FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS)

NCT04768972 | Active Not Recruiting Phase 3 DMC FDA Drug

• 2 other identifiers: ION363-CS12020-005522-28
• Study Type: interventional
• Target: 89
• Locations: 16 countries
• Sites: 25

Brief Summary

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

Conditions

Amyotrophic Lateral Sclerosis

Keywords

Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations; Amyotrophic Lateral Sclerosis; Sarcoma Mutations

Outcome Measures

Primary Outcomes (1)

• Change from Baseline (Day 1) through Study Day 505 in Part 1 in functional impairment

  Functional impairment to be measured by joint rank analysis of the combined assessment of: In-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score, time of rescue or discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and ventilation assistance-free survival (VAFS). ALSFRS-R measures functional disease severity. The scale measures four functional domains, bulbar function, gross motor skills, fine motor skills, and respiratory function. The assessment will contain 12 questions scored from 0 (no function) to 4 (full function), with a total possible score of 48, which will indicate the highest level of function. ALSFRS-R will be a part of the combined assessment of joint rank analysis to assess efficacy in Part 1.

  Baseline, Day 505 in Part 1

Secondary Outcomes (7)

• Change from Baseline in ALS Assessment Questionnaire, 5-item (ALSAQ-5)

  Baseline, Day 505 in Part 1

• Change from Baseline in the in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)

  Baseline, Day 505 in Part 1

• Survival and Ventilation Assistance-Free Survival (VAFS)

  Up to Day 505 in Part 1

• Change from Baseline in In-clinic Slow Vital Capacity (SVC) to Day 505 in Part 1

  Baseline, Day 505 in Part 1

• Change from Baseline in Handheld Dynamometry (HHD) to Day 505 in Part 1

  Baseline, Day 505 in Part 1

Study Arms (2)

ION363

EXPERIMENTAL

ION363 will be administered by lumbar intrathecal (IT) bolus injection every 12 weeks, with an additional loading dose at 4 weeks, over a 60-week double-blind treatment period in Part 1; every 12 weeks for 84 weeks in the open-label extension treatment period (Part 2), with an additional loading dose administered 4 weeks after the first dose. Patients may continue to receive open-label ION363 every 12 weeks in Part 3 for up to 3 additional years or until ION363 becomes commercially available in the patient's country or until the Sponsor discontinues the development program, whichever occurs earlier.

Drug: ION363

Placebo

PLACEBO COMPARATOR

Placebo will be administered by lumbar IT bolus injection every12 weeks, with an additional loading dose at 4 weeks, over a 60-week double-blind treatment period (Part 1).

Drug: Placebo

Interventions

ION363 DRUG

ION363 will be administered by IT bolus injection.

ION363

Placebo DRUG

Placebo will be administered by IT bolus injection.

Placebo

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be ≥10 years of age at the time of informed consent and have signs or symptoms consistent with an ALS disease (in the opinion of the Investigator).
• Genetic mutation in FUS confirmed by a testing laboratory that is Clinical Laboratory Improvement Amendments (CLIA) certified and European Conformity (CE)-marked, or equivalent. Mutations must be reviewed and approved by a variant classification committee.
• Upright (sitting position) slow vital capacity (SVC) is ≥ 50% of predicted value (as adjusted for sex, age, and height) OR if SVC is \< 50% of predicted value, must be 10 to 30 years of age (inclusive) at the time of informed consent AND had ALS symptom onset within 12 months before the time of informed consent.
• Participants taking edaravone, riluzole, Relyvrio (sodium phenylbutyrate/taurursodiol combination, called Albrioza in Canada), sodium phenylbutyrate, or tauroursodeoxycholic acid (TUDCA, also known as taurursodiol or urosodiol) 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.
• Stable concomitant medications and nutritional support for at least 1 month prior to Study Day 1. Concomitant 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.
• Females must not be pregnant or lactating. Males and females must be willing to following protocol-specified contraception requirements, or be surgically sterile, or be post-menopausal (females).
• 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 throughout the study. In addition, a patient who is \< 18 years old must have a trial partner (parent, caregiver, or other) who is reliable, competent, at least 18 years of age, and willing to accompany the patient to all trial visits.
• Completed, or rescued from, Part 1, or
• Enrolled and received at least 1 dose of ION363 in the Investigator-initiated study program
• Patient meeting Criteria #1-2 is otherwise suitable for study participation, in the opinion of the Investigator

You may not qualify if:

• Requiring permanent ventilation (\> 22 hours of mechanical ventilation \[invasive or noninvasive\] per day for \> 21 consecutive days) and/or tracheostomy.
• Any known genetic variant (other than those in the FUS gene) that is pathogenic or likely to be pathogenic for the ALS-frontotemporal dementia (FTD) spectrum of disease.
• Positive test result for:
• Human immunodeficiency virus (HIV)
• Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV RNA negative for at least 6 months after the end of treatment
• Hepatitis B (HBV) by HBV surface antigen test, unless currently on nucleotide/nucleoside analogue treatment
• Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 3 months before Screening, major surgery within 2 months before Screening) or physical examination.
• Uncontrolled hypertension (blood pressure \[BP\] \> 160/100 millimeters of mercury \[mm Hg\]).
• Malignancy within 1 year before 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 not recurred within 6 months may also be eligible per Investigator judgement.
• Obstructive hydrocephalus
• 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, subarachnoid hemorrhage, suggestion of raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis or curvature, Chiari malformation, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome.
• Concurrent participation in any other interventional clinical study.
• Treatment with another investigational drug, biological agent, or device within 1 month before Screening, or 5 half-lives of investigational agent, whichever is longer.
• History of gene therapy or cell transplantation or any other experimental brain surgery.
• Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication that cannot be safely paused before and/or after an LP procedure according to local or institutional guidelines and/or Investigator determination after consultation with the appropriate treating physician. Low-dose aspirin (≤ 100 mg/day, administered as monotherapy) is permitted and may be continued through the LP procedure.

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (25)

University of California San Diego

La Jolla, California, 92037, United States

Location

Stanford University Medical Center

Palo Alto, California, 94304, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21205, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

UZ Leuven

Leuven, VL-Brabant, 3000, Belgium

Location

PSEG Centro de Pesquisa Clinica S.A.

São Paulo, 04038-002, Brazil

Location

Montreal Neurological Institute

Montreal, Quebec, H3A 2B4, Canada

Location

Universitaetsmedizin Rostock

Rostock, 18147, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

St. James Hospital

Dublin, D08 A978, Ireland

Location

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

Torino, 10126, Italy

Location

Toho University Omori Medical Center

Tokyo, 143-8541, Japan

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Linden spólka z ograniczona odpowiedzialnoscia spólka komandytow

Krakow, 30-721, Poland

Location

Seoul National University Hospital

Seoul, 3080, South Korea

Location

Hanyang University Seoul Hospital

Seoul, 4763, South Korea

Location

Hospital Universitari de Bellvitge

Barcelona, 8907, Spain

Location

University Hospital of Umea

Umeå, SE-901 85, Sweden

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

Taipei Veterans General Hospital (VGHTP)

Taipei, 11217, Taiwan

Location

King's College Hospital

London, SE5 9RT, United Kingdom

Location

Related Publications (1)

• Codron P, Cassereau J, Vourc'h P. InFUSing antisense oligonucleotides for treating ALS. Trends Mol Med. 2022 Apr;28(4):253-254. doi: 10.1016/j.molmed.2022.02.006. Epub 2022 Mar 1.

  PMID: 35246398 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2021
• First Posted: February 24, 2021
• Study Start: June 14, 2021
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): March 1, 2028
• Last Updated: February 18, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); ES (1); NL (1); CH (1); IT (1); TW (1); SE (1); IE (1); BE (1); BR (1); KR (2); GB (1); US (8); JP (1); DE (2); PL (1)