Inclusion Criteria:
\- ALS Criteria for Phase 1b:
1. Participants in Phase 1b must have:
1. Diagnosis of ALS per Gold Coast Criteria; and
2. Symptom onset ≤48 months prior to randomization on Day 1. Date of first ALS symptom (any ALS symptom) onset is defined as the onset of weakness in the limbs, bulbar region, or trunk. Weakness in the bulbar region includes dysarthria and dysphagia.
- ALS Criteria for Phase 2:
2. Participants in Phase 2 must have:
1. Diagnosis of ALS per Gold Coast Criteria; and
2. Symptom onset ≤24 months prior to randomization on Day 1. Date of first ALS symptom (any ALS symptom) onset is defined as the onset of weakness in the limbs, bulbar region, or trunk. Weakness in the bulbar region includes dysarthria and dysphagia.
- Additional Inclusion Criteria (All Participants):
3. Male or female participants aged ≥18 years and ≤80 years at the time of signing informed consent.
4. Participants must demonstrate functional oral intake and be independent of enteral nutritional support (e.g., PEG, G-tube) at the time of screening per Principal Investigator's judgement.
5. Slow vital capacity (SVC) ≥60% of predicted at Screening.
6. If taking riluzole, participant must be on a stable dose for ≥60 days prior to Screening lab blood draw.
7. If taking edaravone, participant must have completed at least 1 cycle of edaravone prior to screening labs.
8. Willing to adhere to contraceptive requirements during the study period as described in Appendix 1.
9. Capable of giving signed informed consent, as described in Section 13.2.2, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria:
1. Presence of tracheostomy or permanent assisted ventilation; defined as > 22 hours daily of mechanical ventilation for more than 1 week (7 days).
2. History or presence of clinically significant uncontrolled medical conditions (other than ALS) that include cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study drugs; or interfering with the interpretation of data as determined by the Investigator.
3. Lifetime history of cancer except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. Fully resected basal cell carcinoma and squamous cell carcinoma with no evidence of recurrence for 1 year are permitted.
4. Female participants who have a positive serum pregnancy test at Screening, positive urine pregnancy test on Day 1, or who are breastfeeding on Day 1.
5. Has a spinal deformity or other condition that may prevent the performance of a lumbar puncture.
6. International Normalized Ratio (INR) >1.4, platelet count <50,000/μL, or use of warfarin, heparin, or direct oral anticoagulants.
7. History of Class III/IV heart failure (per New York Heart Association \[NYHA\]).
8. Inability to swallow or tolerate oral medications at Screening.
9. Current participation in any other investigational drug study or receipt of an investigational drug within 30 days or 5 half-lives (whichever is longer) before Screening.
10. Known sensitivity to the NB-4746 study drug or any of the formulation components.
11. Has received NB-4746 at any time prior to initial Screening.
12. Any other reason that, in the opinion of the Investigator, would confound the conduct of this study or the interpretation of the results or that could compromise the participant's safety.
13. Currently taking or planning to receive tofersen for the treatment of ALS.
14. If a participant does not transition to the OLE in ≤30 days following completion of the main study, the participant will need to be rescreened for laboratory criteria and contraception/pregnancy criteria.