The goal of this clinical trial is to learn whether a nasal spray medicine called foralumab is safe and easy to tolerate in adults with amyotrophic lateral sclerosis (ALS). ALS is a disease that slowly damages the nerve cells that control movement, causing muscles to grow weaker over time. Foralumab is being studied as a possible way to calm the inflammation and immune system activity that are thought to play a role in ALS.

The main questions it aims to answer are:

1. Is nasal foralumab safe for people with ALS, and how well do they tolerate it over 12 and 24 weeks of treatment?
2. Does foralumab change certain markers in the blood and spinal fluid, and lower inflammation in the brain, compared with a placebo?

Researchers will compare people who take foralumab to people who take a placebo (a matching nasal spray with no medicine in it) to see how the two groups differ in safety and in these markers.

About 44 adults aged 18 to 75 with ALS will take part. For the first 12 weeks, participants will be randomly assigned so that about 3 in 4 use foralumab and about 1 in 4 use the placebo. Neither the participants nor the study staff will know who is using which during this time (this is called "double-blind"). After the first 12 weeks, everyone who continues will use foralumab for the next 12 weeks.

Participants will:

• Spray the study treatment into both nostrils 3 times a week, on alternate days, in cycles of 2 weeks on treatment followed by 1 week off
• Learn to use the nasal spray device so they or a caregiver can give most doses at home
• Take part for about 8.5 months in total, which includes screening, 24 weeks of treatment, and a safety check-in about 4 weeks after the last dose
• Attend some visits at the study clinic and complete others remotely by phone or video
• Have study tests that may include blood samples, breathing and muscle-strength checks, and - for those who agree and at certain study centers - spinal fluid samples and brain scans to measure inflammation

Inclusion Criteria:

• Adults ≥18 years of age and ≤75 years of age with a diagnosis of symptomatic ALS by revised El Escorial Criteria (clinically possible, probable, probable lab-supported, or definite).
• Participant must be actively enrolled and must have met eligibility criteria for the Healey ALS MyMatch Common Screening Protocol (MCSP) AND determined to have met preliminary eligibility on targeted medical history and review of systems and safety laboratory results required for this trial.
• Blood neurofilament (NfL) level of greater than 40 pg/mL as measured by the MyMatch Common Screening Protocol specific NfL assay.
• Ability to provide written informed consent.
• Less than or equal to 24-months since onset of weakness or spasticity attributed to ALS.
• Slow vital capacity (SVC) of at least 65% predicted value for gender, height and age at trial screening visit.
• Participant must not have taken riluzole and/or edaravone for at least 30 days, or be on a stable dose of riluzole and/or edaravone for at least 30 days prior to baseline (riluzole-naïve or edaravone-naïve participants are permitted in the study).
• Negative urine pregnancy test within 7 days prior to the first dose of study therapy for women of child-bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive months). Sexually active women of child-bearing potential and male participants must agree to use highly effective methods to avoid pregnancy (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study and for 90 days after the completion of study treatment.
• Participants must be able to travel to the study site for study visits and complete required study procedures.
• Participants who are participating in the PET or Lumbar Puncture (LP) outcomes, must be determined to be able to safely tolerate these study procedure(s) in the opinion of the study investigator AND as determined by the targeted medical history and review of systems in the MCSP. Both procedures are highly encouraged.
• Participants whose immunizations are fully up to date at Screening, according to the assessment of their primary care physician and neurologist.

Exclusion Criteria:

• Clinically significant medical condition that would pose a risk to the participant, according to the PI's judgment and examination prior to baseline.
• Active ENT disease (such as allergic rhinitis, chronic rhinitis, active sinusitis treated within the past 30 days or deemed as clinically relevant, clinically significant deviated nasal septum, nasal polyps) that might interfere with safely administering the drug nasally.
• Active clinically significant infection or immunocompromised condition.
• Treatment with chronic immunosuppressants or other immunosuppressants within the past 90 days.
• Concomitant use of investigational treatments for ALS within 5 half-lives or 30 days prior to the Baseline visit, whichever is longest (high dosage methylcobalamin permitted).
• Exposure to any gene or cell therapies under investigation for treatment of ALS.
• Inability to tolerate nasally administered medications.
• Participant reported history of any vaccines within past 14 days (prior to first dose of foralumab).