Gene therapy agent, AMT-162, developed by UniQure Biopharma, is not yet actively recruiting but will soon start a clinical trial, NCT06100276, to research the use of AMT-162 in patients with rapidly progressive ALS and SOD1 mutations. AMT-162, a one-time treatment, is comprised of a recombinant AAVrh10 vector that expresses a miRNA targeting the SOD1 gene. This clinical trial will research the safety and efficacy of AMT-162, evaluating if it will silence the expression of mutant SOD1 and improve the course of ALS. Small molecule drug FB1006, fully discovered and developed using artificial intelligence (AI), is being advanced as a new potential treatment for ALS. 4B Technologies with collaborative efforts completed the development process of FB1006, from target identification and compound screening to patient enrollment, in less than 2 years. Phase IV clinical trial NCT05923905 recently completed enrollment of 64 patients which will evaluate the efficacy of safety of FB1006 in the treatment of ALS patients. The trial is being conducted at the Third Hospital of Peking University and is expected to complete double-blind dosing in August 2024, followed by 1-year of clinical observation in February 2025. The last two small molecules we highlight for the treatment of ALS are both part of the HEALEY ALS Platform trial (NCT04297683). This trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of ALS treatments. There is a single master protocol dictating the conduct of the trials with each regimen sharing placebo patients. The first drug ibudilast is being investigated by MediciNova. A Phase I/II clinical trial NCT02714036 revealed ibudilast to be safe and showed no drug related severe adverse reactions. However, the tolerability was limited due to gastrointestinal side effects, fatigue, and insomnia. Data from another completed Phase II study NCT02238626 showed ibudilast, when in combination with approved therapy Rilutek showed a marked increase in number of patients who saw no functional decline in six months comparted to Rilutek alone and it also helped increase patient lifespan. 431 Ibudilast will also be investigated in a Phase II/III clinical trial (NCT04057898) currently recruiting and enrolling up to 230 participants across the USA and Canada to evaluate the efficacy, safety, and tolerability of ibudilast for 12 months followed by a 6-month open-label extension phase. Ibudilast is a glial attenuator that suppresses pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, and may upregulate the anti-inflammatory cytokine IL-10. It has additionally been shown to be a toll-like receptor 4 antagonist that may contribute to its attenuation of neuroinflammation. Ibudilast received both fast track 433 and orphan drug designations 434 in 2016 from the US FDA for treating ALS.