J, Milici AJ, Flynt A, Naughton E, Rodino-Klapac LR, Sahenk Z, Schnell FJ, Young GD, Mendell JR, Lowes LP. Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy. Medicine (Baltimore). 2019 Jun;98(26):e15858. doi: 10.1097/MD.0000000000015858.
• Background Chamberlain JR, Chamberlain JS. Progress toward Gene Therapy for Duchenne Muscular Dystrophy. Mol Ther. 2017 May 3;25(5):1125-1131. doi: 10.1016/j.ymthe.2017.02.019. Epub 2017 Apr 15.
• Background Relizani K, Echevarria L, Zarrouki F, Gastaldi C, Dambrune C, Aupy P, Haeberli A, Komisarski M, Tensorer T, Larcher T, Svinartchouk F, Vaillend C, Garcia L, Goyenvalle A. Palmitic acid conjugation enhances potency of tricyclo-DNA splice switching oligonucleotides. Nucleic Acids Res. 2022 Jan 11;50(1):17-34. doi: 10.1093/nar/gkab1199.
• Background Berard C, Payan C, Hodgkinson I, Fermanian J; MFM Collaborative Study Group. A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul Disord. 2005 Jul;15(7):463-70. doi: 10.1016/j.nmd.2005.03.004.
• Background Mayhew AG, Coratti G, Mazzone ES, Klingels K, James M, Pane M, Straub V, Goemans N, Mercuri E; Pul Working Group. Performance of Upper Limb module for Duchenne muscular dystrophy. Dev Med Child Neurol. 2020 May;62(5):633-639. doi: 10.1111/dmcn.14361. Epub 2019 Sep 19.
• Background McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, Atkinson L, Reha A, Hirawat S, Miller LL. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010 Apr;41(4):500-10. doi: 10.1002/mus.21544.
• Background ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available.
• Background Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005 Jul;26(1):153-61. doi: 10.1183/09031936.05.00034505. No abstract available.
• Background Servais L, Deconinck N, Moraux A, Benali M, Canal A, Van Parys F, Vereecke W, Wittevrongel S, Mayer M, Desguerre I, Maincent K, Themar-Noel C, Quijano-Roy S, Serari N, Voit T, Hogrel JY. Innovative methods to assess upper limb strength and function in non-ambulant Duchenne patients. Neuromuscul Disord. 2013 Feb;23(2):139-48. doi: 10.1016/j.nmd.2012.10.022. Epub 2012 Dec 5.
• Background Davis SE, Hynan LS, Limbers CA, Andersen CM, Greene MC, Varni JW, Iannaccone ST. The PedsQL in pediatric patients with Duchenne muscular dystrophy: feasibility, reliability, and validity of the Pediatric Quality of Life Inventory Neuromuscular Module and Generic Core Scales. J Clin Neuromuscul Dis. 2010 Mar;11(3):97-109. doi: 10.1097/CND.0b013e3181c5053b.
• Background Rouillon J, Poupiot J, Zocevic A, Amor F, Leger T, Garcia C, Camadro JM, Wong B, Pinilla R, Cosette J, Coenen-Stass AM, Mcclorey G, Roberts TC, Wood MJ, Servais L, Udd B, Voit T, Richard I, Svinartchouk F. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies. Hum Mol Genet. 2015 Sep 1;24(17):4916-32. doi: 10.1093/hmg/ddv214. Epub 2015 Jun 9.
• Background McMillan HJ, Gregas M, Darras BT, Kang PB. Serum transaminase levels in boys with Duchenne and Becker muscular dystrophy. Pediatrics. 2011 Jan;127(1):e132-6. doi: 10.1542/peds.2010-0929. Epub 2010 Dec 13.
• Background Spurney CF, Ascheim D, Charnas L, Cripe L, Hor K, King N, Kinnett K, McNally EM, Sauer JM, Sweeney L, Villa C, Markham LW. Current state of cardiac troponin testing in Duchenne muscular dystrophy cardiomyopathy: review and recommendations from the Parent Project Muscular Dystrophy expert panel. Open Heart. 2021 Mar;8(1):e001592. doi: 10.1136/openhrt-2021-001592.
• Background Braat E, Hoste L, De Waele L, Gheysens O, Vermeersch P, Goffin K, Pottel H, Goemans N, Levtchenko E. Renal function in children and adolescents with Duchenne muscular dystrophy. Neuromuscul Disord. 2015 May;25(5):381-7. doi: 10.1016/j.nmd.2015.01.005. Epub 2015 Jan 19.
• Background Filler G, Lepage N. Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol. 2003 Oct;18(10):981-5. doi: 10.1007/s00467-003-1271-5. Epub 2003 Aug 13.

Drugs

Indications