Background: Identification of reliable predictors of response to disease modifying therapies in SMA is important to support and improve patient management.
Objectives: To identify predictive factors of nusinersen treatment response in infantile-onset SMA using data from the ENDEAR/SHINE studies. Multiple baseline patient and clinical characteristics were considered, including age at treatment initiation, weight-by-age percentile, disease duration (time from SMA symptom onset), ventilatory and nutritional support, compound motor action potential, and motor function measured by CHOP-INTEND. The primary outcome evaluated in these analyses was achievement of independent sitting during the study, as defined by HINE-2 and WHO motor milestones. Firth’s bias-reduced logistic regression and LASSO regularized regression were used to determine significant predictors of treatment response.
Results: Of the 80 patients originally randomized to and who received nusinersen in ENDEAR (median age at first dose: 5.4 [range: 1.7-8.0] months), 41 (51%) patients achieved independent sitting (median follow-up time at last visit: 3.6 [range:0-5.0] years). At baseline, 21 (26%) patients were at < 5% weight-by-age percentile and median (range) CHOP-INTEND score was 27.5 (8.0-48.5). Median (range) disease duration at treatment initiation was 3.0 (0.0-6.0) months. Based on the August 27, 2019 data cut, initial results from the multivariable model identified weight-by-age percentile (≥ 5% vs < 5%), disease duration, and baseline CHOP-INTEND score as significant predictors of achieving independent sitting. Those with a higher weight-by-age percentile had a 4.6-fold increased odds of independent sitting (p=0.03) and each 1-point increase in CHOP-INTEND was associated with a 1.1-fold increased odds of independent sitting (p=0.02). Conversely, each additional month of disease duration at treatment initiation was associated with a 50% reduction of the odds of independent sitting (p=0.02).
Conclusions: Results underscore the prognostic importance of disease duration, baseline motor function and growth parameters while reinforcing the importance of earlier treatment initiation. These observations apply to recently diagnosed, symptomatic patients with 2 SMN2 copies. Additional clinical characteristics and potential biomarkers, such as neurofilament, will be considered in further modeling and results for time to treatment response will also be presented.
Study Support: Biogen