The use of the drug ataluren for the treatment of patients with Duchenne muscular dystrophy in real clinical practice

Aim. To analyze anamnestic, clinical and paraclinical indicators in patients with Duchenne muscular dystrophy (DMD) receiving pathogenetic therapy with a drug for correcting nonsense mutations in the dmd gene — ataluren (translarna), to evaluate the safety of therapy and the dynamics of motor disorders in real clinical practice against the background of use drug.

Materials and methods. The study included 24 patients with DMD receiving ataluren who were hospitalized at the Center for Pediatric Psychoneurology of the National Medical Research Center for Children’s Health of the Ministry of Health of the Russian Federation for the period from January 2019 to February 2024. An analysis of anamnestic data, the most common clinical manifestations and paraclinical indicators, assessed the safety of the drug by the presence of serious adverse events leading to discontinuation of therapy, and the effectiveness of treatment using functional scales of motor activity: the “North Star” scale and the 6-minute walk test.

Results. The age of onset of independent walking was 14.3 ± 2.6 months, the age of onset of the disease was 3.3 ± 2.6 years, the age of visiting a doctor was 4.25 ± 2.00 years, the age of diagnosis was 5.3 ± 2,3 years, age of initiation of glucocorticosteroids (GCS) — 6.3 ± 1.8 years. GCS in an adequate dose and regimen was taken by 13 (56%) patients. Cognitive, emotional-volitional and behavioral disorders were registered in 17 (70.8%) patients, excess body weight — in 6 (25%), and stiffness of the ankle joints — in 9 (37.5%).Pulmonary function was analyzed in 16 (66.6%) patients, of which a decrease was detected in 1 boy. No patient experienced a serious adverse event leading to discontinuation of ataluren. When assessing the effectiveness of treatment in a group of patients under 7 years of age (n = 11), 10 (91%) children showed improvement or stabilization of their condition according to the 6-minute walk test; in 6 (54.5%) — improvement in motor skills when analyzing scores on the “North Star” scale; in 5 (45.5%) the condition was stabilized. the group of patients over 7 years of age (n = 13), according to the 6-minute walk test, 4 (30.8%) children showed stabilization of the condition, 7 (53.8%) had disease progression, 2 (15.4%) the child entered the non-ambulatory stage. When analyzing scores on the “North Star” scale, 1 (7.7%) child showed improvement in performance, 6 (46.1%) — stabilization, 4 (30.8%) — decrease, 2 (15.4%) — loss outpatient.

Conclusion. Early diagnosis of the disease and timely initiation of therapy in compliance with all standards of management of patients with DMD are crucial for maintaining motor function. Pathogenetic therapy with ataluren increases the duration of the outpatient stage, improving and/or stabilizing the motor skills of patients.

Compliance with ethical standards. Voluntary informed consent was obtained from the legal representatives of all patients.

Contribution:
Popovich S.G. — concept and design of the article, text writing, editing;
Kuzenkova L.M. — concept and design of the article, text writing, editing;
Uvakina E.V. — concept and design of the article, editing;
Podkletnova T.V. — editing;
Kozhevnikova O.V. — editing;
Bushueva T.V. — editing;
Zvonkova N.G. — editing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article

Acknowledgment. The study had no sponsorship.

Conflict of interest. Popovich S.G., Kuzenkova L.M., Uvakina E.V., Podkletnova T.V. are lecturers receiving honoraria from the pharmaceutical company PTC Therapeutics LLC.

Received May 31, 2024
Accepted June 20, 2024
Published July 31, 2024

1. Emery A.E. The muscular dystrophies. Lancet. 2002; 359(9307): 687–95. https://doi.org/1016/S0140-6736(02)07815-7

2. Davies K.E., Pearson P.L., Harper P.S., Murray J.M., O’Brien T., Sarfarazi M., et al. Linkage analysis of two cloned DNA sequences flanking the Duchenne muscular dystrophy locus on the short arm of the human X chromosome. Nucleic Acids Res. 1983; 11(8): 2303–12. https://doi.org/1093/nar/11.8.2303

3. Moat S.J., Bradley D.M., Salmon R., Clarke A., Hartley L. Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK). Eur. J. Hum. Genet. 2013; 21(10): 1049–53. https://doi.org/1038/ejhg.2012.301

4. Parent Project Muscular Dystrophy. About Duchenne. Available at: https://parentprojectmd.org/about-duchenne/

5. Gao Q.Q., McNally E.M. The dystrophin complex: structure, function, and implications for therapy. Compr. Physiol. 2015; 5(3): 1223–39. https://doi.org/1002/cphy.c140048

6. Falzarano M.S., Scotton C., Passarelli C., Ferlini A. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. 2015; 20(10): 18168–84. https://doi.org/3390/molecules201018168

7. Ricotti V., Ridout D.A., Pane M., Main M., Mayhew A., Mercuri E., et al. The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials. J. Neurol. Neurosurg. Psychiatry. 2016; 87(2): 149–55. https://doi.org/1136/jnnp-2014-309405

8. Sienko Thomas S., Buckon C.E., Nicorici A., Bagley A., McDonald C.M., Sussman M.D. Classification of the gait patterns of boys with Duchenne muscular dystrophy and their relationship to function. J. Child Neurol. 2010; 25(9): 1103–9. https://doi.org/10.1177/0883073810371002

9. Bushby K., Finkel R., Birnkrant D.J., Case L.E., Clemens P.R., Cripe L., et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010; 9(1): 77–93. https://doi.org/10.1016/s1474-4422(09)70271-6

10. Verma S., Anziska Y., Cracco J. Review of Duchenne muscular dystrophy (DMD) for the pediatricians in the community. Clin. Pediatr. 2010; 49(11): 1011–7. https://doi.org/10.1177/0009922810378738

11. Hartnett M.J., Lloyd-Puryear M.A., Tavakoli N.P., Wynn J., Koval-Burt C.L., Gruber D., et al. Newborn screening for Duchenne muscular dystrophy: first year results of a population-based pilot. Int. J. Neonatal. Screen. 2022; 8(4): 50. https://doi.org/3390/ijns8040050

12. Awano H., Nambu Y., Itoh C., Kida A., Yamamoto T., Lee T., et al. Longitudinal data of serum creatine kinase levels and motor, pulmonary, and cardiac functions in 337 patients with Duchenne muscular dystrophy. Muscle Nerve. 2024; 69(5): 604–12. https://doi.org/10.1002/mus.28073

13. Zatz M., Rapaport D., Vainzof M., Passos-Bueno M.R., Bortolini E.R., Pavanello de C.R., et al. Serum creatine-kinase (CK) and pyruvate-kinase (PK) activities in Duchenne (DMD) as compared with Becker (BMD) muscular dystrophy. J. Neurol. Sci. 1991; 102(2): 190–6. https://doi.org/10.1016/0022-510x(91)90068-i

14. Ciafaloni E., Fox D.J., Pandya S., Westfield C.P., Puzhankara S., Romitti P.A., et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J. Pediatr. 2009; 155(3): 380–5. https://doi.org/1016/j.jpeds.2009.02.007

15. Broomfield J., Hill M., Chandler F. et al. Developing a natural history model for Duchenne muscular dystrophy. Pharmacoecon. Open. 2024; 8(1): 79–89. https://doi.org/10.1007/s41669-023-00450-x

16. Eagle M., Baudouin S.V., Chandler C., Giddings D.R., Bullock R., Bushby K. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul. Disord. 2002; 12(10): 926–9. https://doi.org/10.1016/s0960-8966(02)00140-2

17. Landfeldt E., Thompson R., Sejersen T., McMillan H.J., Kirschner J., Lochmüller H. Life expectancy at birth in Duchenne muscular dystrophy: a systematic review and meta-analysis. Eur. J. Epidemiol. 2020; 35(7): 643–53. https://doi.org/10.1007/s10654-020-00613-8

18. Clinical recommendations. Progressive Duchenne muscular dystrophy. Becker’s progressive muscular dystrophy; 2023. (in Russian)

19. Ferizovic N., Summers J., de Zárate I.B.O., Werner C., Jiang J., Landfeldt E., et al. Prognostic indicators of disease progression in Duchenne muscular dystrophy: A literature review and evidence synthesis. PLoS One. 2022; 17(3): e0265879. https://doi.org/10.1371/journal.pone.0265879

20. Weber F.J., Latshang T.D., Blum M.R., Kohler M., Wertli M.M. Prognostic factors, disease course, and treatment efficacy in Duchenne muscular dystrophy: A systematic review and meta-analysis. Muscle Nerve. 2022; 66(4): 462–70. https://doi.org/1002/mus.27682

21. Viltolarsen Uses, Side Effects & Warnings. Available at: https://drugs.com/mtm/viltolarsen.html

22. Lim K.R.Q., Maruyama R., Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des. Devel. Ther. 2017; 11: 533–45. https://doi.org/2147/DDDT.S97635

23. Assefa M., Gepfert A., Zaheer M., Hum J.M., Skinner B.W. Casimersen (AMONDYS 45™): An antisense oligonucleotide for Duchenne muscular dystrophy. Biomedicines. 2024; 12(4): 912. https://doi.org/3390/biomedicines12040912

24. Bladen C.L., Salgado D., Monges S., Foncuberta M.E., Kekou K., Kosma K., et al. The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum. Mutat. 2015; 36(4): 395–402. https://doi.org/10.1002/humu.22758

25. Mah J.K. Current and emerging treatment strategies for Duchenne muscular dystrophy. Neuropsychiatr. Dis. Treat. 2016; 12: 1795–807. https://doi.org/10.2147/ndt.s93873

26. Zinina E., Bulakh M., Chukhrova A., Ryzhkova O., Sparber P., Shchagina O., et al. Specificities of the DMD gene mutation spectrum in Russian patients. Int. J. Mol. Sci. 2022; 23(21):12710. https://doi.org/10.3390/ijms232112710

27. Welch E.M., Barton E.R., Zhuo J., Tomizawa Y., Friesen W.J., Trifillis P., et al. PTC124 targets genetic disorders caused by sense mutations. Nature. 2007; 447(7140): 87–91. https://doi.org/10.1038/nature05756

28. EMA SMH. Translarna, INN-ataluren. Available at: https://www.ema.europa.eu/en/documents/overview/translarna-epar-medicine-overview_en.pdf

29. McDonald C.M., Henricson E.K., Abresch R.T., Florence J., Eagle M., Gappmaier E., et al. The 6-minute walk test and other clinical endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve. 2013; 48(3): 357–68. https://doi.org/1002/mus.23905

30. Muntoni F., Domingos J., Manzur A.Y., Mayhew A., Guglieri M., Sajeev G., et al. Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy. PLoS One. 2019; 14(9): e0221097. https://doi.org/1371/journal.pone.0221097

31. WHO Multicentre Growth Reference Study Group. WHO Motor Development Study: windows of achievement for six gross motor development milestones. Acta Paediatr. Suppl. 2006; 450: 86–95. https://doi.org/1111/j.1651-2227.2006.tb02379.x

32. Norcia G., Lucibello S., Coratti G., Onesimo R., Pede E., Ferrantini G., et al. Early gross motor milestones in Duchenne muscular dystrophy. J. Neuromuscul. Dis. 2021; 8(4): 453–6. https://doi.org/3233/JND-210640

33. Mercuri E., Pane M., Cicala G., Brogna C., Ciafaloni E. Detecting early signs in Duchenne muscular dystrophy: comprehensive review and diagnostic implications. Front. Pediatr. 2023; 11: 1276144. https://doi.org/3389/fped.2023.1276144

34. Duan D., Goemans N., Takeda S., Mercuri E., Aartsma-Rus A. Duchenne muscular dystrophy. Nat. Rev. Dis. Primers. 2021; 7(1): 13. https://doi.org/10.1038/s41572-021-00248-3

35. Markati T., Oskoui M., Farrar M.A., Duong T., Goemans N., Servais L. Emerging therapies for Duchenne muscular dystrophy. Lancet Neurol. 2022; 21(9): 814–29. https://doi.org/10.1016/S1474-4422(22)00125-9

36. Guglieri M., Bushby K., McDermott M.P., Hart K.A., Tawil R., Martens W.B., et al. Effect of different corticosteroid dosing regimens on clinical outcomes in boys with Duchenne muscular dystrophy: a randomized clinical trial. JAMA. 2022; 327(15): 1456–68. https://doi.org/10.1001/jama.2022.4315

37. Gloss D., Moxley R.T. 3rd, Ashwal S., Oskoui M. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016; 86(5): 465–72. https://doi.org/1212/WNL.0000000000002337

38. Lamb M.M., West N.A., Ouyang L., Yang M., Weitzenkamp D., James K., et al. Corticosteroid treatment and growth patterns in ambulatory males with Duchenne muscular dystrophy. J. Pediatr. 2016; 173: 207–13.e. https://doi.org/10.1016/j.jpeds.2016.02.067

39. Lebel D.E., Corston J.A., McAdam L.C., Biggar W.D., Alman B.A. Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne muscular dystrophy: long-term follow-up. J. Bone Joint Surg. Am. 2013; 95(12): 1057–61. https://doi.org/10.2106/jbjs.l.01577

40. Birnkrant D.J., Bushby K., Bann C.M., Apkon S.D., Blackwell A., Brumbaugh D., et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018; 17(3): 251–67. https://doi.org/1016/S1474-4422(18)30024-3

41. Banihani R., Smile S., Peds D.M., Yoon G., Dupuis A., Mosleh M., et al. Cognitive and neurobehavioral profile in boys with Duchenne muscular dystrophy. J. Child Neurol. 2015; 30: 1472–82. https://doi.org/10.1177/0883073815570154

42. Mori-Yoshimura M., Mizuno Y., Yoshida S., Ishihara N., Minami N., Morimoto E., et al. Psychiatric and neurodevelopmental aspects of Becker muscular dystrophy. Neuromuscul. Disord. 2019; 29(12): 930–9. https://doi.org/1016/j.nmd.2019.09.006

43. Gremyakova T.A., Artem’eva S.B., Vashakmadze N.D., Vitkovskaya I.P., Guzeva V.I., Guzeva O.V., et al. The concept of “ambulatory” and “non-ambulatory” in patients with Duchenne muscular dystrophy: definitions and criteria. Nervno-myshechnye bolezni. 2022; 12(2): 10–8. https://doi.org/10.17650/2222-8721-2022-12-2-10-18 https://elibrary.ru/eyenho (in Russian)

44. Mayer O.H., Finkel R.S., Rummey C., Benton M.J., Glanzman A.M., Flickinger J., et al. Characterization of pulmonary function in Duchenne muscular dystrophy. Pediatr. Pulmonol. 2015; 50(5): 487–94. https://doi.org/10.1002/ppul.23172

45. Humbertclaude V., Hamroun D., Bezzou K., Bérard C., Boespflug-Tanguy O., Bommelaer C., et al. Motor and respiratory heterogeneity in Duchenne patients: implication for clinical trials. Eur. J. Paediatr. Neurol. 2012; 16(2): 149–60. https://doi.org/10.1016/j.ejpn.2011.07.001

46. Mercuri E., Osorio A.N., Muntoni F., Buccella F., Desguerre I., Kirschner J., et al. Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis. J. Neurol. 2023; 270(8): 3896–913. https://doi.org/1007/s00415-023-11687-1

47. Poster LSVP 37. Safety and efficacy of ataluren in nmDMD patients from Study 041, a phase 3 placebo-controlled trial. In: 27th International Annual Congress of the World Muscle Society (WMS). Halifax, NS; 2022.

48. Poster 92. Ataluren preserves motor function in nmDMD patients from Study 041, a phase 3, randomized, double-blind, placebo-controlled trial. In: Muscular Dystrophy Association (MDA) Clinical and Scientific Conference. Dallas, TX; 2023.

49. Golli T., Juříková L., Sejersen T., Dixon C. The role of ataluren in the treatment of ambulatory and non-ambulatory children with nonsense mutation Duchenne muscular dystrophy – a consensus derived using a modified Delphi methodology in Eastern Europe, Greece, Israel and Sweden. BMC Neurol. 2024; 24(1): 73. https://doi.org/10.1186/s12883-024-03570-x