A Phase 1-3 Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION363 in Amyotrophic Lateral Sclerosis Patients With Fused in Sarcoma Mutations (FUS-ALS)

Study Purpose:

The primary purpose of this study is to evaluate the clinical efficacy of ION363 on clinical function and survival in carriers of fused in sarcoma mutations with amyotrophic lateral sclerosis (FUS-ALS).

Study Status:



Amyotrophic Lateral Sclerosis

Study Type:


Type of Intervention:


Intervention Name:

ION363, Placebo




Phase 3

Study Chair(s)/Principal Investigator(s):


Clinicaltrials.gov ID:


Neals Affiliated?


Coordinating Center Contact Information

Ionis Pharmaceuticals / email hidden; JavaScript is required / (844) 421-0104

United States

Full Study Summary:

This is a multi-center, two-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 61 weeks, followed by Part 2, in which participants will receive ION363 for a period of 85 weeks.

Study Sponsor:

Ionis Pharmaceuticals, Inc.

Estimated Enrollment:


Estimated Study Start Date:

06 / 14 / 2021

Estimated Study Completion Date:

09 / 01 / 2025

Posting Last Modified Date:

03 / 28 / 2023

Date Study Added to neals.org:

02 / 24 / 2021

Minimum Age:

12 Years

Maximum Age:


Can participants use Riluzole?


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

University of California San Diego | Recruiting

La Jolla, California 92037
United States

Stanford University Medical Center | Recruiting

Palo Alto, California 94304
United States

Johns Hopkins University | Recruiting

Baltimore, Maryland 21205
United States

Massachusetts General Hospital | Recruiting

Boston, Massachusetts 02114
United States

Washington University School of Medicine | Recruiting

Saint Louis, Missouri 63110
United States

Columbia University Medical Center | Recruiting

New York, New York 10032
United States

The Ohio State University Wexner Medical Center | Recruiting

Columbus, Ohio 43210
United States

University of Utah | Recruiting

Salt Lake City, Utah 84132
United States

UZ Leuven | Recruiting

Leuven, VL-Brabant 3000

Montreal Neurological Institute | Recruiting

Montreal, Quebec H3A 2B4

Citta della Salute e della Scienza di Torino - Ospedale le Molinette | Recruiting

Torino 10126

Hanyang University Seoul Hospital | Recruiting

Seoul 4763
Korea, Republic of

Universitair Medisch Centrum Utrecht | Recruiting

Utrecht 3584 CX

King's College Hospital | Recruiting

London SE5 9RT
United Kingdom