Evaluating ION363 for Amyotrophic Lateral Sclerosis with FUS mutations

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)

This study is testing a new treatment called ION363 to see if it can help people with ALS who have specific genetic mutations feel better and live longer.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 95 (estimated)
• Ages: 10 Years and up
• Sex: All
• Sponsor: Ionis Pharmaceuticals, Inc. (Industry-sponsored)
• Locations: 25 sites (La Jolla, California and 24 other locations)
• Trial ID: NCT04768972 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of ION363 in participants with amyotrophic lateral sclerosis (ALS) who have fused in sarcoma (FUS) mutations. It is a multi-center, three-part study involving up to 95 participants, where the first part includes a randomized, placebo-controlled phase lasting 60 weeks. Following this, participants will receive open-label ION363 for 84 weeks, with the option to continue treatment for up to three additional years. The study aims to assess clinical function and survival outcomes in this specific patient population.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 10 years and older with confirmed FUS mutations and specific respiratory function criteria.

Not a fit: Patients without FUS mutations or those with advanced ALS symptoms may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve clinical outcomes and survival for patients with FUS-ALS.

How similar studies have performed: Other studies targeting genetic mutations in ALS have shown promise, but this specific approach with ION363 is novel.

Eligibility criteria

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.

Where this trial is running

La Jolla, California and 24 other locations

• University of California San Diego — La Jolla, California, United States (Recruiting)
• Stanford University Medical Center — Palo Alto, California, United States (Recruiting)
• Johns Hopkins University — Baltimore, Maryland, United States (Recruiting)
• Massachusetts General Hospital — Boston, Massachusetts, United States (Recruiting)
• Washington University School of Medicine — Saint Louis, Missouri, United States (Recruiting)
• Columbia University Medical Center — New York, New York, United States (Recruiting)
• The Ohio State University Wexner Medical Center — Columbus, Ohio, United States (Recruiting)
• University of Utah — Salt Lake City, Utah, United States (Recruiting)
• UZ Leuven — Leuven, VL-Brabant, Belgium (Recruiting)
• PSEG Centro de Pesquisa Clinica S.A. — São Paulo, Brazil (Recruiting)
• Montreal Neurological Institute — Montreal, Quebec, Canada (Recruiting)
• Universitaetsmedizin Rostock — Rostock, Germany (Recruiting)
• Universitätsklinikum Ulm — Ulm, Germany (Recruiting)
• St. James Hospital — Dublin, Ireland (Recruiting)
• Citta della Salute e della Scienza di Torino - Ospedale le Molinette — Torino, Italy (Recruiting)
• Toho University Omori Medical Center — Tokyo, Japan (Recruiting)
• Seoul National University Hospital — Seoul, Korea, Republic of (Recruiting)
• Hanyang University Seoul Hospital — Seoul, Korea, Republic of (Recruiting)
• Universitair Medisch Centrum Utrecht — Utrecht, Netherlands (Recruiting)
• Linden spólka z ograniczona odpowiedzialnoscia spólka komandytow — Kraków, Poland (Recruiting)
• Hospital Universitari de Bellvitge — Barcelona, Spain (Recruiting)
• University Hospital of Umea — Umeå, Sweden (Recruiting)
• Kantonsspital St. Gallen — Saint Gallen, Switzerland (Recruiting)
• Taipei Veterans General Hospital (VGHTP) — Taipei City, Taiwan (Recruiting)
• King's College Hospital — London, United Kingdom (Recruiting)

Study contacts

• Study coordinator: Ionis Pharmaceuticals

Conditions Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations; Sarcoma Mutations