The online version of this article (doi:10.1186/s12895-015-0029-7) contains supplementary material, which is available to authorized users.
All authors are employed by and have a financial interest in Reata Pharmaceuticals, Inc.
SR was the primary author, aided in the design of nonclinical experiments, and conducted laboratory experiments and statistical analyses for the presented biochemical data. CL and JP designed the in vitro and ex vivo studies. CM, AG, JP, KW, and MO designed the protocol, performed statistical analyses, and interpreted data from the clinical study. All authors read and approved the final manuscript.
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.
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-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.
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.
Overall, these data suggest RTA 408 Lotion is well-tolerated, activates Nrf2 in human skin, and appears suitable for continued clinical development.
Additional file 1: Figure S1. After a 16 h incubation with RTA 408 (3–1000 nM), human primary keratinocytes were analyzed using a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to examine cell viability. Data are presented as mean % vehicle control (n=5/group) ± S.E.M. No differences in viability were observed among groups.12895_2015_29_MOESM1_ESM.pdf
Additional file 2: Table S1. Adverse events in phase 1 clinical trial in healthy volunteers.12895_2015_29_MOESM2_ESM.docx
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- Topical application of RTA 408 lotion activates Nrf2 in human skin and is well-tolerated by healthy human volunteers
Scott A. Reisman
Angela R. Goldsberry
Chun-Yue I. Lee
Megan L. O’Grady
Joel W. Proksch
Keith W. Ward
Colin J. Meyer
- BioMed Central
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