A Study to Assess the Safety, Tolerability, and Effect on Disease Progression of BIIB105 in Participants With Amyotrophic Lateral Sclerosis (ALS) and Participants With the ALS Ataxin-2 (ATXN2) Genetic Mutation

Key Inclusion Criteria:

Part 1:

   - Ability of the participant to understand the purpose and risks of the study and
   indicate informed consent, and the ability of the participant or the participant's
   legally authorized representative, to provide signed and dated informed consent and
   authorization to use protected health information in accordance with national and
   local privacy regulations.

   - No known presence or family history of mutations in the superoxide dismutase 1 (SOD1)
   or fused in sarcoma (FUS) genes.

   - Participants in Cohorts A, B, C1 and D1, must meet the laboratory-supported probable,
   probable, or definite criteria for diagnosing ALS according to the World Federation of
   Neurology El Escorial criteria (revised according to the Airlie House Conference 1998
   [Brooks 2000]). Participants in Cohort C2 and D2, must meet any of the prior
   conditions, but may also only meet clinically possible criteria for diagnosing ALS, or
   exhibit weakness attributable to ALS in the presence of ataxin-2 protein (ATXN2)
   intermediate repeats.

   - In participants in Cohorts C2 and D2, confirmed intermediate
   cytosine-adenine-guanine/cytosine-adenine-adenine (CAG/CAA) repeat expansion in the
   ataxin-2 (ATXN2) gene as defined by at least 1 allele carrying 30 to 33 CAG/CAA
   repeats.

   - Slow vital capacity (SVC) criteria:

   - In participants in Cohorts A, B, C1, and D1, SVC ≥60% of predicted value as adjusted
   for sex, age, and height (from the sitting position).

   - In participants in Cohort C2 and D2, SVC ≥50% of predicted value as adjusted for sex,
   age, and height (from the sitting position).

   - If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1
   and expected to remain at that dose until the final study visit, unless the
   Investigator determines that it 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). Participants taking
   concomitant edaravone must be willing to continue with the same dose regimen
   throughout the study, unless the Investigator determines that edaravone should be
   discontinued for medical reasons, in which case it may not be restarted during the
   study. Edaravone may not be administered on dosing days of this study.

   - Screening values of coagulation parameters including platelet count, international
   normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin
   time (aPTT) should be within normal ranges.

   - Has an informant/caregiver who, in the Investigator's judgment, has frequent and
   sufficient contact with the participant as to be able to provide accurate information
   about the participant's cognitive and functional abilities at screening.

Part 2:

   - Ability of the participant to understand the purpose and risks of the study and
   indicate informed consent, and the ability of the participant or the participant's
   legally authorized representative to provide signed and dated informed consent and
   authorization to use protected health information in accordance with national and
   local privacy regulations

   - Participants must have completed Study NCT04494256 Part 1 through Week 25 (Day 175
   Visit for Cohorts A, B, C1, C2; Day 176 Visit for Cohorts D1, D2). This inclusion
   criterion does not apply to a participant if Part 1 was terminated by the Sponsor
   before the participant reached Week 25.

   - Participants from Cohorts A, B, C1, and C2 must have a washout of ≥16 weeks between
   the last dose of study treatment received in Study NCT04494256 Part 1 and the first
   dose of BIIB105 received in Study NCT04494256 Part 2. Participants from Cohorts D1 and
   D2 do not require a washout period.

   - If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1
   and expected to remain at that dose until the final study visit, unless the
   Investigator determines that it 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). Participants taking
   concomitant edaravone must be willing to continue with the same dose regimen
   throughout the study, unless the Investigator determines that edaravone should be
   discontinued for medical reasons, in which case it may not be restarted during the
   study. Edaravone may not be administered on dosing days of this study.

   - Screening values of coagulation parameters including platelet count, INR, PT, and aPTT
   should be within normal ranges.

Key Exclusion Criteria

Part 1:

   - History or positive test result at Screening for human immunodeficiency virus (HIV).

   - Current hepatitis C infection.

   - Current hepatitis B infection.

   - History of alcohol or substance abuse ≤6 months of Screening that would limit
   participation in the study, as determined by the Investigator.

   - Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing
   system during the study period.

   - Presence of tracheostomy.

   - In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as
   determined by the Investigator.

   - In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes
   mellitus defined as hemoglobin A1c (HbA1c) ≥8% during Screening.

   - In participants in Cohorts A, B, and C1, prescreening ALSFRS-R slope >-0.4
   points/month, where prescreening ALSFRS-R slope is defined as: (ALSFRS-R score at
   Screening - 48) / (months from date of symptom onset to date of Screening). This
   criterion is not applicable for Cohorts C2, D1, and D2.

   - Treatment with another investigational drug (including investigational drugs for ALS
   through compassionate use programs) or biological agent within 1 month or 5 half-lives
   of study agent, whichever is longer, before Screening.

   - Treatment with an approved disease-modifying therapy for ALS other than riluzole or
   edaravone within 1 month or 5 half-lives of therapy, whichever is longer, before
   completion of screening.

   - Treatment with an antiplatelet or anticoagulant therapy that cannot safely be
   interrupted for lumbar puncture (LP) according to local standard of care and/or
   institutional guidelines, in the opinion of the Investigator or Prescriber.

   - Female participants who are pregnant or currently breastfeeding and those intending to
   become pregnant during the study.

Part 2:

   - History or positive test result at Screening for HIV. If participants from Cohorts D1
   and D2 who would seamlessly roll from Part 1 into Part 2 test positive for HIV during
   screening for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the
   discretion of the Investigator.

   - Current hepatitis C infection. If participants from Cohorts D1 and D2 who would
   seamlessly roll from Part 1 into Part 2 test positive for hepatitis C during screening
   for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the
   discretion of the Investigator.

   - Current hepatitis B infection. If participants from Cohorts D1 and D2 who would
   seamlessly roll from Part 1 into Part 2 test positive for hepatitis B during screening
   for Part 2 but are clinically asymptomatic, they may enroll in Part 2 at the
   discretion of the Investigator.

   - History of alcohol or substance abuse ≤ 6 months of Screening that would limit
   participation in the study, as determined by the Investigator.

   - Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing
   system during the study period.

   - In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as
   determined by the Investigator.

   - In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes
   mellitus defined as HbA1c ≥8% during Screening.

   - Treatment with another investigational drug (including investigational drugs for ALS
   through compassionate use programs; excluding BIIB105) or biological agent within 1
   month or 5 half-lives of study agent, whichever is longer, before Screening.

   - Treatment with an antiplatelet or anticoagulant therapy that cannot safely be
   interrupted for LP according to local standard of care and/or institutional
   guidelines, in the opinion of the Investigator or Prescriber.

   - Female participants who are pregnant or currently breastfeeding and those intending to
   become pregnant during the study.

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