Background: Topical application of the synthetic triterpenoid RTA 408 to rodents elicits a potent dermal cytoprotective\nphenotype through activation of the transcription factor Nrf2. Therefore, studies were conducted to investigate if such\ncytoprotective properties translate to human dermal cells, and a topical lotion formulation was developed and evaluated\nclinically.\nMethods: In vitro, RTA 408 (3ââ?¬â??1000 nM) was incubated with primary human keratinocytes for 16 h. Ex vivo, RTA 408\n(0.03, 0.3, or 3 %) was applied to healthy human skin explants twice daily for 3 days. A Phase 1 healthy volunteer clinical\nstudy with RTA 408 Lotion (NCT02029716) consisted of 3 sequential parts. In Part A, RTA 408 Lotion (0.5 %, 1 %, and 3 %)\nand lotion vehicle were applied to individual 4-cm2 sites twice daily for 14 days. In Parts B and C, separate groups\nof subjects had 3 % RTA 408 Lotion applied twice daily to a 100-cm2 site for 14 days or a 500-cm2 site for 28 days.\nResults: RTA 408 was well-tolerated in both in vitro and ex vivo settings up to the highest concentrations tested. Further,\nRTA 408 significantly and dose-dependently induced a variety of Nrf2 target genes. Clinically, RTA 408 Lotion was also\nwell-tolerated up to the highest concentration, largest surface area, and longest duration tested. Moreover, significant\nincreases in expression of the prototypical Nrf2 target gene NQO1 were observed in skin biopsies, suggesting\nrobust activation of the pharmacological target.\nConclusions: Overall, these data suggest RTA 408 Lotion is well-tolerated, activates Nrf2 in human skin, and\nappears suitable for continued clinical development
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