TO 12: RSA G: DNL343

2.1 Study Objectives and Endpoints Primary Efficacy Objective: • To evaluate the efficacy of DNL343 as compared to placebo on ALS disease progression Secondary Efficacy Objective: • To evaluate the effect of DNL343 on selected secondary measures of disease progression, including survival Safety Objective: • To evaluate the safety of DNL343 in participants with ALS Exploratory Objectives: • To evaluate the effect of DNL343 on selected biomarkers and endpoints • To evaluate DNL343 concentrations in plasma and cerebrospinal fluid (CSF) Primary Efficacy Endpoint: • Change from baseline through Week 24 in disease severity as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival. Secondary Efficacy Endpoints: • Change in ALSFRS-R total score from baseline to Week 24 • Combined Assessment of Function and Survival (CAFS) to Week 24 • Change in respiratory function as assessed by slow vital capacity (SVC) from baseline to Week 24 • Change in muscle strength as measured isometrically using hand-held dynamometry and grip strength from baseline to Week 24 • Survival evaluated as time to death or permanent assisted ventilation (PAV) • Survival evaluated as time to death