LB1575 SNA-125, a novel selective kinase inhibitor, improves clinical symptoms in a mouse model of psoriasis

Abstract

The efficacy of SNA-125, a first-in-class topical selective kinase inhibitor (including JAK3/TrkA) with low systemic exposure, was evaluated in the imiquimod (IMQ)-induced mouse model of psoriasis (PSO). IMQ 5% cream (Aldara™) was applied once daily for 10 days on ears and shaved backs to induce PSO. SNA-125 (5% or 10%) or vehicle (25% transcutol P; 75% propylene glycol) was applied twice daily to ears and backs (2 and 8 hrs post-IMQ) for 10 days, while the positive control was applied once daily (clobetasol 0.05%; 2 hrs post-IMQ). The PSO clinical score (sum of component erythema [0-4], plaque [0-5], and punctate redness/scabbing [0-3] scores) was assessed daily. Ear thickness was measured on days 0, 4, 6, 8, and 10. On day 4, PSO-associated cytokine levels were measured on ear punch biopsies for 10% SNA-125. On day 10, spleen weight was measured. Both doses of SNA-125 resulted in significantly greater improvement in PSO clinical score relative to vehicle ([5%]: p<0.01 for days 5, 8, 10 and p<0.05 for day 9; [10%]: p<0.01 for days 4-5, 8-10). Specifically, SNA-125 demonstrated greater improvement in erythema score ([5%]: p<0.01 on days 8-10; [10%]: p<0.01 on days 8-10 and p<0.05 on day 5), plaque score ([both doses]: p<0.01 on days 4-5, 8), and punctate redness/scabbing score ([10%]: p<0.01 on days 9-10). Day 4 ear cytokine levels were similar between 10% SNA-125 and vehicle, though a significant reduction in TNF-α was noted with SNA-125 relative to vehicle (mean ± SEM: 3.63 ± 0.63 vs 8.72 ± 1.02 pg/mg, respectively; p<0.01). Both doses of SNA-125 reduced ear thickness relative to the IMQ-only group, though the effect was not greater than vehicle. On day 10, splenic weight with both doses of SNA-125 was similar to vehicle, which was expected given the low systemic exposure of SNA-125 due to Topical by Design™ technology. In summary, these data show that SNA-125 improves clinical features of a well-accepted mouse model of PSO. These findings will be confirmed and extended in ongoing proof-of-concept studies in humans.