Original Title: État des connaissances: Efficacité et innocuité de l’onasemnogène abéparvovec, du nusinersen et du risdiplam dans le traitement de l’amyotrophie spinale 5q

Authors' objectives: In Québec, approximately 7 to 8 children are born with SMA each year. SMA was one of the leading genetic causes of death in newborns and children in Canada before the advent of treatments. Neonatal SMA screening has been implemented in a few countries, including Germany, Australia, Belgium and Taiwan, once treatments became available. In Canada, a pilot screening project was conducted in Ontario from January to July 2020, which resulted in the identification of four affected infants out of the 75,000 who were screened. Since then, SMA has been part of Ontario’s screening program. Currently in Québec, a prenatal diagnosis can be made during pregnancy at the request of parents whose siblings have a family history of SMA. In order to support deliberation when assessing the relevance of implementing or not implementing neonatal SMA screening for all newborns in Québec, the Institut national d’excellence en santé et en services sociaux (INESSS) carried out a state of scientific knowledge review on the efficacy and safety of onasemnogene abeparvovec (OA), nusinersen and risdiplam, three innovative therapies for the treatment of this rare disease recently approved by one or more of the Canadian, American or European regulatory agencies.

Authors' results and conclusions: RESULTS: Three treatments for SMA have been approved in Canada, the United States or Europe. One of these is an intravenous gene therapy, OA, which introduces a complete SMN1 gene into motor neuron cells using a viral vector. The other two treatments, nusinersen, which is administered intrathecally, and risdiplam, which is administered orally, increase SMN protein production by increasing the rate of inclusion of exon 7 into the messenger ribonucleic acid (mRNA) transcripts of the SMN2 gene: Onasemnogene abeparvovec, Nusinersen and Risdiplam. CONCLUSIONS: The present work involved gathering the scientific data available up to April 2021 on the efficacy and safety of the innovative therapies that had received a notice of compliance from Health Canada for the treatment of SMA 5q. Compared to the natural course of the disease, each of the therapies appears to show benefits for motor, lung and oropharyngeal function and for survival, although there remains some uncertainty regarding the persistence of benefits in the long term. These therapies also appear to be safe, although one cannot rule out the occurrence of adverse effects, which in this case are rarely serious. Nevertheless, several limitations inherent in the study designs and the exploratory or preliminary nature of certain results from interim analyses of ongoing studies temper the significance of the conclusions drawn. Despite all of these factors, the current state of scientific knowledge tends to show that the earlier the therapies are administered during the course of the disease, the greater the likelihood of deriving benefit from them, although the maintenance of benefits over the course of growth and into adulthood remains uncertain. For this reason, it is important to continue research efforts and to gather real-world data to document the longer-term benefits and risks of the treatments, and to strengthen the evidence regarding their efficacy and safety in the short and medium terms for both presymptomatic and symptomatic SMA 5q patients.

Authors' methods: In accordance with INESSS’s standards, three systematic reviews were conducted to obtain the most up-to-date portrait possible of the efficacy and safety of the three SMA therapies to coincide with work on newborn screening. The search strategy and the retrieval of scientific literature were carried out by a scientific information advisor, using the MEDLINE, Embase, and EBM Reviews (Cochrane Database of Systematic Reviews) databases. The retrieval of scientific publications indexed in these databases was performed four months after the search strategy was put in place. Subsequently, a systematic watch lasting until April 30, 2021 was set up through the Inoreader platform. In addition, the ClinicalTrials.gov website was queried for ongoing clinical studies and to supplement, if necessary, the results of conference abstracts found during the complementary search via the Google and Google Scholar search engines. The bibliographies of the retained items were checked for additional publications not indexed by the searched databases. Publications were selected on the basis of their title and abstract, retained articles were read in full and methodological quality of the chosen studies was independently assessed by two professional scientists. The methodological quality of the conference abstracts was not assessed. The characteristics of the retained studies and their scientific data were extracted by one professional scientist and validated by a second. The analysis and assessment of the level of scientific evidence for the clinical outcomes of interest were based on the review of all the available scientific data according to four criteria: methodological and scientific limitations, consistency/reliability, clinical impact and generalizability. This assessment was made independently by two professional scientists. A level of scientific evidence for each outcome of interest was assigned according to a scale from insufficient to high. For this purpose, the nature of the publication, the strength of the study design and its methodological quality were considered, as well as the presentation of results of interim or final analyses.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/evaluation-de-la-pertinence-du-depistage-neonatal-de-lamyotrophie-spinale.html

Year Published: 2021

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/evaluation-de-la-pertinence-du-depistage-neonatal-de-lamyotrophie-spinale.html

English language abstract: An English language summary is available

Publication Type: Other

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec