Table 1.
Evaluating the effect of tofersen in presymptomatic SOD1 variant carriers in ATLAS
| Scientific objectives | To evaluate whether presymptomatic initiation of tofersen (upon elevation of NfL) can: | ||
|---|---|---|---|
| Prevent or delay the emergence of clinically manifest ALS | Reduce the loss of function over time, as compared to delayed tofersen initiation (i.e., upon emergence of clinically manifest ALS) | Reduce the loss of function following emergence of clinically manifest ALS, as compared to delayed tofersen initiation (i.e., upon emergence of clinically manifest ALS) | |
| PD/efficacy endpoints |
Primary endpoint: • Proportion of Part B participants in whom clinically manifest ALS emerges within 12 months of randomization (i.e., Part B baseline) Secondary endpoints: • Proportion of Part B participants in whom clinically manifest ALS emerges within 24 months of randomization (i.e., Part B baseline) • Time from Part B baseline to emergence of clinically manifest ALS |
Secondary endpoints: • Changes from Part B baseline to end of study (~ 24 months) in: o Plasma NfL levels o Total CSF SOD1 protein levels o ALSFRS-R total score o % predicted SVC • From Part B baseline to end of study: o Estimated proportion of deaths or permanent ventilations o Estimated proportion of deaths Exploratory endpoints: • Changes from Part B baseline to end of study in: o Home digital assessments o QoL endpoints (i.e., ALSAQ-5, FSS, WPAI, EQ-5D-5L, SF-36) |
Secondary endpoints: • Changes from Part C baseline to end of study in: o Plasma NfL levels o Total CSF SOD1 protein levels Exploratory endpoints: • Changes from Part C baseline to end of study in: o ALSFRS-R total score o % predicted SVC o Home digital assessments o QoL endpoints (i.e., ALSAQ-5, FSS, WPAI, EQ-5D-5L, SF-36) o ROADS o Clinical and Patient Global Impression scales (PGI-S/C, CGI-S/C) • From Part C baseline to end of study: o Estimated proportion of deaths or permanent ventilations o Estimated proportion of deaths |
| Analysis population | Part B population | Combined Parts B and C population | Part C population |
ALSAQ-5 Amyotrophic Lateral Sclerosis Assessment Questionnaire-5, ALSFRS-R ALS Functional Rating Scale – Revised, CGI-C Clinical Global Impression of Change, CGI-S Clinical Global Impression of Severity, CSF cerebrospinal fluid, EQ-5D-5L EuroQol-5 Dimensions — 5 Levels, FSS Fatigue Severity Scale, NfL neurofilament light chain, PGI-C Patient Global Impression of Change, PGI-S Patient Global Impression of Severity, QoL quality of life, ROADS Rasch Overall ALS Disability Scale, SF-36 Short Form 36 Health Survey Questionnaire, SOD1 superoxide dismutase1, SVC slow vital capacity, WPAI Work Productivity and Activity Impairment Questionnaire