ATI-1777 a topical JAK1/3 inhibitor may benefit atopic dermatitis without systemic drug exposure, results from preclinical development and Phase 2a randomized-control study ATI-1777-AD-201
Atopic dermatitis (AD), a chronic, pruritic skin disease, affects 10%-30% of children and up to 14% of adults in developed countries. Since current AD treatments may lead to systemic drug exposure and AD pathophysiology is partially mediated by JAK1/3 signaling, ATI-1777, a potent and selective JAK1/3 inhibitor, was designed with multiple sites of metabolism to deliver local efficacy in the skin and limit systemic exposure. In preclinical studies, ATI-1777 selectively inhibited JAK1/3 with limited systemic exposure and without any adverse effects. ATI-1777-AD-201 (NCT04598269), a Phase 2a, first-in-human, randomized, double-blind,vehicle-controlled, parallel-group study, evaluated the efficacy, safety, tolerability, and pharmacokinetics of ATI-1777 topical solution in 48participants with AD over 4 weeks. The primary outcome was reduction of a modified EASI score from baseline; reduction was significantly greater in the ATI-1777 group at Day28 compared to vehicle (percent reduction from baseline 74.45% [SE6.455] and 41.43% [SE6.189], respectively [p<0.001]). Average plasma  concentrations of ATI-1777 were <5% of the IC50 of ATI-1777 for inhibiting JAK1/3. No deaths or serious adverse events were reported. This demonstrates that topical ATI-1777 does not lead to pharmacologically relevant systemic drug exposure and may reduce clinical signs of AD. Overall design: We developed a pharmacodynamic porcine topical model to assess the effects of ATI-1777 on JAK1/3 signaling and selected a suitable formulation for the compound. To select the most robustly induced genes by intradermal injection (ID) of IL-15 in the Yorkshire swine skin, we performed the RNA seq for 8 skin biopsy samples. For each of two pigs, two sites were injected with ID IL15 and two sites without injection, resulting in a total of 4 samples for IL-5 and 4 samples for control.  Biopsy samples of these sites were extracted for RNA, followed by RNA Seq and qPCR to determine the gene expression, and select optimal genes for the readouts.