South San Francisco-based Acelot has dosed the first healthy volunteer in a Phase Ia clinical trial of ACE-2223, an orally bioavailable small molecule designed to directly bind and disrupt aggregated TDP-43 in amyotrophic lateral sclerosis (ALS), according to a company announcement. The trial will evaluate safety, tolerability, and pharmacokinetics in healthy adults. Enrollment size, dosing schedule, and trial completion date have not been disclosed.
In preclinical ALS mouse models, Acelot reported that ACE-2223 demonstrated target engagement, reduced neuroinflammation, lowered neurofilament light chain (Nf-L) levels, and extended survival. The molecule also rescued downstream mRNA splicing, as measured by reduction of cryptic exons STMN2 and UNC13A — molecular signatures of TDP-43 loss of function. Acelot developed ACE-2223 using its proprietary RESOLUTE computational platform, which the company said enabled in silico identification of small molecules capable of engaging the structurally challenging aggregated form of TDP-43.
TDP-43 is a nuclear RNA-binding protein that, in approximately 97% of sporadic ALS cases, mislocalizes to the cytoplasm and forms insoluble aggregates. This process drives neurodegeneration through both loss of nuclear RNA-processing function — including aberrant pre-mRNA splicing — and cytoplasmic gain-of-function toxicity from the aggregates themselves, as described in published literature. The resulting splicing errors in genes such as STMN2 and UNC13A are increasingly recognized as tractable pharmacodynamic biomarkers for TDP-43 dysfunction.
Approved ALS therapies — riluzole, edaravone, and tofersen (the latter restricted to the roughly 2% of patients with SOD1 mutations) — act on downstream mechanisms or symptom management rather than TDP-43 pathology directly. AMX0035 (sodium phenylbutyrate/taurursodiol), which received US FDA approval in 2022, was withdrawn from the market in April 2024 after its confirmatory Phase III trial showed no effect on disease progression.