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


Trial ID: NCT04768972


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).

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)

Stanford Investigator(s)

John W. Day, MD, PhD
John W. Day, MD, PhD

Professor of Neurology (Adult Neurology), of Pediatrics (Genetics) and, by courtesy, of Pathology


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

   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

   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

   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

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.


drug: ION363

drug: Placebo


Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305