ULEFNERSEN for Amyotrophic lateral sclerosis (ALS) | FUS mutation-associated amyotrophic lateral sclerosis (FUS-ALS)

Inclusion criteria

• {"criterion_text":"- 1. Must provide written informed consent\n- Part 2: Inclusion Criterion 1: Completed or was rescued from Part 1, or enrolled and received at least 1 dose of ION363 in the IIS. Patients from the IIS must provide written informed consent (and assent, if indicated per patient's age and institutional guidelines) (signed and dated) and any authorizations required by local law.\n- Part 2: Inclusion Criterion 2: Satisfy the following: a. Females: must be non-pregnant and non-lactating and either: i. surgically sterile 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 (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 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.\n- Part 2: Inclusion Criterion 3: Is suitable for study participation, in the opinion of the Investigator\n- 2. At the time of informed consent, a patient must be >= 10 years of age and have signs or symptoms consistent with an ALS disease process (in the opinion of the Investigator)\n- 3. 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\n- 4. Upright (sitting position) 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\n- 5. Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, assessments, and visits.\n- 6. 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.\n- 7. Satisfies the following: a. Females: 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.\n- 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's Judment\n- 9. Has an informant_caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the patient to be able to provide accurate information about the patient'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."}

Exclusion criteria

• {"criterion_text":"- 1. Requiring permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days) and/or tracheostomy\n- 6. Uncontrolled hypertension (blood pressure [BP] > 160_100 mmHg).\n- 7. 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. Patients 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 judgment\n- 8. Obstructive hydrocephalus\n- 9. Presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter\n- 14. Treatment with another investigational drug, biological agent, or device, including, but not limited to sodium phenylbutyrate, within 1 month before Screening, or 5 half-lives of investigational agent, whichever is longer\n- 15. History of gene therapy or cell transplantation or any other experimental brain surgery\n- 16. 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.\n- 17. Clinically significant low platelet count (defined as < 100,000_mm3), coagulation tests, or laboratory abnormalities that would render a patient unsuitable for inclusion\n- 18. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator\n- 19. Has any other condition that would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study, in the opinion of the Investigator.\n- 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\n- 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\n- 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\n- 5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1"}

Primary endpoints

• {"endpoint_text":"- Pr.EndPoint 1: Evaluate the effects of ION363 vs. placebo on change from Baseline to Study Day 505 in Part 1 Cohorts A and B—on functional impairment, measured by joint rank analysis of the combined assessment of the following - In-clinic ALSFRS-R Total Score; ALSFRS-R measures functional disease severity.The scale measures four functional domains, bulbar function, gross motor skills, fine motor skills, and respiratory.","definition_or_measurement_approach":"Effect on functional impairment assessed by joint rank analysis of a combined assessment that includes the in-clinic ALSFRS-R Total Score."}
• {"endpoint_text":"- Pr.EndPoint 1 (continuation): 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.","definition_or_measurement_approach":"ALSFRS-R instrument: 12 items scored 0–4 (total 0–48); included as part of the joint rank combined assessment; change from Baseline to Study Day 505 is analysed."}
• {"endpoint_text":"- Pr.EndPoint 2: time of rescue (Rescue takes place if there is a deterioration to an ALSFRS_R total score of < 15 points AND a decrease of ≥10 points from baseline at Study Day 253, or later, that is confirmed after an interval of at least 4 weeks. Rescue means the patient may discontinue Part 1 and enter Part 2 of the study);","definition_or_measurement_approach":"Time-to-rescue defined by pre-specified ALSFRS-R deterioration criteria (total score <15 and decrease ≥10 points from baseline confirmed after ≥4 weeks); event triggers discontinuation from Part 1 and entry to Part 2."}
• {"endpoint_text":"- Pr.EndPoint 3: Ventilation Assistance-free survival (VAFS) defined as the time to the earliest occurrence of one of the following events: a. Death b. Permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days in the absence of an acute reversible event)","definition_or_measurement_approach":"VAFS is a time-to-event endpoint defined as time to earliest of death or permanent ventilation (specified as >22 hours/day for >21 consecutive days in absence of acute reversible event)."}

Secondary endpoints

• {"endpoint_text":"- Evaluate the effects of ION363 vs. placebo on change (or geometric mean ratio, as appropriate) from Baseline to Study Day 505 in Part 1 Cohorts A and B—on clinical assessments and biomarkers of disease severity, specifically the following endpoints: • Geometric mean ratio from Baseline in serum neurofilament light chain (NfL)","definition_or_measurement_approach":"Change or geometric mean ratio from Baseline to Day 505 for serum neurofilament light chain (NfL) concentration."}
• {"endpoint_text":"- Time to earliest of death, permanent ventilation, rescue, or withdrawal due to disease progression","definition_or_measurement_approach":"Time-to-event composite endpoint: earliest occurrence of death, permanent ventilation, rescue, or withdrawal due to disease progression."}
• {"endpoint_text":"- • Change from Baseline in the in-clinic SVC","definition_or_measurement_approach":"Change from Baseline in in-clinic slow vital capacity (SVC) measured per site procedures."}
• {"endpoint_text":"- • Change from Baseline in handheld dynamometry (HHD)","definition_or_measurement_approach":"Change from Baseline in handheld dynamometry (HHD) measures of muscle strength."}
• {"endpoint_text":"- • Change from Baseline in the in-clinic ALSFRS-R","definition_or_measurement_approach":"Change from Baseline in in-clinic ALSFRS-R total score."}
• {"endpoint_text":"- • VAFS (i.e., time to earliest of death or permanent ventilation)","definition_or_measurement_approach":"Ventilation Assistance-free Survival: time to earliest of death or permanent ventilation."}
• {"endpoint_text":"- Change from Baseline in ALS Assessment Questionnaire, 5-item (ALSAQ-5)","definition_or_measurement_approach":"Change from Baseline in ALSAQ-5 patient-reported measure."}
• {"endpoint_text":"- • Geometric mean ratio from Baseline in CSF NfL","definition_or_measurement_approach":"Geometric mean ratio from Baseline to assessment timepoints for cerebrospinal fluid neurofilament light chain (CSF NfL)."}
• {"endpoint_text":"- • Geometric mean ratio from Baseline in CSF FUS protein","definition_or_measurement_approach":"Geometric mean ratio from Baseline in CSF FUS protein concentration."}

Belgium

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

02-03-2026

Processing Time Days

567

Number Of Sites

1

Number Of Participants

10

Germany

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

27-02-2026

Processing Time Days

564

Number Of Sites

2

Number Of Participants

6

Netherlands

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

02-03-2026

Processing Time Days

567

Number Of Sites

1

Number Of Participants

15

Spain

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

03-03-2026

Processing Time Days

568

Number Of Sites

1

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

02-03-2026

Processing Time Days

567

Number Of Sites

1

Number Of Participants

10

Sweden

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

02-03-2026

Processing Time Days

567

Number Of Sites

1

Number Of Participants

4

Ireland

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

30-03-2026

Processing Time Days

595

Number Of Sites

1

Number Of Participants

4

Poland

Earliest CTIS Part Ii Submission Date

12-08-2024

Latest Decision Or Authorization Date

15-04-2025

Processing Time Days

246

Number Of Sites

1

Number Of Participants

4

Primary sponsor

Full Name

Ionis Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

IQVIA Limited

Responsibilities

Patient interview

Name

Parexel International Co. Ltd.

Name

PPD Development LP

Responsibilities

Specialty laboratory -PK analysis

Name

Medpace Inc.

Name

Perceptive Informatics Inc.

Responsibilities

Central imaging, medical image analysis/ review - X-ray, MRI, ultrasound, etc.

Third parties

• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"Central imaging, medical image analysis/ review - X-ray, MRI, ultrasound, etc.","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Patient interview","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"Interactive voice response system (IVRS)","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Charles River Laboratories Montreal ULC","duties_or_roles":"Specialty laboratory (anti-drug antibodies)","organisation_type":"Pharmaceutical company"}
• {"country":"Taiwan","full_name":"Parexel International Co. Ltd.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"QPS LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario Medical Imaging Inc.","duties_or_roles":"spirometry and ECG cardiac safety","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Sitero LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Arup Laboratories Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Nuvoair Inc.","duties_or_roles":"Home based vital capacity assessment, ventilatory patient diary","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Medpace Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"MEDPACE LABORATORIES","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Preventiongenetics LLC","duties_or_roles":"Specialty laboratory (genetic testing)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Aural Analytics Inc.","duties_or_roles":"Patient speech vitals","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Biologics Development Services LLC","duties_or_roles":"Specialty laboratory (NFL analysis)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"Patient travel services (Greenphire-Clincierge-Gray Consulting)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Cognizant Worldwide Limited","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Specialty laboratory -PK analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"site vendor training; study committee management","organisation_type":"Pharmaceutical company"}