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

• ClinicalTrials.gov Identifier: NCT04768972
• Recruitment Status: Recruiting
• First Posted: February 24, 2021
• Last Update Posted: March 28, 2023
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Study Description

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 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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 77 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)
• Actual Study Start Date: June 14, 2021
• Estimated Primary Completion Date: June 2025
• Estimated Study Completion Date: September 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: ION363; ION363 will be administered by lumbar intrathecal (IT) bolus injection with 1 dose every 4-12 weeks, after a loading dose at 4 weeks, over a 61-week double-blind treatment period in Part 1 and every 12 weeks for 85 weeks in the open-label extension treatment period, aside from a loading dose administered 4 weeks after the first dose in Part 2.	Drug: ION363; ION363 will be administered by IT bolus injection.
Placebo Comparator: Placebo; Placebo will be administered by lumbar IT bolus injection with 1 dose every 4-12 weeks over a 61-week double-blind treatment period.	Drug: Placebo; Placebo will be administered by IT bolus injection.

Outcome Measures

Primary Outcome Measures :

1. Change from Baseline (Day 1) through Study Day 505 in Part 1 in functional impairment [ Time Frame: Baseline, Day 505 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 505 in Part 1 [ Time Frame: Baseline, Day 505 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. Change from Baseline in in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) [ Time Frame: Baseline, Day 505 in Part 1 ]
   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
3. Survival [ Time Frame: Up to Day 505 in Part 1 ]
4. Change From Baseline in In-clinic Slow Vital Capacity (SVC) to Day 505 in Part 1 [ Time Frame: Baseline, Day 505 in Part 1 ]
5. Change From Baseline in Handheld Dynamometry (HHD) to Day 505 in Part 1 [ Time Frame: Baseline, Day 505 in Part 1 ]
6. Change From Baseline in Neurofilament Light (NfL) Concentration in Cerebrospinal Fluid (CSF) to Day 505 [ Time Frame: Baseline, Day 505 in Part 1 ]

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Ionis Pharmaceuticals; (844) 421-0104; ionisNCT04768972study@clinicaltrialmedia.com

Locations

United States, California

University of California San Diego; Recruiting

La Jolla, California, United States, 92037

Stanford University Medical Center; Recruiting

Palo Alto, California, United States, 94304

United States, Maryland

Johns Hopkins University; Recruiting

Baltimore, Maryland, United States, 21205

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

United States, New York

Columbia University Medical Center; Recruiting

New York, New York, United States, 10032

United States, Ohio

The Ohio State University Wexner Medical Center; Recruiting

Columbus, Ohio, United States, 43210

United States, Utah

University of Utah; Recruiting

Salt Lake City, Utah, United States, 84132

Belgium

UZ Leuven; Recruiting

Leuven, VL-Brabant, Belgium, 3000

Canada, Quebec

Montreal Neurological Institute; Recruiting

Montreal, Quebec, Canada, H3A 2B4

Italy

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

Torino, Italy, 10126

Korea, Republic of

Hanyang University Seoul Hospital; Recruiting

Seoul, Korea, Republic of, 4763

Netherlands

Universitair Medisch Centrum Utrecht; Recruiting

Utrecht, Netherlands, 3584 CX

United Kingdom

King's College Hospital; Recruiting

London, United Kingdom, SE5 9RT

Sponsors and Collaborators

Ionis Pharmaceuticals, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04768972
• Other Study ID Numbers: ION363-CS1; 2020-005522-28 ( EudraCT Number )
• First Posted: February 24, 2021
• Last Update Posted: March 28, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Sarcoma; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases