Ionis FUS-ALS trial

A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered IMP in Amyotrophic Lateral Sclerosis Patients with Fused in Sarcoma Mutations (FUS-ALS)

UK Chief Investigator

Professor Chris Shaw

Research summary

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease. Patients suffer with loss of muscle mass, strength, and function in bulbar, respiratory, and voluntary muscle. Decline is inevitable, with death from respiratory failure following 2 to 5 years after diagnosis for most patients. ALS-associated Fused in Sarcoma (FUS) mutations are often associated with a more severe course compared to ALS patients associated with other genetic mutations.

It is a severe disorder with no available disease-modifying treatment. The only currently approved treatments for ALS are riluzole and edaravone. Riluzole provides a modest increase in survival (2 to 3 months) without noticeable improvement in strength or disability. The effect of edaravone on survival is unknown. No specific FUS-ALS treatments are available. For these reasons, there is a substantial unmet medical need to delay or prevent further progression of this devastating disease.

The primary purpose of this study is to evaluate the clinical efficacy of ION363 in clinical functioning and survival in FUS-ALS patients. Ionis Pharmaceuticals, Inc. is developing ION363 for the treatment of ALS patients with FUS mutation. ION363 is a drug that selectively targets a specific region of the FUS pre-messenger ribonucleic acid (pre-mRNA), thereby reducing FUS mRNA which encodes FUS protein expression. The reduction of toxic mutant FUS protein may delay, halt, or even reverse disease progression in FUS-ALS patients.

This is a Phase 1-3, global, multi-center, two-part study. Part 1 will consist of participants (maximum of 63 patients) that will be randomized in a 2:1 ratio to receive a multi-dose regimen of ION363 or placebo for 29 weeks treatment period, followed by Part 2, which will be an open-label extension study where all participants will receive ION363 for 77 weeks treatment period. Currently, only one site is selected in the United Kingdom.

Inclusion / exclusion criteria

Inclusion criteria

Inclusion Criteria for Part 1:

  • 1. Must have given written informed consent and assent, if indicated per patient’s age and institutional guidelines (signed and dated) and any authorizations required by local law and be able to comply with all study requirements.

  • 2. Patients in: a. Cohort A, at the time of informed consent, must be 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). b. Cohort B, at the time of informed consent, must be > 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 CLIA certified, CE-marked, or equivalent, testing laboratory and pre-approved per the Variant Classification Manual. Mutations not pre-approved per the Variant Classification Manual must be reviewed and approved by a variant classification committee.

  • 4. Upright (sitting position) SVC as adjusted for sex, age, and height ≥ 50% of predicted value.

  • 5. Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, assessments and visits.

  • 6. Patients 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.

  • 7. Satisfy the following: a. Females: must be non-pregnant and non-lactating and either: i. surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or vasectomized male partner). ii. post-menopausal (defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient). 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 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, i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception.

  • 8. 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 per Investigator judgement.

  • 9. 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: a. Patients < 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 patient 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 patient’s ongoing condition to respond to Study Center inquiries about the patient.

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.

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) 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.

  • 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 EhlersDanlos syndrome and Marfan syndrome.

  • 11. Presence of significant cognitive impairment, not due to a developmental disability, with a score on the Mini-Mental State Examination (MMSE) < 20, 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 conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study.

Current status

Open to recruitment


King's College Hospital

Information about study sites

Contact details

Recruitment group(s)

Patients with MND

Recruitment target(s)

Up to 44 participants globally (3 particiapnts in the UK)

Key dates

Actual opening date (UK): 30 December 2021

Planned recruitment end date (UK): 30 May 2023


Ionis Pharmaceuticals, Inc.


Ionis Pharmaceuticals, Inc.

Study design

Interventional (drug), randomised controlled trial

Intervention (if applicable)

  • Drug: ION363

  • Placebo

Phase (if applicable)


Outcome measures

Primary outcome measure

Change from Baseline (Day 1) through Study Day 505 in Part 1 in 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), time of rescue or discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and Ventilation Assistance-free survival (VAFS).

Secondary outcome measures

  • Change From Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) Score to Day 505 in Part 1
    Change from Baseline in in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)

  • Change From Baseline in In-clinic Slow Vital Capacity (SVC) to Day 505 in Part 1

  • Change From Baseline in Handheld Dynamometry (HHD) to Day 505 in Part 1

  • Change From Baseline in Neurofilament Light (NfL) Concentration in Cerebrospinal Fluid (CSF)

Publications / Results reports

Links will be provided when papers are published.