Experience with exon 45 skipping therapy in patients with Duchenne muscular dystrophy

   Duchenne muscular dystrophy (DMD) is the most common neuromuscular disease in the world. DMD belongs to the group of so-called dystrophinopathies associated with mutations in the DMD gene, is inherited in an X-linked recessive manner and is caused by either the complete absence of the dystrophin protein or its defective synthesis. Currently, several pathogenetic drugs have appeared aimed at restoring the synthesis of the dystrophin protein. One of them is the antisense oligonucleotide casimersen, which works using exon skipping technology of exon 45 in DMD gene. The article presents the first experience of using the drug casimersen in 6 patients from Russia, and the patients differed significantly from each other in functional status and existing complications of the underlying disease. In all patients, the use of casimersen was safe, and no adverse events associated with the use of the drug were identified. And in one of the patients, who was at an early outpatient stage of the disease, for whom pathogenetic therapy was initiated at the age of 7 years, pronounced positive dynamics were noted in the form of an increase in distance by 140 meters according to the results of a 6-minute walking test and an increase of 10 points on the «North Star».

1. Drousiotou A., Ioannou P., Georgiou T., et al. Neonatal screening for Duchenne muscular dystrophy: a novel semiquantitative application of the bioluminescence test for creatine kinase in a pilot national program in Cyprus. Genet Test 1998; 2: 55–60.

2. Emery A.E. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord 1991; 1: 19–29.

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

4. Happi Mbakam C., Lamothe G., Tremblay J.P. Therapeutic Strategies for Dystrophin Replacement in Duchenne Muscular Dystrophy. Front Med (Lausanne). 2022;9:859930. doi: 10.3389/fmed.2022.859930

5. Hoffman E.P., Brown R.H. Jr, Kunkel L.M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51: 919–28.

6. Klinicheskiye rekomendatsii «Progressiruyushchaya myshechnaya distrofiya Dyushenna. Progressiruyushchaya myshechnaya distrofiya Bekkera» [Clinical recommendations “Progressive Duchenne muscular dystrophy. Becker’s progressive muscular dystrophy]. https://cr.minzdrav.gov.ru/schema/773 (In Russ.)

7. Poysky J., Behavior in DMD Study Group. Behavior patterns in Duchenne muscular dystrophy: report on the Parent Project Muscular Dystrophy behavior workshop 8–9 of December 2006, Philadelphia, USA. Neuromuscul Disord 2007; 17: 986–94.

8. Ryder S., Leadley R.M., Armstrong N., et al. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis. 2017;12(1):79.

9. Coratti G., Pane M., Brogna C., et al. North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up. PLoS One. 2021;16(6):e0253882. doi: 10.1371/journal.pone.0253882

10. de Feraudy Y., Ben Yaou R., Wahbi K., et al.Very Low Residual Dystrophin Quantity Is Associated with Milder Dystrophinopathy. Ann Neurol. 2021;89(2):280-292. doi: 10.1002/ana.25951.

11. Shirley M. Casimersen: First Approval. Drugs. 2021;81(7):875-879. doi: 10.1007/s40265-021-01512-2.

12. Iannaccone S. et al. Casimersen in Patients With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping: Interim Results From the Phase 3 ESSENCE Trial. World Muscle Society Congress 2022. Neuromuscular Disorders 32 (2022) S42–S136. doi: 10.1016/j.nmd.2022.07.248.

13. Iannaccone S. et al. Casimersen in Patients With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping: Interim Results From the Phase 3 ESSENCE Trial. Presented at the Muscular Dystrophy Association Clinical & Scientific Conference, March 13–16, 2022, Nashville, TN. https://investorrelations.sarepta.com/static-files/d6ad5b34-752b-4d8b-ba15-bfa88394296f Access date 18. 12. 2023

14. Iannaccone S. et al. Casimersen in Patients With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping: Interim Results From the Phase 3 ESSENCE Trial. Presented at the 27^th International Hybrid Annual Congress of the World Muscle Society; October 11–15, 2021; Halifax, Nova Scotia, Canada. Neuromuscular Disorders 31 (2021) S47–S162. doi: 10.1016/j.nmd.2021.07.175

15. Iannaccone S. et al. Casimersen in Patients With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping: Interim Results From the Phase 3 ESSENCE Trial. Presented at the Muscular Dystrophy Association Clinical & Scientific Conference, March 12–22, 2023, Dallas, TX & Virtual. https://www.mdaconference.org/abstract-library/casimersen-in-patients-with-duchenne-muscular-dystrophy-amenable-to-exon-45-skipping-interim-results-from-the-phase-3-essence-trial/ Access date 18. 12. 2023

16. Wagner K. et al. 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 and Nerve. 2021;64(3):285-292.

17. NCT02500381. https://clinicaltrials.gov/ct2/show/NCT02500381.

18. NCT02530905. https://clinicaltrials.gov/ct2/show/NCT02530905.

19. NCT03532542. An Extension Study to Evaluate Casimersen or Golodirsen in Patients With Duchenne Muscular Dystrophy. https://www.clinicaltrials.gov/study/NCT03532542.