New Therapies for Spinal Muscular Atrophy: Where We Stand and What is Next

Overview

Journal Eur J Pediatr

Specialty Pediatrics

Date 2023 Apr 17

PMID 37067602

Authors

Laura Antonaci

Maria Carmela Pera

Eugenio Mercuri

Affiliations

Soon will be listed here.

Abstract

The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration. Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug's approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated.

Citing Articles

High Expression of SMN circ4-2b-3 in SMA I Children Treated with Nusinersen is Associated with Improved Motor Outcomes.

Guerra M, Marini A, Pagliarini V, Pitolli C, Coratti G, Bonvissuto D Mol Neurobiol. 2024; .

PMID: 39592557 DOI: 10.1007/s12035-024-04605-7.

Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.

Matera A, Steiner R, Mills C, McMichael B, Herring L, Garcia E Front RNA Res. 2024; 2.

PMID: 39492846 PMC: 11529804. DOI: 10.3389/frnar.2024.1448194.

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network.

Matera A, Steiner R, Mills C, Herring L, Garcia E bioRxiv. 2024; .

PMID: 38903116 PMC: 11188114. DOI: 10.1101/2024.05.15.594402.

Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.

Brkusanin M, Kosac A, Brankovic-Sreckovic V, Jovanovic K, Peric S, Karanovic J Front Neurol. 2024; 15:1394001.

PMID: 38756215 PMC: 11097956. DOI: 10.3389/fneur.2024.1394001.

Exploring variability in cognitive functioning in patients with spinal muscular atrophy: a scoping review.

Giannotta G, Ruggiero M, De Rinaldis M, Trabacca A Neurol Sci. 2024; 45(8):3699-3710.

PMID: 38580877 DOI: 10.1007/s10072-024-07503-x.

References

Pera M, Coratti G, Bovis F, Pane M, Pasternak A, Montes J . Nusinersen in pediatric and adult patients with type III spinal muscular atrophy. Ann Clin Transl Neurol. 2021; 8(8):1622-1634. PMC: 8351459. DOI: 10.1002/acn3.51411. View

Darras B, Crawford T, Finkel R, Mercuri E, De Vivo D, Oskoui M . Neurofilament as a potential biomarker for spinal muscular atrophy. Ann Clin Transl Neurol. 2019; 6(5):932-944. PMC: 6530526. DOI: 10.1002/acn3.779. View

Chan S, Chae J, Chien Y, Ko T, Lee J, Lee Y . Nusinersen in spinal muscular atrophy type 1 from neonates to young adult: 1-year data from three Asia-Pacific regions. J Neurol Neurosurg Psychiatry. 2021; 92(11):1244-1246. PMC: 8522455. DOI: 10.1136/jnnp-2020-324532. View

Matesanz S, Battista V, Flickinger J, Jones J, Kichula E . Clinical Experience With Gene Therapy in Older Patients With Spinal Muscular Atrophy. Pediatr Neurol. 2021; 118:1-5. DOI: 10.1016/j.pediatrneurol.2021.01.012. View

Finkel R, McDermott M, Kaufmann P, Darras B, Chung W, Sproule D . Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83(9):810-7. PMC: 4155049. DOI: 10.1212/WNL.0000000000000741. View

Dubowitz V . Chaos in classification of the spinal muscular atrophies of childhood. Neuromuscul Disord. 1991; 1(2):77-80. DOI: 10.1016/0960-8966(91)90051-s. View

Sansone V, Pirola A, Albamonte E, Pane M, Lizio A, DAmico A . Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen. J Pediatr. 2020; 219:223-228.e4. DOI: 10.1016/j.jpeds.2019.12.047. View

Pane M, Coratti G, Pera M, Sansone V, Messina S, DAmico A . Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy. Ann Clin Transl Neurol. 2022; 9(3):404-409. PMC: 8935309. DOI: 10.1002/acn3.51514. View

Chand D, Mitchell S, Sun R, LaMarca N, Reyna S, Sutter T . Safety of Onasemnogene Abeparvovec for Patients With Spinal Muscular Atrophy 8.5 kg or Heavier in a Global Managed Access Program. Pediatr Neurol. 2022; 132:27-32. DOI: 10.1016/j.pediatrneurol.2022.05.001. View

10.

Pirruccello-Straub M, Jackson J, Wawersik S, Webster M, Salta L, Long K . Blocking extracellular activation of myostatin as a strategy for treating muscle wasting. Sci Rep. 2018; 8(1):2292. PMC: 5797207. DOI: 10.1038/s41598-018-20524-9. View

11.

Trucco F, Ridout D, Scoto M, Coratti G, Main M, Lofra R . Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study. Neurology. 2020; 96(4):e587-e599. PMC: 7905794. DOI: 10.1212/WNL.0000000000011051. View

12.

Chand D, Mohr F, McMillan H, Tukov F, Montgomery K, Kleyn A . Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J Hepatol. 2020; 74(3):560-566. DOI: 10.1016/j.jhep.2020.11.001. View

13.

Mercuri E, Finkel R, Muntoni F, Wirth B, Montes J, Main M . Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018; 28(2):103-115. DOI: 10.1016/j.nmd.2017.11.005. View

14.

Maggi L, Bello L, Bonanno S, Govoni A, Caponnetto C, Passamano L . Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3. J Neurol Neurosurg Psychiatry. 2020; 91(11):1166-1174. DOI: 10.1136/jnnp-2020-323822. View

15.

Kirschner J, Butoianu N, Goemans N, Haberlova J, Kostera-Pruszczyk A, Mercuri E . European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy. Eur J Paediatr Neurol. 2020; 28:38-43. PMC: 7347351. DOI: 10.1016/j.ejpn.2020.07.001. View

16.

Bitetti I, Lanzara V, Margiotta G, Varone A . Onasemnogene abeparvovec gene replacement therapy for the treatment of spinal muscular atrophy: a real-world observational study. Gene Ther. 2022; 30(7-8):592-597. PMC: 10457192. DOI: 10.1038/s41434-022-00341-6. View

17.

Mercuri E, Darras B, Chiriboga C, Day J, Campbell C, Connolly A . Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018; 378(7):625-635. DOI: 10.1056/NEJMoa1710504. View

18.

De Wel B, Goosens V, Sobota A, Van Camp E, Geukens E, Van Kerschaver G . Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4. J Neurol. 2020; 268(3):923-935. DOI: 10.1007/s00415-020-10223-9. View

19.

Chen K, Widger J, Teng A, Fitzgerald D, DSilva A, Farrar M . Real-world respiratory and bulbar comorbidities of SMA type 1 children treated with nusinersen: 2-Year single centre Australian experience. Paediatr Respir Rev. 2020; 39:54-60. DOI: 10.1016/j.prrv.2020.09.002. View

20.

Sturm S, Gunther A, Jaber B, Jordan P, Al Kotbi N, Parkar N . A phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier. Br J Clin Pharmacol. 2018; 85(1):181-193. PMC: 6303280. DOI: 10.1111/bcp.13786. View