Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers

Abstract

BackgroundTopical application of the synthetic triterpenoid RTA 408 to rodents elicits a potent dermal cytoprotective phenotype through activation of the transcription factor Nrf2. Therefore, studies were conducted to investigate if such cytoprotective properties translate to human dermal cells, and a topical lotion formulation was developed and evaluated clinically.MethodsIn vitro, RTA 408 (3–1000 nM) was incubated with primary human keratinocytes for 16 h. Ex vivo, RTA 408 (0.03, 0.3, or 3 %) was applied to healthy human skin explants twice daily for 3 days. A Phase 1 healthy volunteer clinical study with RTA 408 Lotion (NCT02029716) consisted of 3 sequential parts. In Part A, RTA 408 Lotion (0.5 %, 1 %, and 3 %) and lotion vehicle were applied to individual 4-cm2 sites twice daily for 14 days. In Parts B and C, separate groups of 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.ResultsRTA 408 was well-tolerated in both in vitro and ex vivo settings up to the highest concentrations tested. Further, RTA 408 significantly and dose-dependently induced a variety of Nrf2 target genes. Clinically, RTA 408 Lotion was also well-tolerated up to the highest concentration, largest surface area, and longest duration tested. Moreover, significant increases in expression of the prototypical Nrf2 target gene NQO1 were observed in skin biopsies, suggesting robust activation of the pharmacological target.ConclusionsOverall, these data suggest RTA 408 Lotion is well-tolerated, activates Nrf2 in human skin, and appears suitable for continued clinical development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12895-015-0029-7) contains supplementary material, which is available to authorized users.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

“…mRNA was quantified using Quantigene Plex 2.0 technology according to manufacturer’s protocol (Affymetrix Inc., Santa Clara, CA, USA) and as previously described. 13 Probe sets were designed against the human genome for analysis of Nrf2 target genes; a modified version of Panel 11834 (Affymetrix) was used. Genes were normalized to the mean expression of housekeeping genes RPL13A (60S ribosomal protein L13a) and peptidyl-prolyl cis – trans isomerase B.…”

“… 10 Furthermore, topical application of omaveloxolone causes dose-proportional induction of Nrf2-target genes in the skin of rats, and in punch biopsies in human volunteers. 11 – 13 Along these lines, pretreatment with omaveloxolone also protects retinal pigment epithelial cells from oxidative destruction via activation of Nrf2. 14 Based on in vitro and animal studies, omaveloxolone exhibited high protein binding with extensive tissue distribution, making it a suitable potential oncologic agent.…”

Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin

“…These compounds are promiscuous electrophilic molecules that also react with cysteine 151 of KEAP1, induce NRF2, and confer protection against a number of chemical insults or radiation damage (including UV) observable in vitro and in vivo [ 34 , 35 , 36 ]. Recently, a synthetic triterpenoid NRF2 modulator and bardoxolone-derivative, RTA 408, has been tested for topical NRF2 activation in rat, murine, and human skin [ 37 , 38 ], but limited data on skin protection properties are available. Taken together, a significant opportunity for the development of cutaneous NRF2-dependent skin protection strategies using nutrient-derived molecular entities remains to be explored.…”

NRF2-targeted therapeutics: New targets and modes of NRF2 regulation

“…It was later defined that most of these compounds activated the NRF2 pathway, and the race to discover and characterize NRF2-dependent chemopreventive compounds started. Since then, only canonical NRF2 activators— sulforaphane (SF), bardoxolone methyl (CDDO-Me), RTA 408, and dimethyl fumarate (DMF, Tecfidera)—have entered clinical trials in the USA (clinicaltrials.gov), and only DMF has been FDA-approved for the treatment of multiple sclerosis (Table 1) [15–18]. This therapeutic deficit has drawn attention to some key aspects that are defining current and future investigations for the development of NRF2-targeted drugs.…”