Why do 97% of previously tested ALS drugs fail in both iPSC models and clinical trials despite preclinical promise?

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Composite

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Novelty

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Mechanistic

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Druggability

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Priority

72%

Importance

90%

Tractability

60%

Market price

50%

Description

The high failure rate suggests fundamental gaps in understanding ALS pathophysiology or limitations in preclinical models used for drug development. Identifying the common failure mechanisms could improve future therapeutic development strategies.

Gap type: open_question Source paper: Large-scale drug screening in iPSC-derived motor neurons from sporadic ALS patients identifies a potential combinatorial therapy. (2026, Nature neuroscience, PMID:41286450)

Evidence summary

Resolved by hypothesis h-f1c67177: Optimized Temporal Window for Metabolic Boosting Therapy Determines Success of Microglial State Transition Restoration. Score: 0.887. Supporting PMIDs: 31257151, 37291336, STRING:0.685, 39002124, computational:ad_clinical_trial_failures.

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