What is the mechanism of action of this treatment?

The most common treatments for Amyotrophic Lateral Sclerosis (ALS) include riluzole, edaravone, masitinib, and sodium phenylbutyrate-taurursodiol. Riluzole works by inhibiting glutamate release, which may reduce excitotoxicity that leads to motor neuron death. Edaravone is an antioxidant that helps to reduce oxidative stress, a contributing factor in ALS progression. Masitinib targets neuroinflammation by inhibiting tyrosine kinase, which may slow disease progression. Sodium phenylbutyrate-taurursodiol reduces neuronal cell death by targeting cellular stress pathways. These treatments are crucial for ALS patients as they aim to slow disease progression and improve quality of life. Additionally, treatments like ION363, which target specific genetic mutations such as FUS, are important as they offer a more personalized approach, potentially leading to more effective management of ALS in patients with these mutations.

What side effects are associated with this type of intervention?

Common treatments for ALS include riluzole, edaravone, and sodium phenylbutyrate-taurursodiol. Riluzole can cause side effects such as nausea, weakness, decreased lung function, and liver enzyme elevations. Edaravone is associated with bruising, gait disturbances, and allergic reactions. Sodium phenylbutyrate-taurursodiol may lead to gastrointestinal issues, fatigue, and elevated liver enzymes. While specific side effects for ION363 are not detailed, it is important to monitor for similar adverse effects given its investigational status in targeting FUS gene mutations.

What prior FDA approvals exist?

The FDA has approved several treatments for Amyotrophic Lateral Sclerosis (ALS), including riluzole and edaravone. Riluzole is believed to reduce damage to motor neurons by decreasing the release of glutamate, while edaravone is thought to act as an antioxidant, reducing oxidative stress. Although there are ongoing studies like ION363 targeting specific genetic mutations such as FUS in ALS, no FDA-approved treatments specifically target FUS gene mutations as of now. Current research continues to explore gene-targeted therapies and other novel approaches to modify disease progression in ALS.

What other types of research exist?

Promising novel alternatives to ION363 for ALS patients with FUS gene mutations include antisense oligonucleotides (ASOs) targeting other ALS-related genes, CRISPR-Cas9 gene editing therapies, and RNA interference (RNAi) therapies. These approaches aim to modify or silence the expression of mutant genes responsible for ALS, potentially slowing disease progression. Additionally, therapies targeting aberrant splicing regulation, as identified in recent studies, represent another potential strategy.

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Antisense Oligonucleotide

ION363 for ALS

Phase 3

Recruiting

Research Sponsored by Ionis Pharmaceuticals, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participants in Cohort A must be 12 - 65 years of age with signs or symptoms consistent with an ALS disease. If 30 to 65 years of age, have an ALSFRS-R pre-study slope ≥ 0.4 points per month

Cohort B must be > 30 years of age, with signs or symptoms consistent with an ALS disease process and have an ALSFRS-R pre-study slope < 0.4 points per month

Must not have

History of gene therapy or cell transplantation or any other experimental brain surgery

Uncontrolled hypertension (blood pressure [BP] > 160/100 millimeters of mercury [mm Hg])

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline, day 505 in part 1

Awards & highlights

Pivotal Trial

Summary

This trial is testing a new drug called ION363 to help people with a specific genetic form of ALS (FUS-ALS). The study will see if the drug can help these patients live longer and maintain their abilities better. Participants will receive the drug for a period of time, then all will get the drug for an extended duration.

Who is the study for?

This trial is for ALS patients with FUS mutations. Adults over 30 and children aged 12-65 can join if they meet certain disease progression rates and breathing capacity criteria. Participants must have stable medication use, a caregiver to report on their condition, and no recent participation in other trials or treatments like gene therapy.

What is being tested?

The study tests ION363's effect on ALS symptoms and survival compared to a placebo. It aims to understand how the drug works in the body (pharmacokinetics) and its impact on the disease process (pharmacodynamics).

What are the potential side effects?

While specific side effects of ION363 are not listed here, similar drugs may cause injection site reactions, flu-like symptoms, potential liver issues, or changes in blood counts.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 12-65 years old with ALS symptoms, and if I'm 30-65, my ALS is progressing quickly.

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I am over 30, show ALS symptoms, and my ALS condition is progressing slowly.

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My test shows a FUS gene mutation from a certified lab.

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My lung function, when sitting, is at least half of what's expected for my age, sex, and height.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have never had gene therapy, cell transplantation, or experimental brain surgery.

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My blood pressure is not higher than 160/100 mm Hg.

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I have a condition where fluid builds up in my brain.

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I need a machine to help me breathe almost all day, every day.

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I do not have brain or spinal conditions that would affect a spinal tap.

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I haven't had cancer, except for certain skin cancers or cervical cancer in situ, in the last year.

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I have an ALS mutation, but it's not FUS.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline, day 505 in part 1

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline, day 505 in part 1

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline, day 505 in part 1 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change from Baseline (Day 1) through Study Day 505 in Part 1 in functional impairment

Secondary study objectives

Change from Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) Score to Day 505 in Part 1

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: ION363Experimental Treatment1 Intervention

ION363 will be administered by lumbar intrathecal (IT) bolus injection every 12 weeks, with an additional loading dose at 4 weeks, over a 60-week double-blind treatment period in Part 1; every 12 weeks for 84 weeks in the open-label extension treatment period (Part 2), with an additional loading dose administered 4 weeks after the first dose. Patients may continue to receive open-label ION363 every 12 weeks in Part 3 for up to 3 additional years or until ION363 becomes commercially available in the patient's country or until the Sponsor discontinues the development program, whichever occurs earlier.

Group II: PlaceboPlacebo Group1 Intervention

Placebo will be administered by lumbar IT bolus injection every12 weeks, with an additional loading dose at 4 weeks, over a 60-week double-blind treatment period (Part 1).

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Amyotrophic Lateral Sclerosis (ALS) include riluzole, edaravone, masitinib, and sodium phenylbutyrate-taurursodiol. Riluzole works by inhibiting glutamate release, which may reduce excitotoxicity that leads to motor neuron death. Edaravone is an antioxidant that helps to reduce oxidative stress, a contributing factor in ALS progression. Masitinib targets neuroinflammation by inhibiting tyrosine kinase, which may slow disease progression. Sodium phenylbutyrate-taurursodiol reduces neuronal cell death by targeting cellular stress pathways. These treatments are crucial for ALS patients as they aim to slow disease progression and improve quality of life. Additionally, treatments like ION363, which target specific genetic mutations such as FUS, are important as they offer a more personalized approach, potentially leading to more effective management of ALS in patients with these mutations.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.