Inclusion Criteria for Part 1:
1. Participants in:
Cohort A must be 12 - 65 years of age with signs or symptoms consistent with an ALS disease. If 30 to 65 years of age, have an ALSFRS-R pre-study slope ≥ 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset) Cohort B must be> 30 years of age, with signs or symptoms consistent with an ALS disease process and have an ALSFRS-R pre-study slope < 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset). If between the ages of 30 - 65 years, inclusive, or > 65 years of age with no ALSFRS-R pre-study slope criterion 2. Confirmed genetic mutation in FUS in a clinical laboratory improvement amendments (CLIA) certified, CE-marked, or equivalent testing laboratory. Mutations must be reviewed and approved by a variant classification committee.
3. Upright (sitting position) slow vital capacity (SVC) as adjusted for sex, age, and height ≥ 50 percent (%) of predicted value 4. Participants taking edaravone must be on a stable dose for ≥ 28 days prior to Screening and riluzole must be on a stable dose for ≥ 28 days prior to Day 1, and willing to continue on that dose throughout the duration of the study, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study 5. Stable accompanied medications and nutritional support for at least 1 month prior to Study Day 1. Accompanied medications or nutritional support that have not been stable for at least 1 month prior to Study Day 1 may be allowed in consultation with the Sponsor Medical Monitor or designee.
6. 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. Participants < 18 years old at Screening must have a trial partner (parent, caregiver or other) who is reliable, competent and at least 18 years of age, is willing to accompany the participant to trial visits and to be available to the Study Center by phone if needed, and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of participant's ongoing condition to respond to Study Center inquiries about the participant Inclusion Criteria for Part 2:
1. Completed, or rescued from, Part 1, or 2. Enrolled and received at least 1 dose of ION363 in the Investigator-initiated EAP program 3. Patient meeting Criteria #1-2 is otherwise suitable for study participation, in the opinion of the Investigator Exclusion Criteria for Part 1:
1. Requiring permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days) and/or tracheostomy 2. Any known ALS-associated mutations except FUS 3. Positive test result for:
1. Human immunodeficiency virus (HIV) 2. Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV RNA negative for at least 6 months after the end of treatment 3. Hepatitis B (HBV) by HBV surface antigen test, unless currently on nucleotide/nucleoside analogue treatment 4. Clinically significant (CS) abnormalities in medical history (e.g., previous acute coronary syndrome within 3 months of Screening, major surgery within 2 months of Screening) or physical examination 5. Uncontrolled hypertension (blood pressure [BP] > 160/100 millimeters of mercury [mm Hg]) 6. Malignancy within 1 year of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
Participants with a history of other malignancies that have been treated with curative intent and which have no recurrence within 6 months may also be eligible per Investigator judgement.
7. Obstructive hydrocephalus 8. Known significant brain or spinal disease that would interfere with the lumbar puncture (LP) process, CSF circulation or safety assessment, including tumors or abnormalities by magnetic resonance imaging (MRI) or computed tomography (CT), subarachnoid hemorrhage, suggestion of raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis or curvature, chiari malformation, obstructive hydrocephalus, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome 9. Concurrent participation in any other interventional clinical study 10. Previous treatment with an oligonucleotide (including small interfering RNA [siRNA]).
This exclusion criterion does not apply to COVID-19 vaccinations, which are allowed 11. Treatment with another investigational drug, biological agent, or device, including, but not limited to sodium phenylbutyrate, within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 12. History of gene therapy or cell transplantation or any other experimental brain surgery 13. Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion, or could interfere with the individual participating in or completing the study

This is a multi-center, three-part study of ION363 in up to 77 participants. Part 1 will consist of participants that will be randomized in a 2:1 ratio to receive a multi-dose regimen of ION363 or placebo for a period of 60 weeks, followed by Part 2, in which participants will receive ION363 for a period of 80 weeks.Participants who have completed Part 2 are eligible to participate in Part 3 and continue to receive ION363 for an additional 156 weeks. Treatment extension period was added to allow patients who complete Part 2 to continue to receive ION363 until the drug may become commercially available.

• Ionis Pharmaceuticals, Inc.

NCT04768972 (First Published: 2/22/2021)