Safety profile of onasemnogene abeparvovec in children with spinal muscular atrophy

Goal. To evaluate the safety profile of onasemnogene abeparvovec (Zolgensma®) gene therapy in children with spinal muscular atrophy (SMA) in real clinical practice.

Materials and methods. The study included 30 SMA children who underwent gene replacement therapy with onasemnogene abeparvovec (Zolgensma®) from December 2020 to December 2021 at the Center for Pediatric Psychoneurology. All children had a diagnosis of SMA confirmed by molecular genetic methods, with no more than 3 copies of the SMN2 gene and the absence of antibodies to the adeno-associated virus serotype 9. The safety profile was assessed by monitoring the clinical and laboratory data of the patients after administration of onasemnogene abeparvovec. Clinical events included all changes in the child’s condition that could be associated with the administration of the drug (hyperthermia, decreased appetite, nausea, vomiting, stool disorders). Laboratory assessment included monitoring of complete blood count, biochemical blood tests, blood coagulation indices. The degree of laboratory changes was estimated according to common terminology criteria for adverse events (CTCAE version 5.0).

Results. The safety profile of the drug Zolgensma® was studied in 30 children aged from 3 to 39 months, with a weight of 5.2 kg to 14.2 kg.

Twenty-eight (93.3%) children had at least one clinical event associated with the administration of the drug. Hyperthermia was observed in 24 (80%) children, nausea and vomiting in 18 (60%) children, decreased appetite in 20 (66.7%) children, stool changes in 4 (13.3%) children. Monitoring of laboratory indices revealed thrombocytopenia and monocytosis in twenty-two (73.3%) children and neutropenia in twelve (40%) children in the general blood test. An increase in the level of transaminases was noted in all children, the CTCAE grade 1 was detected in fifteen (50%) children, the CTCAE grade 2 in 7 (23.3%) children, CTCAE grade 3 in 6 (20%) children, CTCAE grade 4 in 2 (6.7%) children. Children with CTCAE grade 3 required correction of the prednisone dose up 2 mg/kg per day for 2-4 weeks. Two children with CTCAE grade 4 required pulse therapy with methylprednisolone at a dose of 30 mg/kg per day. Regardless of the level of transaminases, no change in the level of total and direct bilirubin was observed in any case. A decrease in prothrombin time was observed in 14 (46.6%) children. An increase in the level of troponin I was detected in four (13.3%) children. In all cases of serious adverse events, according to laboratory indices, the clinical condition of the children remained stable. The average duration of prednisone intake was 17.8 ± 6.6 weeks.

Conclusion. The safety profile of the drug onasemnogene abeparvovec (Zolgensma®) in real clinical practice in children with SMA is presented.

Contributions:
Kuzenkova L.M., Uvakina E.V., Popovich S.G., Podkletnova T.V. — concept and design of the research;
Nezhelskaya A.A., Abdullaeva L.M., Fisenko D.A., Naidenko A.V. — collection and processing of materials;
Kuzenkova L.M., Uvakina E.V., Popovich S.G., Podkletnova T.V. — text writing;
Kuzenkova L.M. — editing.
Аll co-authors — аpproval of the final version of the article, responsibility for the integrity of all its parts.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: February 10, 2022
Accepted: February 17, 2022
Published: March 15, 2022

1. D’Amico A., Mercuri E., Tiziano F.D., Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011; 6: 71. https://doi.org/10.1186/1750-1172-6-71

2. Brzustowicz L.M., Lehner T., Castilla L.H., Penchaszadeh G.K., Wilhelmsen K.C., Daniels R., et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990; 344(6266): 540–1. https://doi.org/10.1038/344540a0

3. Bürglen L., Lefebvre S., Clermont O., Burlet P., Viollet L., Cruaud C., et al. Structure and organization of the human survival motor neurone (SMN) gene. Genomics. 1996; 32(3): 479–82. https://doi.org/10.1006/geno.1996.0147

4. Lefebvre S., Bürglen L., Reboullet S., Clermont O., Burlet P., Viollet L., et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995; 80(1): 155–65. https://doi.org/10.1016/0092-8674(95)90460-3

5. Proximal spinal muscular atrophy 5q. Russian clinical guidelines. [Proksimal’naya spinal’naya myshechnaya atrofiya 5q. Rossiyskie klinicheskie rekomendatsii]. Available at: https://cr.minzdrav.gov.ru/recomend/593_1 (In Russian)

6. Finkel R.S., McDermott M.P., Kaufmann P., Darras B.T., Chung W.K., Sproule D.M., et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83(9): 810–7. https://doi.org/10.1212/WNL.0000000000000741

7. Schorling D.C., Pechmann A., Kirschner J. Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care. J Neuromuscul Dis. 2020; 7(1): 1–13. https://doi.org/10.3233/JND-190424

8. Ramdas S., Servais L. New treatments in spinal muscular atrophy: an overview of currently available data. Expert Opin Pharmacother. 2020; 21(3): 307–15. https://doi.org/10.1080/14656566.2019.1704732

9. Kichula E.A., Proud C.M., Farrar M.A., Kwon J.M., Saito K., Desguerre I., et al. Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy. Muscle Nerve. 2021; 64(4): 413–27. https://doi.org/10.1002/mus.27363

10. Mendell J.R., Al-Zaidy S., Shell R., Arnold W.D., Rodino-Klapac L.R., Prior T.W., et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017; 377(18): 1713–22. https://doi.org/10.1056/NEJMoa1706198

11. Day J., Chiriboga C.A., Crawford T., Darras B., Finkel R., Connolly A. et al. Onasemnogene Abeparvovec-xioi Gene Therapy for Spinal Muscular Atrophy Type 1 (SMA1): Phase 3 US Study (STR1VE) Update Oral presentation at MDA congress, Gene therapy session, 25.03.2020, https://mdaconference.org/node/929

12. Mercuri E., Muntoni F., Baranello G., Masson R., Boespflug-Tanguy O., Bruno C., et al. STR1VE-EU study group. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021; 20(10): 832–41. https://doi.org/10.1016/S1474-4422(21)00251-9

13. Weiß C., Ziegler A., Becker L.L., Johannsen J., Brennenstuhl H., Schreiber G., et al. Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study. Lancet Child Adolesc Health. 2022; 6(1): 17–27. https://doi.org/10.1016/S2352-4642(21)00287-X

14. Matesanz S.E., Battista V., Flickinger J., Jones J.N., Kichula E.A. Clinical experience with gene therapy in older patients with spinal muscular atrophy. Pediatr Neurol. 2021; 118: 1–5. https://doi.org/10.1016/j.pediatrneurol.2021.01.012

15. Waldrop M.A., Karingada C., Storey M.A., Powers B., Iammarino M.A., Miller N.F., et al. Gene therapy for spinal muscular atrophy: Safety and early outcomes. Pediatrics. 2020; 146(3): e20200729. https://doi.org/10.1542/peds.2020-0729

16. Artemyeva S.B., Papina Yu.O., Shidlovskaya O.A., Monakhova A.V., Vlodavets D.V. Experience of using hormone replacement therapy with Zolgensma® (onasemnogen abeparvovek) in real clinical practice in Russia. Nervnomishechnye bolezni. 2022; 12(1): 29–38. (In Russian) https://doi.org/10.17650/2222‑8721‑2022‑12‑1‑29‑38

17. Nevmerzhitskaya K.S., Sapega E.Yu., Morozova D.A. Short-term safety and efficacy of onasemnogen abeparvovek in 10 patients with spinal muscular atrophy: a cohort study. Voprosy sovremennoy terapii. 2021; 20(6S): 589–94. (In Russian). https://doi.org/10.15690/vsp.v20i6S.2367