The primary objective of this study is to evaluate the safety, tolerability of single-ascending doses of BIIB100 in adults with amyotrophic lateral sclerosis (ALS). The secondary objective of the study is to characterize the pharmacokinetic profile of BIIB100.

Key Inclusion Criteria:

• Must meet the laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria.
• Participants taking concomitant riluzole at study entry must be on a stable dose for greater than or equals to (>=) 30 days prior to the first dose of study treatment (Day 1). Participants taking concomitant riluzole must be willing to continue with the same dose regimen throughout the study, unless the Investigator determines that riluzole should be discontinued for medical reasons, in which case it may not be restarted during the study.
• Participants taking concomitant edaravone at study entry must be on a stable dose for >= 60 days prior to the first dose of study treatment (Day 1).
• Adequate respiratory function as indicated by slow vital capacity (SVC) >= 65% of predicted value as adjusted for sex, age, and height (from the sitting position).

Key Exclusion Criteria:

• Ongoing medical condition (e.g., wasting or cachexia, severe anemia) that would, in the opinion of the Investigator, interfere with the conduct or assessments of the study.
• Significant cognitive impairment or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression less than or equals to (<=) 90 days of Screening, which in the opinion of the Investigator would interfere with the study procedures.
• Treatment with drugs that are transported by Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp) including, but not limited to, rosuvastatin, sulfasalazine, dabigatran, digoxin and fexofenadine.
• Current enrollment or plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 30 days or 5 half-lives of the agent, whichever is longer, prior to the Baseline Visit (pre-dose on Day 1). Participation in a noninterventional study focused on ALS natural history may be allowed at the discretion of the Investigator and after consultation with the Sponsor.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/