LB992 NTX-2009, a novel charged sodium channel blocker has significant anti-inflammatory activity in an atopic dermatitis model and produces sustained inhibition of chloroquine-induced itch

Abstract

Charged sodium channel blockers (CSCBs) such as NTX-2009 do not cross membranes, and selectively inhibit sensory nerves by gaining access to nociceptors through large pore channels (eg TRPV1, TRPA1) that are open due to inflammation. Evidence suggests that sensory nerves transmit itch and pain signals to the CNS and play an important role in driving the immune response in psoriasis and atopic dermatitis. We examined whether NTX-2009 blockade of sodium channels in skin sensory nerves would have anti-inflammatory activity as well as anti-pruritic effects in models of atopic dermatitis (AD). A topical gel formulation of NTX-2009 was tested for its ability to inhibit chloroquine (CQ)-induced scratching. Injection of CQ produced an eight-fold increase in the scratching duration compared to saline injected mice. NTX-2009 gel (0.1 - 1.0%) applied 3 hours before CQ injection dose dependently decreased scratching duration, with 0.3% producing a 73% inhibition and 1% a complete inhibition. The duration of action of 1% NTX-2009 was characterized with >70% reduction in the scratching response maintained out to 15 hrs. NTX-2009 (0.3% gel QD) was evaluated in the calcipotriol model of AD. Calcipotriol (CP) was administered to mice once daily for 10 days and ruxolitinib (10 mM, QD) was used as a positive control. Experimental endpoints were skin clinical score (erythema, edema and desquamation), gene expression and histology. NTX-2009 significantly reduced the clinical score producing a greater effect than ruxolitinib. CP increased IL-4 gene expression while decreasing Filaggrin-2 expression. Both effects were significantly reversed by NTX-2009 and ruxolitinib. Dermal thickness and mast cell infiltration produced by CP were both inhibited by NTX-2009 and ruxolitinib. This data demonstrates the anti-inflammatory and anti-pruritic potential of a new class of CSCBs, such as NTX-2009.