ISRIB - ALS Untangled®

Key Information

Click on any letter grade below for more info:

Mechanism Grade: B

Preclinical Trials Grade: B

Cases Grade: D

Trials Grade: U

Risks Grade: U

Published: Aug 2025

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ISR over-activation may play an important role in ALS pathogenesis, as supported by data from pre-clinical models and PALS. Several different ISR inhibitors have been tried in ALS models or inPALS with mixed results; but given the differents pecific actions of these, it is not possible to generalize across the whole class. ISRIB can attenuate parts of the ISR and has shown benefits in cell models of familial ALS. A group of PALS in Spain who are taking ISRIB report subjective improvements in some ALS-related symptoms, but objective evidence is lacking. Reported side effects are minimal, but no published trials of ISRIB exist,leaving questions about safety and tolerability unanswered. In addition, concerns remain about its solubility and human bioavailability. Currently,there is not enough information to support the regular use of ISRIB for treating ALS. Furthers tudies are required to evaluate its pharmacokinetics, safety, and efficacy in PALS.

Mechanistic plausibility

Grade A: Shown in a peer-reviewed publication to act on a relevant mechanism in humans

Mechanistic plausibility

Grade B: Shown in a peer-reviewed publication to act on a relevant mechanism in pre-clinical model(s)

Mechanistic plausibility - C

Grade C: Theoretically and plausibly acts on an ALS-relevant mechanism in humans

Mechanistic plausibility

Grade D: Acts on a biological mechanism but it is not clear that this mechanism is relevant in ALS

Mechanistic plausibility

Grade F: Implausible; would violate known principles or laws of biology

Mechanistic plausibility

Grade U: No useful information was found for this category

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade A: Two or more peer-reviewed publications reporting benefits in well-designed studies.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade B: One peer-reviewed publication reporting benefits in a well-designed study.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade C: One or more peer-reviewed publication(s) reporting benefits in flawed studies.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade D: One or more non-peer reviewed studies reporting benefits (published on a website or in an abstract)

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade F: The only studies available show no benefit

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade U: No useful information was found for this category

Patient case reports

Grade A: One or more peer-reviewed publications reporting benefits with validated diagnosis and benefits

Patient case reports

Grade B: More than one unpublished report of benefit with validated diagnosis and benefits

Patient case reports

Grade C: One unpublished report of benefit with validated diagnosis and benefits

Patient case reports

Grade D: Subjective report(s) of benefit without validated diagnoses and/or benefits

Patient case reports

Grade F: The only reports available show no benefit

Patient case reports

Grade U: No useful information was found for this category

Patient trials

Two or more peer-reviewed publications describing benefits in well-designed randomized, blinded placebo-controlled phase III trials

Patient trials

Grade C: One or more peer-reviewed publications reporting benefits in a well-designed randomized, blinded, placebo-controlled phase I or II trial

Patient trials

Grade D: One or more peer-reviewed publications reporting benefits in a flawed trial.

Flawed trials means those in which there are identifiable problems with patient selection, randomization, blinding, controls or follow-up. These have ‘high or unclear risk of bias’ according to published criteria. Well-designed trials are those that have ‘low risk of bias’.

Patient trials

Grade F: The only trials available show no benefit

Patient trials

Grade U: No useful information was found for this category

Risks (harms that occurred on this treatment)

Grade A: No exposed patients appear to have experienced harms

Risks (harms that occurred on this treatment)

Grade B: More than 0% but less than 10% of exposed patients experienced harms (no hospitalizations or deaths)

Risks (harms that occurred on this treatment)

Grade B (oral): More than 0% but less than10% of exposed patients experienced harms (no hospitalizations or deaths)

Grade D (intravenous): More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Risks (harms that occurred on this treatment)

Grade C: At least 10% of exposed patients experienced harms (no hospitalizations or deaths)

Risks (harms that occurred on this treatment)

Grade D: More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Risks (harms that occurred on this treatment)

Grade D: More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Grade F: At least 5% of exposed patients experienced death or hospitalization

Risks (harms that occurred on this treatment)

Grade F: At least 5% of exposed patients experienced death or hospitalization

Risks (harms that occurred on this treatment)

Grade U: No useful information was found for this category