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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ionis Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

26 Jan 2022 → ongoing

Decision date (initial)

2024-08-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-512163-31-00

EudraCT number

2020-005522-28

WHO UTN

U1111-1308-8756

ClinicalTrials.gov

NCT04768972

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

To evaluate the clinical efficacy of ION363 in clinical functioning and survival in FUS-ALS patients.

Secondary objectives 1

1. To further evaluate the effects of ION363 in halting, reversing, or slowing the deterioration of clinical functioning and biomarkers of disease severity in FUS-ALS patients.

Conditions and MedDRA coding

Amyotrophic Lateral Sclerosis with Fused in Sarcoma mutations

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

EMA paediatric investigation plan (PIP)

EMEA-003024-PIP01-21

Plan to share IPD

Yes

IPD plan description

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Must provide written informed consent
2. 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)
3. 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
4. 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
5. 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. 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.
7. 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.
8. 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
9. 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.
10. 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.
11. 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.
12. Part 2: Inclusion Criterion 3: Is suitable for study participation, in the opinion of the Investigator

Exclusion criteria 19

1. 1. Requiring permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days) and/or tracheostomy
2. 10. Known significant brain or spinal disease that would interfere with the lumbar puncture (LP) procedure, CSF circulation, or safety assessment, including tumors or abnormalities by magnetic resonance imaging (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 Ehlers-Danlos syndrome and Marfan syndrome
3. 11. Presence of significant cognitive impairment, not due to a developmental disability, based on the Mini-Mental State Examination (MMSE) (score of < 20) or an equivalent assessment, clinical dementia, and unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression, as determined by the Investigator
4. 12. Concurrent participation in any other interventional clinical study
5. 13. Previous or current treatment with an oligonucleotide (including small interfering RNA [siRNA], tofersen). This exclusion criterion does not apply to coronavirus disease 2019 (COVID-19) vaccinations, which are allowed.
6. 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
7. 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
8. 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
9. 5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
10. 6. Uncontrolled hypertension (blood pressure [BP] > 160_100 mmHg).
11. 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
12. 8. Obstructive hydrocephalus
13. 9. Presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
14. 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
15. 15. History of gene therapy or cell transplantation or any other experimental brain surgery
16. 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.
17. 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. 18. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
19. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. 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.
2. 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.
3. 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);
4. 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)

Secondary endpoints 9

1. 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)
2. Time to earliest of death, permanent ventilation, rescue, or withdrawal due to disease progression
3. • Change from Baseline in the in-clinic SVC
4. • Change from Baseline in handheld dynamometry (HHD)
5. • Change from Baseline in the in-clinic ALSFRS-R
6. • VAFS (i.e., time to earliest of death or permanent ventilation)
7. Change from Baseline in ALS Assessment Questionnaire, 5-item (ALSAQ-5)
8. • Geometric mean ratio from Baseline in CSF NfL
9. • Geometric mean ratio from Baseline in CSF FUS protein

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ionis Pharmaceuticals Inc.

Sponsor organisation

Ionis Pharmaceuticals Inc.

Address

2855 Gazelle Court

City

Carlsbad

Postcode

92010-6670

Country

United States

Scientific contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Public contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Third parties 20

Locations

8 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 163 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications