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
Conditions
Interventions
Product Name: ION363
Product Code: ION363
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Not assigned
CAS Number: Not assigned
Current Sponsor code: ION363
Other descriptive name: al
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion 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 65 years of age with no ALSFRS-R pre-study slope criterion 3.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 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. Females: a) must be non-pregnant and non-lactating and either: i. surgically sterile ii. post-menopausal iii. abstinent* or iv. if engaged in sexual relations of childbearing potential, agree to use a highly effective contraceptive method from the time of signing the ICF until at least 40 Weeks after the last dose of Study Drug b. Males must be abstinent*, surgically sterile (vasectomy with negative semen analysis at follow-up, or a surgically sterile non-pregnant female partner) or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method must be used (refer to Section 6.3.1) from the time of signing the ICF until at least 40 weeks after the last dose of Study Drug * Abstinence is only acceptable as true abstinence. 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, E
Exclusion criteria
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. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 6. Uncontrolled hypertension (BP > 160/100 mm Hg) 7. 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. Patients 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 8. Obstructive hydrocephalus 9. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter 10. Known significant brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, including tumors or abnormalities by 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 11. Presence of significant cognitive impairment, not due to a developmental disability, with either a score on the Mini-Mental State Examination (MMSE) < 20 or equivalent assessment, clinical dementia, and unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression, as determined by the Investigator 12. Concurrent participation in any other interventional clinical study 13. Previous treatment with an oligonucleotide (including siRNA). This exclusion criterion does not apply to COVID-19 vaccinations, which are allowed. 14. 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 15. History of gene therapy or cell transplantation or any other experimental brain surgery 16. Antiplatelet or anticoagulant therapy within the 14 days prior to Day 1 or anticipated use during the study, including but not limited to daily, low-dose aspirin (defined as = 150 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban 17. Clinically significant low platelet count (defined as < 100,000/mm3), coagulation tests, or laboratory abnormalities that would render a patient unsuitable for inclusion 18. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator 19. Have any other condit
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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).;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.;Primary end point(s): Change from 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 Rescue takes place if there is a deterioration to an ALSFRS-R total score of 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days in the absence of an acute reversible event) 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.;Timepoint(s) of evaluation of this end point: From Baseline to Study Day 505 in Part 1 Cohort A | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Evaluate the effects of ION363 vs. placebo on change and/or percent change, if appropriate, from Baseline to Study Day 505 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;Timepoint(s) of evaluation of this end point: From Baseline to Study Day 505 in Part 1 | — |
Countries
Belgium, Brazil, Canada, France, Germany, Ireland, Italy, Japan, Korea, Democratic People's Republic of, Netherlands, Poland, Spain, Sweden, Turkey, United Kingdom, United States
Contacts
Public ContactIonis Clinical Trial Information
Ionis Pharmaceuticals, Inc.
Outcome results
None listed