Effects of LL-340001 were evaluated in vitro on the induction of T₃-regulated genes, including ABCD2, in primary human fibroblasts from healthy subjects and AMN patients and in brain slices from neonatal mice. The effects of the prodrug ABX-002 on T₃-sensitive genes were studied in vivo in mice in a variety of dosing paradigms. Effects on remyelination biology were examined by measuring OPC differentiation in culture and in vivo by evaluating the ability of ABX-002 to stimulate remyelination in demyelinating disease models. Additional studies to assess effects of ABX-002 on VLCFAs in Abcd1 (-/y) mice are in progress.

LL-340001 increased ABCD2 gene expression by 10-fold in X-ALD fibroblasts (EC₅₀ ~4 nM).  In vivo, ABX-002 enhanced delivery of LL-340001 to the brain by 30x and induced T₃-dependent gene expression in the brain and liver at 13 µg/kg p.o. Abcd2 expression was increased in brain, spinal cord and liver of hypothyroid mice. LL-340001 enhanced OPC differentiation (EC₅₀ = 2 nM) and ABX-002 improved clinical scores in an EAE model. Additional effects on remyelination and VLCFA levels in vivo will be discussed.

Preclinical data indicate that ABX-002 is a novel CNS-penetrant thyromimetic with potential for treatment of demyelinating disorders as well as other neuroinflammatory and/or neurodegenerative diseases. ABX-002 is currently in IND-enabling studies to support FIH trials in mid-2021.