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

• Register: EUCTR
• Last refreshed on: 3 December 2024
• Main ID: EUCTR2020-005522-28-IT
• Date of registration: 09/08/2021
• Prospective Registration: Yes
• Primary sponsor: IONIS PHARMACEUTICALS, INC.
• Public title: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS).
• Scientific 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) - FUSION: A Phase 1-3 study to evaluate the effects of ION363 in FUS-ALS patients
• Date of first enrolment: 26/09/2022
• Target sample size: 64
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-005522-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: yes Other: yes Other trial design description: Part 1 double blind and Part 2 open label If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, France, Germany, Ireland, Italy, Japan, Korea, Republic of, Netherlands, Poland, Spain, Sweden, Turkey, United Kingdom, United States

Contacts

• Name: Ionis Clinical Trial Information
• Affiliation: Ionis Pharmaceuticals, Inc.

• Name: Ionis Clinical Trial Information
• Affiliation: Ionis Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion Criteria for Part 1:
1.Signs or symptoms consistent with an ALS disease process in the opinion of the Investigator
2.Participants in:
Cohort A must be, at the time of informed consent, 12 – 65 years of age, inclusive, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator and if 30 to 65 years of age, inclusive, 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, at the time of informed consent, > 30 years of age, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator 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)
3.Confirmed genetic mutation in FUS in a clinical laboratory improvement amendments (CLIA) certified, CE-marked, or equivalent testing laboratory and classified as "pathogenic" or "likely pathogenic".
Mutations not pre-approved per the Variant Classification Manual must be reviewed and approved by a variant classification committee
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
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
Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

Exclusion criteria:
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:
a.Human immunodeficiency virus (HIV)
b.Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV RNA negative for at least 6 months after the end of treatment
c.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, 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]). 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Amyotrophic Lateral Sclerosis with Fused in Sarcoma mutations
MedDRA version: 21.1 Level: PT Classification code 10002026 Term: Amyotrophic lateral sclerosis System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: ION363
Product Code: [ION363]
Pharmaceutical Form: Solution for injection
Current Sponsor code: ION363
Other descriptive name: all-P-ambo-2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'-O->5'-O)-2'-O-(2-methoxyethyl)-5-methylcytidylyl-(3'-O->5'-O)-2'-O-(2-methoxyethyl)adenylyl-(3'-O->5'-O)-2'-O-(2-methoxyethyl)adenylyl-(3'-O->5'-O)-2'-O-(2-methoxyethyl)-5-methyluridylyl-(3'-O->5'-O)-2'-deoxy-P-thioguanylyl-(3'-O->5'-O)-P-thiothymidylyl-(3'-O->5'-O)-2'-deoxy-5-methyl-P-thiocytidylyl-(3'-O->5'-O)-2'-deoxy-Pthioadenylyl-(3'-O->5'-O)-2'-deoxy-5-methyl-P-thiocytidylyl-(3'-O->5'-O)-2'-deoxy-
5-methyl-P-thiocytidylyl-(3'-O->5'-O)-P-t
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 30-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Intrathecal use

Primary Outcome(s)

Main Objective: To evaluate the clinical efficacy of ION363 in clinical functioning and survival in Amyotrophic Lateral Sclerosis (ALS) patients with Fused in Sarcoma mutations (FUS-ALS).

Timepoint(s) of evaluation of this end point: From Baseline to Study Day 225 in Part 1 Cohort A

Primary end point(s): The primary endpoint is the evaluation of the effects of ION363 vs. placebo on change from Day 1 to Study Day 225 in Part 1 Cohort A in functional impairment, measured by joint rank analysis of the combined assessment of the following:
•In-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score
•Time of rescue or a discontinuation of Part 1 and entering Part 2 due to a marked deterioration in function. Rescue takes place if there is a deterioration relative to Baseline in ALSFRS-R score of > 10 points or a decline in slow vital capacity (SVC) of < 40% of predicted value at Study Day 141, or later, that is confirmed after an interval of 4 weeks. Rescue means the patient may discontinue Part 1 and enter Part 2 of the study
•Ventilation assistance-free survival (VAFS), defined as the time to the earliest occurrence of 1 of the following events:
oDeath
oPermanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days in the absence of an acute reversible event)

Secondary Objective: To further evaluate the effects of ION363 in halting, reversing, or slowing the deterioration of clinical functioning and biomarkers of disease severity in FUS-ALS patients.

Secondary Outcome(s)

Secondary end point(s): Evaluate the effects of ION363 vs. placebo on change from Baseline to Study Day 225 in Part 1 Cohort A on clinical assessments and biomarkers of disease severity. Specifically, on the following endpoints:
• Change from Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life – Revised (ALSSQOL-R)
• Change from Baseline in in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
• Survival
• Change from Baseline in in-clinic Slow Vital Capacity (SVC)
• Change from Baseline in Handheld Dynamometry (HHD)
• Change from Baseline in Neurofilament light (NfL) concentration in CSF
• Change from Baseline in FUS protein concentration in CSF

Timepoint(s) of evaluation of this end point: From Baseline to Study Day 225 in Part 1

Secondary ID(s)

ION363-CS1

NCT04768972

2020-005522-28-DE

Source(s) of Monetary Support

Ionis Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date: 26/09/2022
Contact: