𝐀𝐦𝐲𝐨𝐭𝐫𝐨𝐩𝐡𝐢𝐜 𝐥𝐚𝐭𝐞𝐫𝐚𝐥 𝐬𝐜𝐥𝐞𝐫𝐨𝐬𝐢𝐬 (𝐀𝐋𝐒) 𝐢𝐬 𝐚 𝐟𝐚𝐭𝐚𝐥 𝐧𝐞𝐮𝐫𝐨𝐝𝐞𝐠𝐞𝐧𝐞𝐫𝐚𝐭𝐢𝐯𝐞 𝐝𝐢𝐬𝐞𝐚𝐬𝐞. 𝐌𝐞𝐝𝐢𝐚𝐧 𝐬𝐮𝐫𝐯𝐢𝐯𝐚𝐥 𝐟𝐫𝐨𝐦 𝐬𝐲𝐦𝐩𝐭𝐨𝐦 𝐨𝐧𝐬𝐞𝐭 𝐢𝐬 𝟐𝟒 𝐭𝐨 𝟒𝟖 𝐦𝐨𝐧𝐭𝐡𝐬, 𝐚𝐧𝐝 𝐟𝐨𝐫 𝐦𝐨𝐬𝐭 𝐩𝐚𝐭𝐢𝐞𝐧𝐭𝐬, 𝐧𝐨 𝐚𝐯𝐚𝐢𝐥𝐚𝐛𝐥𝐞 𝐭𝐡𝐞𝐫𝐚𝐩𝐲 𝐦𝐞𝐚𝐧𝐢𝐧𝐠𝐟𝐮𝐥𝐥𝐲 𝐬𝐥𝐨𝐰𝐬 𝐭𝐡𝐚𝐭 𝐝𝐞𝐜𝐥𝐢𝐧𝐞.

Since riluzole’s 1995 approval — which extended median survival by only weeks — 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 — 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 — starting with CTx1000, a gene therapy now in early human testing. Link: https://authors.elsevier.com/sd/article/S1359-6446(26)00157-1