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).
This is a multi-center, three-part study of ION363 in up to 95 participants. Part 1 will consist of participants who will be randomized in a 2:1 ratio to receive a multi-dose regimen of ION363 or placebo for a period of 60 weeks, followed by Part 2, in which participants will receive open-label ION363 for a period of 84 weeks. Participants may continue to receive open-label ION363 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 ION363 development program, whichever occurs earlier.
Inclusion Criteria for Part 1:
1. 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).
2. 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.
3. 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.
4. 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.
5. 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.
6. 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).
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 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.
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 study
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 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.
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 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.
5. Uncontrolled hypertension (blood pressure [BP] > 160/100 millimeters of mercury [mm
Hg]).
6. 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.
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,
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.
9. Concurrent participation in any other interventional clinical study.
10. Previous or current treatment with an oligonucleotide (including small interfering
RNA [siRNA], tofersen). This exclusion criterion does not apply to COVID-19
vaccinations, which are allowed.
11. Treatment with another investigational drug, biological agent, or device within 1
month before 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. 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.
14. 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, in the opinion of the Investigator.