Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

Laurent Servais, Eugenio Mercuri, Volker Straub, Michela Guglieri, Andreea M Seferian, Mariacristina Scoto, Daniela Leone, Erica Koenig, Navid Khan, Ashish Dugar, Xiaodong Wang, Baoguang Han, Dan Wang, Francesco Muntoni, SKIP-NMD Study Group, Chiara Brusa, Laura Antonaci, Claudia Brogna, Laura Merli, Mauro Monforte, Giulia Norcia, Marika Pane, Gloria Ferrantini, George Dickson, Jennifer Morgan, Valentina Sardone, Cody Akana, Jay S Charleston, Cody A Desjardins, Saleh H El-Husayni, Diane E Frank, Frederick J Schnell, Laurent Servais, Eugenio Mercuri, Volker Straub, Michela Guglieri, Andreea M Seferian, Mariacristina Scoto, Daniela Leone, Erica Koenig, Navid Khan, Ashish Dugar, Xiaodong Wang, Baoguang Han, Dan Wang, Francesco Muntoni, SKIP-NMD Study Group, Chiara Brusa, Laura Antonaci, Claudia Brogna, Laura Merli, Mauro Monforte, Giulia Norcia, Marika Pane, Gloria Ferrantini, George Dickson, Jennifer Morgan, Valentina Sardone, Cody Akana, Jay S Charleston, Cody A Desjardins, Saleh H El-Husayni, Diane E Frank, Frederick J Schnell

Abstract

The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P < 0.001) and exon skipping (28.9-fold; P < 0.001). At 3 years, 6MWT change from baseline was -99.0 m for golodirsen-treated patients versus -181.4 m for external controls (P = 0.067), and loss of ambulation occurred in 9% versus 26% (P = 0.21). FVC%p declined 8.4% over 3 years in golodirsen-treated patients, comparing favorably with literature-reported rates. This study provides evidence for golodirsen biologic activity and long-term safety in a declining DMD population and suggests functional benefit versus external controls. Clinical Trial Registration number: NCT02310906.

Keywords: Duchenne muscular dystrophy; exon skipping; golodirsen.

Conflict of interest statement

L.S. has served on advisory boards for Sarepta Therapeutics, Inc.; E.M. has received consultant fees from Sarepta Therapeutics, Inc.; V.S. has received speaker honoraria from Sanofi Genzyme, is or has recently been on advisory boards for Audentes Therapeutics, Biogen, Exonics Therapeutics/Vertex, Novartis, Roche, Sarepta Therapeutics, Inc., and Wave Therapeutics, and has research collaborations with Sanofi Genzyme and Ultragenyx; M.G. has received speaker honoraria from Sarepta Therapeutics, Inc., is on advisory boards for Pfizer, has research collaboration with Sarepta Therapeutics, Inc., and is the Chair of the VBP15-004 study but does not have any financial interest with ReveraGen; A.M.S., M.S., and D.L. have nothing to disclose; E.K., N.K., A.D., X.W., B.H., and D.W. are or have been employees of Sarepta Therapeutics, Inc.; F.M. has received consultant fees and speaker honoraria from Sarepta Therapeutics, Inc., and is supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre.

Figures

FIG. 1.
FIG. 1.
(A) Study design. Part 1 was a double-blind, placebo-controlled, dose-titration period; each dose level was administered for ≥2 weeks. Part 2 was an open-label extension period, including all patients from Part 1 plus 13 new patients amenable to exon 53 skipping. The untreated arm consisted of patients not amenable to exon 53 skipping and, per protocol, was not a control group but was included to evaluate DMD natural history and exploratory biomarkers. Adapted with permission from Frank et al. [21]. DOI: https://doi.org/10.1212/WNL.0000000000009233. (B) Patient disposition. aPatients continued on treatment as randomized through enrollment and DSMB review. bReasons included enrollment in a therapeutic study (n = 2) and personal reasons (n = 1). B, biopsy; DMD, Duchenne muscular dystrophy; DSMB, Data Safety Monitoring Board.
FIG. 2.
FIG. 2.
(A) Mean dystrophin protein by western blot, (B) exon skipping by RT-PCR, (C) dystrophin protein by immunohistochemistry, and (D) percentage of F/D myosin-positive fibers were measured at baseline and after 48 weeks of golodirsen treatment. F/D, fetal/developmental; ns, not significant; RT-PCR, reverse transcription polymerase chain reaction.
FIG. 3.
FIG. 3.
Ambulatory function: (A) 6MWT distance and (B) loss of ambulation over 3 years in golodirsen-treated patients and matched exon 53 skip-amenable natural history external controls. 6MWT, 6-minute walk test.

References

    1. Bello L, Morgenroth LP, Gordish-Dressman H, Hoffman EP, McDonald CM and Cirak S. (2016). DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study. Neurology 87:401–409.
    1. Mah JK. (2016). Current and emerging treatment strategies for Duchenne muscular dystrophy. Neuropsychiatr Dis Treat 12:1795–1807.
    1. Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, Case LE, Clemens PR, Hadjiyannakis S, et al. (2018). Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol 17:251–267.
    1. Crisafulli S, Sultana J, Fontana A, Salvo F, Messina S and Trifiro. G (2020). Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. Orphanet J Rare Dis 15:141.
    1. Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R and Bushby K. (2002). Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 12:926–929.
    1. Rall S and Grimm T. (2012). Survival in Duchenne muscular dystrophy. Acta Myol 31:117–120.
    1. Van Ruiten HJ, Marini Bettolo C, Cheetham T, Eagle M, Lochmuller H, Straub V, Bushby K and Guglieri M. (2016). Why are some patients with Duchenne muscular dystrophy dying young: an analysis of causes of death in North East England. Eur J Paediatr Neurol 20:904–909.
    1. Brogna C, Coratti G, Pane M, Ricotti V, Messina S, D'Amico A, Bruno C, Vita G, Berardinelli A, et al. (2019). Long-term natural history data in Duchenne muscular dystrophy ambulant patients with mutations amenable to skip exons 44, 45, 51 and 53. PLoS One 14:e0218683.
    1. Mazzone E, Vasco G, Sormani MP, Torrente Y, Berardinelli A, Messina S, D'Amico A, Doglio L, Politano L, et al. (2011). Functional changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study. Neurology 77:250–256.
    1. Mazzone ES, Pane M, Sormani MP, Scalise R, Berardinelli A, Messina S, Torrente Y, D'Amico A, Doglio L, et al. (2013). 24 month longitudinal data in ambulant boys with Duchenne muscular dystrophy. PLoS One 8:e52512.
    1. McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Atkinson L, Elfring GL, Reha A and Miller LL. (2010). The 6-minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations. Muscle Nerve 42:966–974.
    1. Bello L, D'Angelo G, Villa M, Fusto A, Vianello S, Merlo B, Sabbatini D, Barp A, Gandossini S and Magri F. (2020). Genetic modifiers of respiratory function in Duchenne muscular dystrophy. Ann Clin Transl Neurol 7:786–798.
    1. Wang RT, Barthelemy F, Martin AS, Douine ED, Eskin A, Lucas A, Lavigne J, Peay H, Khanlou N, et al. (2018). DMD genotype correlations from the Duchenne Registry: endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype. Hum Mutat 39:1193–1202.
    1. Hogrel JY, Decostre V, Ledoux I, de Antonio M, Niks EH, de Groot I, Straub V, Muntoni F, Ricotti V, et al. (2020). Normalized grip strength is a sensitive outcome measure through all stages of Duchenne muscular dystrophy. J Neurol 267:2022–2028.
    1. Servais L, Montus M, Guiner CL, Ben Yaou R, Annoussamy M, Moraux A, Hogrel JY, Seferian AM, Zehrouni K, et al. (2015). Non-ambulant Duchenne patients theoretically treatable by exon 53 skipping have severe phenotype. J Neuromuscul Dis 2:269–279.
    1. Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ and den Dunnen JT. (2009). Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 30:293–299.
    1. Lim KR, Maruyama R and Yokota T. (2017). Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 11:533–545.
    1. Vyondys 53 [package insert]. Sarepta Therapeutics, Inc., Cambridge, MA, 2020.
    1. Exondys 51 [package insert]. Sarepta Therapeutics, Inc., Cambridge, MA, 2020.
    1. Viltepso [package insert]. NS Pharma, Inc., Paramus, NJ, 2020.
    1. Amondys 45 [package insert]. Sarepta Therapeutics, Inc., Cambridge, MA, 2021.
    1. Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan J, Charleston JS, Sardone V, Domingos J, et al. (2020). Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology 94:e2270–e2282.
    1. Scaglioni D, Catapano F, Ellis M, Torelli S, Chambers D, Feng L, Beck M, Sewry C, Monforte M, et al. (2021). The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy. Acta Neuropathol Commun 9:7.
    1. Scaglioni D, Catapano F, Ellis M, Torelli S, Chambers D, Feng L, Beck M, Sewry C, Monforte M, et al. (2021). The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy. Acta Neuropathol Commun 9:7.
    1. Alfano LN, Charleston JS, Connolly AM, Cripe L, Donoghue C, Dracker R, Dworzak J, Eliopoulos H, Frank DE, et al. (2019). Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy. Medicine (Baltimore) 98:e15858.
    1. Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, et al. (2013). Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 74:637–647.
    1. Wagner KR, Kuntz NL, Koenig E, East L, Upadhyay S, Han B, Shieh PB. (2021). Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: A randomized, double-blind, placebo-controlled, dose-titration trial. Muscle Nerve 64:285–292.
    1. van Putten M, Hulsker M, Young C, Nadarajah VD, Heemskerk H, van der Weerd L, PAC ‘t Hoen, van Ommen GJ and Aartsma-Rus AM. (2013). Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double-knockout mice. FASEB J 27:2484–2495.
    1. Anthony K, Arechavala-Gomeza V, Ricotti V, Torelli S, Feng L, Janghra N, Tasca G, Guglieri M, Barresi R, et al. (2014). Biochemical characterization of patients with in-frame or out-of-frame DMD deletions pertinent to exon 44 or 45 skipping. JAMA Neurol 71:32–40.
    1. de Feraudy Y, Ben Yaou R, Wahbi K, Stalens C, Stantzou A, Laugel V, Desguerre I, Network F, Servais L, Leturcq F and Amthor H. (2021). Very low residual dystrophin quantity is associated with milder dystrophinopathy. Ann Neurol 89:280–292.
    1. Charleston JS, Schnell FJ, Dworzak J, Donoghue C, Lewis S, Chen L, Young GD, Milici AJ, Voss J, et al. (2018). Eteplirsen treatment for Duchenne muscular dystrophy: exon skipping and dystrophin production. Neurology 90:e2146–e2154.
    1. McDonald CM, Shieh PB, Abdel-Hamid HZ, Connolly AM, Ciafaloni E, Wagner KR, Goemans N, Mercuri E, Khan N, et al. (2021). Open-label evaluation of eteplirsen in patients with Duchenne muscular dystrophy amenable to exon 51 skipping: PROMOVI trial. J Neuromuscul Dis 8:989–1001.
    1. Summit Therapeutics. Proof of concept study to assess activity and safety of C1100 SMT(ezutomid) in boys with Duchenne muscular dystrophy. Accessed March 9, 2021.
    1. Straub V and Mercuri E; DMD Outcome Measure Study Group. (2018). Report on the workshop: meaningful outcome measures for Duchenne muscular dystrophy, London, UK, 30–31 January 2017. Neuromuscul Disord 28:690–701.
    1. Mendell JR, Khan N, Sha N, Eliopoulos H, McDonald CM, Goemans N, Mercuri E, Lowes LP and Alfano LN. (2021). Comparison of long-term ambulatory function in patients with Duchenne muscular dystrophy treated with eteplirsen and matched natural history controls. J Neuromuscul Dis 8:469–479.
    1. Khan N, Eliopoulos H, Han L, Kinane TB, Lowes LP, Mendell JR, Gordish-Dressman H, Henricson EK and McDonald CM. (2019). Eteplirsen treatment attenuates respiratory decline in ambulatory and non-ambulatory patients with Duchenne muscular dystrophy. J Neuromuscul Dis 6:213–225.
    1. Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM and Mercuri E. (2016). Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 79:257–271.
    1. Buyse GM, Voit T, Schara U, Straathof CSM, D'Angelo MG, Bernert G, Cuisset JM, Finkel RS, Goemans N, et al. (2015). Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet 385:1748–1757.
    1. Connolly AM, Florence JM, Zaidman CM, Golumbek PT, Mendell JR, Flanigan KM, Karachunski PI, Day JW, McDonald CM, et al. (2016). Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up. Muscle Nerve 54:681–689.
    1. Hahn A, Bach JR, Delaubier A, Renardel-Irani A, Guillou C and Rideau Y. (1997). Clinical implications of maximal respiratory pressure determinations for individuals with Duchenne muscular dystrophy. Arch Phys Med Rehabil 78:1–6.
    1. Henricson EK, Abresch RT, Cnaan A, Hu F, Duong T, Arrieta A, Han J, Escolar DM, Florence JM, et al. (2013). The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve 48:55–67.
    1. Khirani S, Ramirez A, Aubertin G, Boule M, Chemouny C, Forin V and Fauroux B. (2014). Respiratory muscle decline in Duchenne muscular dystrophy. Pediatr Pulmonol 49:473–481.
    1. Mayer OH, Finkel RS, Rummey C, Benton MJ, Glanzman AM, Flickinger J, Lindstrom BM and Meier T. (2015). Characterization of pulmonary function in Duchenne Muscular Dystrophy. Pediatr Pulmonol 50:487–494.
    1. McDonald CM, Abresch RT, Carter GT, Fowler WM Jr., Johnson ER, Kilmer DD and Sigford BJ. (1995). Profiles of neuromuscular diseases. Duchenne muscular dystrophy. Am J Phys Med Rehabil 74:S70–S92.
    1. McDonald CM, Gordish-Dressman H, Henricson EK, Duong T, Joyce NC, Jhawar S, Leinonen M, Hsu F, Connolly AM, et al. (2018). Longitudinal pulmonary function testing outcome measures in Duchenne muscular dystrophy: long-term natural history with and without glucocorticoids. Neuromuscul Disord 28:897–909.
    1. Miller F, Moseley CF, Koreska J and Levison H. (1988). Pulmonary function and scoliosis in Duchenne dystrophy. J Pediatr Orthop 8:133–137.
    1. Ricotti V, Selby V, Ridout D, Domingos J, Decostre V, Mayhew A, Eagle M, Butler J, Guglieri M, et al. (2019). Respiratory and upper limb function as outcome measures in ambulant and non-ambulant subjects with Duchenne muscular dystrophy: a prospective multicentre study. Neuromuscul Disord 29:261–268.
    1. Trucco F, Domingos JP, Tay CG, Ridout D, Maresh K, Munot P, Sarkozy A, Robb S, Quinlivan R, et al. (2020). Cardiorespiratory progression over 5years and role of corticosteroids in Duchenne muscular dystrophy: a single-site retrospective longitudinal study. Chest 158:1606–1616.
    1. Hiller M, Falzarano MS, Garcia-Jimenez I, Sardone V, Verheul RC, Popplewell L, Anthony K, Ruiz-Del-Yerro E, Osman H, et al. (2018). A multicenter comparison of quantification methods for antisense oligonucleotide-induced DMD exon 51 skipping in Duchenne muscular dystrophy cell cultures. PLoS One 13:e0204485.
    1. Clemens PR, Rao VK, Connolly AM, Harper AD, Mah JK, Smith EC, McDonald CM, Zaidman CM, Morgenroth LP, et al. (2020). Safety, tolerability, and efficacy of viltolarsen in boys with Duchenne muscular dystrophy amenable to exon 53 skipping: a phase 2 randomized clinical trial. JAMA Neurol 77:982–991.

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