title: Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers.
abstract: BACKGROUND
  Topical 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.
  
  
  METHODS
  In 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-cm(2) 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-cm(2) site for 14 days or a 500-cm(2) site for 28 days.
  
  
  RESULTS
  RTA 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.
  
  
  CONCLUSIONS
  Overall, these data suggest RTA 408 Lotion is well-tolerated, activates Nrf2 in human skin, and appears suitable for continued clinical development.
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX, 75063, USA. scott.reisman@reatapharma.com.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Reisman
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX, 75063, USA. angie.goldsberry@reatapharma.com.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Goldsberry
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX, 75063, USA. ivy.lee@reatapharma.com.
authors.forename: Chun-Yue I
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX, 75063, USA. megan.ogrady@reatapharma.com.
authors.forename: Megan L
authors.initials: ML
authors.lastname: O'Grady
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX, 75063, USA. joel.proksch@reatapharma.com.
authors.forename: Joel W
authors.initials: JW
authors.lastname: Proksch
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX, 75063, USA. keith.ward@reatapharma.com.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.affiliation: Reata Pharmaceuticals, Inc., 2801 Gateway Dr. Ste 150, Irving, TX, 75063, USA. colin.meyer@reatapharma.com.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
mesh_terms: D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D000368:Aged; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000187:drug effects* / Q000235:genetics; D012867:Skin / Q000187:drug effects* / Q000378:metabolism*; D063465:Skin Cream; D046509:Tissue Culture Techniques; D014315:Triterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D051267:NF-E2-Related Factor 2; D014315:Triterpenes; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C000589490:omaveloxolone