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Since riluzole’s 1995 approval â which extended median survival by only weeks â more than 60 compounds have entered clinical trials for ALS, and nearly all have failed. Some of these were uninformative failures: trials without biomarkers that ended in a null result and little else. Others were negative but scientifically useful, generating real mechanistic insight even without clinical benefit.
The most recent example is instructive. AMX0035 won accelerated FDA approval in 2022 after a Phase 2 trial showed a 25% slowing of functional decline. Two years later, the confirmatory Phase 3 trial found no difference from placebo, and the manufacturer withdrew the drug from the market. It’s a case study in how fragile early open-label signals can be once tested under full blinding.
Tofersen, approved in 2023, is a genuine precision-medicine breakthrough â but it treats a specific genetic mutation found in under 2% of ALS patients. The remaining 98%, whose disease involves sporadic TDP-43 protein pathology, still have no therapy that stops or reverses neurodegeneration.
My new article in Drug Discovery Today examines this history and asks what it would take for a new therapy to break the pattern â starting with CTx1000, a gene therapy now in early human testing. Link: https://authors.elsevier.com/sd/article/S1359-6446(26)00157-1
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