Dataset Information

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

ABSTRACT:

Background

Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.

Methods

The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.

Results

The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.

Conclusion

Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

SUBMITTER: Hodgkinson VL

PROVIDER: S-EPMC7656664 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

Hodgkinson Victoria L VL Oskoui Maryam M Lounsberry Joshua J M'Dahoma Saïd S Butler Emily E Campbell Craig C MacKenzie Alex A McMillan Hugh J HJ Simard Louise L Vajsar Jiri J Brais Bernard B Chapman Kristine M KM Chrestian Nicolas N Crone Meghan M Dobrowolski Peter P Dojeiji Susan S Dowling James J JJ Dupré Nicolas N Genge Angela A Gonorazky Hernan H Hasal Simona S Izenberg Aaron A Johnston Wendy W Leung Edward E Lochmüller Hanns H Mah Jean K JK Marerro Alier A Massie Rami R McAdam Laura L McCormick Anna A Melanson Michel M Mezei Michelle M MM Nguyen Cam-Tu E CE O'Connell Colleen C O'Ferrall Erin K EK Pfeffer Gerald G Phan Cecile C Plamondon Stephanie S Poulin Chantal C Rodrigue Xavier X Schellenberg Kerri L KL Selby Kathy K Sheriko Jordan J Shoesmith Christen C Smith Garth G Taillon Monique M Taylor Sean S Warman Chardon Jodi J Worley Scott S Korngut Lawrence L

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 20200604 6

<h4>Background</h4>Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of ...[more]

PMID: 32493524

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Project description:BackgroundSpinal muscular atrophy (SMA) is one of the most frequent and severe genetic diseases leading to premature death or severe motor disability. New therapies have been developed in recent years that change the natural history of the disease. The aim of this study is to describe patients included in the Polish Registry of SMA, with a focus on the course of type 3 SMA (SMA3) before the availability of disease-modifying treatments.Results790 patients with SMA were included in the registry (173 with type 1 [SMA1], 218 with type 2 [SMA2], 393 with SMA3, and six with type 4 SMA [SMA4]), most (52%) of whom were adults. Data on SMN2 gene copy number were available for 672 (85%) patients. The mean age of onset was 5 months for SMA1, 11.5 months for SMA2, and 4.5 years for SMA3. In patients with SMA3, the first symptoms occurred earlier in those with three copies of SMN2 than in those with four copies of SMN2 (3.2 years vs. 6.7 years). The age of onset of SMA3 was younger in girls than in boys (3.1 years vs. 5.7 years), with no new cases observed in women older than 16 years. Male patients outnumbered female patients, especially among patients with SMA3b (49 female vs. 85 male patients) and among patients with SMA3 with four copies of SMN2 (30 female vs. 69 male patients). 44% of patients with SMA3 were still able to walk; in those who were not still able to walk, the mean age of immobilization was 14.0 years. Patients with SMA3a (age of onset < 3 years) and three copies of SMN2 had significantly worse prognosis for remaining ambulant than patients with SMA3b (age of onset ≥ 3 years) and four copies of SMN2.ConclusionsThe Registry of SMA is an effective tool for assessing the disease course in the real world setting. SMN2 copy number is an important prognostic factor for the age of onset and ambulation in SMA3. Sex and age of disease onset also strongly affect the course of SMA. Data supplied by this study can aid treatment decisions.

Project description:BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a biallelic mutation in the SMN1 gene, resulting in progressive muscle weakness and atrophy. Nusinersen is the first disease-modifying drug for all SMA types. We report on effectiveness and safety data from 120 adults and older children with SMA types 1c-3 treated with nusinersen.MethodsPatients were evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE; n = 73) or the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; n = 47). Additionally, the Revised Upper Limb Module (RULM) and 6-minute walk test (6MWT) were used in a subset of patients. Patients were followed for up to 30 months of nusinersen treatment (mean, SD; 23, 14 months). Subjective treatment outcomes were evaluated with the Patients Global Impression-Improvement (PGI-I) scale used in all patients or caregivers at each follow-up visit.ResultsAn increase in the mean HFMSE score was noted at month 14 (T14) (3.9 points, p < 0.001) and month 30 (T30) (5.1 points, p < 0.001). The mean RULM score increased by 0.79 points at T14 (p = 0.001) and 1.96 points (p < 0.001) at month 30 (T30). The mean CHOP-INTEND increased by 3.6 points at T14 (p < 0.001) and 5.6 points at month 26 (p < 0.001). The mean 6MWT improved by 16.6 m at T14 and 27 m at T30 vs. baseline. A clinically meaningful improvement in HFMSE (≥ 3 points) was seen in 62% of patients at T14, and in 71% at T30; in CHOP INTEND (≥ 4 points), in 58% of patients at T14 and in 80% at T30; in RULM (≥ 2 points), in 26.6% of patients at T14 and in 43.5% at T30; and in 6MWT (≥ 30-meter increase), in 26% of patients at T14 and in 50% at T30. Improved PGI-I scores were reported for 75% of patients at T14 and 85% at T30; none of the patients reporting worsening at T30. Adverse events were mild and related to lumbar puncture.ConclusionsIn our study, nusinersen led to continuous functional improvement over 30-month follow-up and was well tolerated by adults and older children with a wide spectrum of SMA severity.

Project description:BackgroundReal-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg.MethodsThis observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements.FindingsNinety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported.InterpretationOA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients.FundingNovartis Innovative Therapies AG provided a grant for independent medical writing services.

Project description:IntroductionThe recent advent of disease-modifying therapies (DMTs) has dramatically changed the treatment landscape of spinal muscular atrophy (SMA), and the multifaceted impact of this advancement has not been assessed thoroughly in the growing body of literature. We sought to summarize the literature on the natural history of SMA and the impact of SMA DMTs, including health-related quality of life (HRQOL) and utilities, clinical efficacy and safety, and economic impact.MethodsSystematic literature reviews were conducted following PRISMA guidelines with no inclusive dates. Relevant studies were identified by searching full-text databases on November 12-13, 2020, including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and EconLit, conference proceedings, health technology assessment databases, and clinical trial registries. All searches used a combination of MeSH and key terms. Studies were screened according to criteria based upon population, intervention, outcomes, and study design structure.ResultsFindings from 17, 23, 32, and 42 studies were included for the evaluation of natural history of SMA, HRQOL and utilities, clinical efficacy and safety, and economic impact of DMTs, respectively. Currently available data indicate that untreated SMA is associated with considerable humanistic and economic burden, with estimates of costs varying by treatment. While a variety of interventions have been evaluated in SMA clinical trials, quantitative synthesis of safety and efficacy findings was not feasible because of inconsistencies in reported outcomes. Data assessing impacts of DMTs on HRQOL were also lacking.ConclusionsOverall, this systematic literature review highlights a clear need for up-to-date and methodologically rigorous clinical, HRQOL, and economic data to support unbiased assessments of the relative clinical and economic effectiveness of SMA treatments. More research is required to extend our understanding of the burden of SMA on HRQOL utility assessments and the impact of new DMTs on HRQOL and utilities for patients with SMA.

Dataset Information

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

Background

Methods

Results

Conclusion

Publications

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

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