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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04768972
Recruitment Status : Recruiting
First Posted : February 24, 2021
Last Update Posted : April 9, 2021
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: ION363 Drug: Placebo Phase 3

Detailed Description:
This is a multi-center, two-part study of ION363 in up to 64 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 29 weeks, followed by Part 2, which will be an open-label period where all participants will receive ION363 for a period of 73 weeks.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Estimated Study Start Date : April 2021
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : March 2024

Arm Intervention/treatment
Experimental: ION363
ION363 will be administered by lumbar intrathecal (IT) bolus injection beginning with 1 dose every 4 weeks followed by 1 dose every 8 weeks over a 29-week double-blind treatment period and every 8 weeks for 73 weeks in the open-label extension treatment period.
Drug: ION363
ION363 will be administered by IT bolus injection.

Placebo Comparator: Placebo
Placebo will be administered by lumbar IT bolus injection beginning with 1 dose every 4 weeks followed by 1 dose every 8 weeks a 29-week double-blind treatment period.
Drug: Placebo
Placebo will be administered by IT bolus injection.

Primary Outcome Measures :
  1. 1. Change from Day 1 through Study Day 253 in Part 1 in functional impairment [ Time Frame: Baseline, Day 253 in Part 1 ]
    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. 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.

Secondary Outcome Measures :
  1. Change From Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) Score to Day 253 in Part 1 [ Time Frame: Baseline, Day 253 in Part 1 ]
    The ALSSQOL-R is a disease-specific 50-item assessment that measures the quality of life (QoL). Each item will be rated by the participant on a scale of 0 to 10, with 0 being the least desirable situation and 10 being the most desirable.

  2. Survival [ Time Frame: Day 253 in Part 1 ]
  3. Change From Baseline in In-clinic Slow Vital Capacity (SVC) to Day 253 in Part 1 [ Time Frame: Baseline, Day 253 in Part 1 ]
  4. Change From Baseline in Handheld Dynamometry (HHD) to Day 253 in Part 1 [ Time Frame: Baseline, Day 253 in Part 1 ]
  5. Change From Baseline in Neurofilament Light (NfL) Concentration in Cerebrospinal Fluid (CSF) to Day 253 [ Time Frame: Baseline, Day 253 in Part 1 ]
  6. Change From Baseline in Fused in Sarcoma (FUS) Protein Concentration in CSF to Day 253 [ Time Frame: Baseline, Day 253 in Part 1 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Signs or symptoms consistent with an ALS disease process in the opinion of the Investigator
  2. Confirmed genetic mutation in FUS in a clinical laboratory improvement amendments (CLIA) certified testing laboratory and classified as "pathogenic" or "likely pathogenic". Mutations classified as "Variants of Unknown Significance" must be approved by a variant classification committee
  3. An Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) pre-study slope ≥ 0.4 prior to Screening if 30 to 65 years of age, inclusive, at the time of informed consent
  4. Upright (sitting position) slow vital capacity (SVC) as adjusted for sex, age, and height ≥ 50 percentage (%) of predicted value
  5. 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
  6. 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.
  7. 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

Exclusion Criteria:

  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 indicating chronic or active hepatitis B or hepatitis C or human immunodeficiency virus (HIV), hepatitis C or hepatitis B diagnosed by initial serological testing and confirmed with RNA testing, or prior treatment for hepatitis C.
  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, unless discussed and approved by the Sponsor Medical Monitor
  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 if approved by the Sponsor medical monitor
  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])
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04768972

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Contact: Ionis Pharmaceuticals 1-800-679-4747

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United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Sonya Aziz-Zaman    646-799-2175   
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
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Responsible Party: Ionis Pharmaceuticals, Inc. Identifier: NCT04768972    
Other Study ID Numbers: ION363-CS1
2020-005522-28 ( EudraCT Number )
First Posted: February 24, 2021    Key Record Dates
Last Update Posted: April 9, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Ionis Pharmaceuticals, Inc.:
Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations
Amyotrophic Lateral Sclerosis
Sarcoma Mutations
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases