Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

Arlene M D'Silva^{1

2}, Sandra Holland¹, Didu Kariyawasam^{1

2}, Karen Herbert³, Peter Barclay⁴, Anita Cairns⁵, Suzanna C MacLennan^{6

7}, Monique M Ryan^{8

9

10}, Hugo Sampaio¹, Nicholas Smith¹¹, Ian R Woodcock^{8

9

10}, Eppie M Yiu^{8

9

10}, Ian E Alexander^{11

12}, Michelle A Farrar^{1

2}

Affiliations

¹ Department of Neurology, Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
² School of Clinical Medicine, UNSW Medicine & Health, Randwick Clinical Campus, Discipline of Paediatrics, University of New South Wales, Sydney, New South Wales, Australia.
³ Physiotherapy, Sydney Children's Hospital, Sydney, New South Wales, Australia.
⁴ Department of Pharmacy, Prince of Wales Hospital, Sydney Children's Hospital Randwick and The Royal Hospital for Women, Randwick, New South Wales, Australia.
⁵ Neurosciences Department, Queensland's Children Hospital, South Brisbane, Queensland, Australia.
⁶ Neurology Department, Women's & Children's Hospital, North Adelaide, South Australia, Australia.
⁷ School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
⁸ Department of Neurology, Royal Children's Hospital, Melbourne, Australia.
⁹ Neuroscience Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁰ Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
¹¹ Gene Therapy Research Unit, Sydney Children's Hospitals Network and Children's Medical Research Institute, The University of Sydney, Westmead, Australia.
¹² Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.

PMID: 35170254
PMCID: PMC8935277
DOI: 10.1002/acn3.51519

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

Arlene M D'Silva et al. Ann Clin Transl Neurol. 2022 Mar.

. 2022 Mar;9(3):339-350.

doi: 10.1002/acn3.51519. Epub 2022 Feb 16.

Authors

Affiliations

¹ Department of Neurology, Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
² School of Clinical Medicine, UNSW Medicine & Health, Randwick Clinical Campus, Discipline of Paediatrics, University of New South Wales, Sydney, New South Wales, Australia.
³ Physiotherapy, Sydney Children's Hospital, Sydney, New South Wales, Australia.
⁴ Department of Pharmacy, Prince of Wales Hospital, Sydney Children's Hospital Randwick and The Royal Hospital for Women, Randwick, New South Wales, Australia.
⁵ Neurosciences Department, Queensland's Children Hospital, South Brisbane, Queensland, Australia.
⁶ Neurology Department, Women's & Children's Hospital, North Adelaide, South Australia, Australia.
⁷ School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
⁸ Department of Neurology, Royal Children's Hospital, Melbourne, Australia.
⁹ Neuroscience Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁰ Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
¹¹ Gene Therapy Research Unit, Sydney Children's Hospitals Network and Children's Medical Research Institute, The University of Sydney, Westmead, Australia.
¹² Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.

PMID: 35170254
PMCID: PMC8935277
DOI: 10.1002/acn3.51519

Abstract

Objective: To provide a greater understanding of the tolerability, safety and clinical outcomes of onasemnogene abeparvovec in real-world practice, in a broad population of infants with spinal muscular atrophy (SMA).

Methods: A prospective cohort study of children with SMA treated with onasemnogene abeparvovec at Sydney Children's Hospital Network, Australia was conducted from August 2019 to November 2021. Safety outcomes included clinical and laboratory evaluations. Efficacy assessments included World Health Organisation (WHO) motor milestones, oral and swallowing abilities, and requirements for respiratory support. The implementation of a model of care for onasemnogene abeparvovec administration in health practice is described.

Results: 21 children were treated (age range, 0.65-24 months; body weight range, 2.5-12.5 kg) and 19/21 (90.4%) had previous nusinersen. Transient treatment-related side effects occurred in all children; vomiting (100%), transaminitis (57%) and thrombocytopaenia (33%). Incidence of moderate/severe transaminitis was significantly greater in infants weighing ≥8 kg compared with <8 kg (p < 0.05). Duration of prednisolone following treatment was prolonged (mean 87.5 days, range 57-274 days). 16/21 (76%) children gained at least one WHO motor milestone. Stabilisation or improvement in bulbar or respiratory function was observed in 20/21 (95.2%) patients. Implementation challenges were mitigated by developing standard operating procedures and facilitating exchange of knowledge.

Interpretation: This study provides real-world evidence to inform treatment decisions and guide therapeutic expectations for onasemnogene abeparvovec and combination therapy for SMA in health practice, especially for children weighing ≥8 kg receiving higher vector loads. Proactive clinical and laboratory surveillance is essential to facilitate individualised management of risks.

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Conflict of interest statement

Dr. Farrar and Prof. Ryan have received compensation as a member of scientific advisory boards for Biogen, Roche, and Novartis Gene Therapies. Sandra Holland has received compensation as a member of the scientific advisory board for Novartis Gene Therapies.

All other authors declare no potential conflict of interest. These funding bodies had no role in the design of the study, data collection, data analysis, manuscript design, preparation of the manuscript or decision to publish. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**Figure 1**
(A) Asparatate aminotransferase (AST) and (B) Alanine Aminotransferase (ALT) (number of times above the upper limit of normal) following onasemnogene dosing. Mean (circles) with standard deviation (dashed grey line) in (C) AST and (D) ALT following onasemnogene dosing. Children weighing ≥8 kg are represented by orange lines and children weighing <8 kg are represented by blue lines. [Colour figure can be viewed at wileyonlinelibrary.com]

**Figure 2**
Developmental WHO motor milestones at baseline and following administration of OAV101 in treated children with (A) 2 copies of *SMN2* and (B) 3 copies of *SMN2*. WHO developmental assessments were completed for 21 participants at baseline and follow up. Infants were followed for a median of 16 (2–26) months post dosing and median age at data cut off was 2 years (range 0.17 to 3.3 years). [Colour figure can be viewed at wileyonlinelibrary.com]

**Figure 3**
Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‐INTEND) values on the left and Hammersmith Functional Motor Scale/ extended version (HFMSE) values on the right in treated children at baseline and 6 months post dosing with onasemnogene abeparvovec.

See this image and copyright information in PMC

References

1. D'Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;6:71. - PMC - PubMed
1. Calucho M, Bernal S, Alías L, et al. Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018;28:208‐215. - PubMed
1. Singh NN, Howell MD, Androphy EJ, Singh RN. How the discovery of ISS‐N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 2017;24:520‐526. - PMC - PubMed
1. Mendell JR, Al‐Zaidy S, Shell R, et al. Single‐dose gene‐replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377:1713‐1722. - PubMed
1. Waldrop MA, Karingada C, Storey MA, et al. Gene therapy for spinal muscular atrophy: safety and early outcomes. Pediatrics. 2020;146. - PubMed

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Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

Affiliations

Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Medical