ARKD‐104, A Potential Treatment of Frontotemporal Dementia and Other Neurodegenerative Disorders

Abstract

AbstractBackgroundHeterozygous mutations in the gene encoding progranulin (GRN) that lead to haploinsufficiency of the progranulin protein (PGRN) cause the fatal neurodegenerative disease frontotemporal dementia (FTD‐GRN). A promising treatment approach for FTD‐GRN is to restore PGRN to levels detected in healthy individuals. In pursuit of this objective, Arkuda Therapeutics is developing brain‐penetrant, orally bioavailable small molecules that increase PGRN levels within the central nervous system (CNS).MethodA functional cell‐based assay was utilized to identify novel compounds that stimulate PGRN secretion from a murine microglial cell line. Compounds with good in vitro potency were further optimized through an iterative series of selectivity, ADME, pharmacokinetic (PK), safety and pharmacology assessments.ResultWhen applied to cells, ARKD‐104 increased PGRN and PSAP secretion and engaged lysosomal pathways as evidenced by intracellular changes in granulins, saposins, and lysosomal lipids including bis(monoacylglycero)phosphate (BMP). Oral administration of ARKD‐104 to cynomolgus monkeys resulted in a dose and exposure‐dependent increase in PGRN measured in cerebrospinal fluid (CSF). The exposure‐response relationship demonstrated that a systemic exposure of 8 nM ARKD‐104 in plasma (unbound) doubled the amount PGRN in CSF. PGRN levels were further increased to more than 4‐times pre‐dose levels at the highest tested dose. Elevation of PGRN levels was sustained with repeat dosing of ARKD‐104. ARKD‐104 was characterized for CNS drug‐like properties including PK, metabolism, brain penetration, selectivity, and safety. In these assessments, ARKD‐104 demonstrated a profile suggesting that beneficial increases in PGRN can be achieved with once daily oral dosing in human.ConclusionARKD‐104 has excellent CNS drug‐like properties, increases PGRN in the CNS of non‐human primates and increases important cofactors of lysosomal enzymes, . ARKD‐104 is therefore a promising candidate for continued development as a treatment for FTD‐GRN, Parkinson’s disease and other neurodegenerative disorders exhibiting lysosomal dysfunction.