Nuevolution has identified multiple novel and potent chemical series of small-molecule RORγt inverse agonists (inhibitors) showing strong efficacy in multiple animal disease models.

Our Development Candidate is selective for RORγt, it has an attractive pharmacokinetic (PK) profile (orally available for tablet-based medication), have proven high activity in several animal inflammatory disease models including models of Rheumatoid Arthritis and Psoriasis, with good oral exposure in both mice & dogs and no apparent pre-clinical toxicity issues. Nuevolution plans to conduct IND enabling (final regulatory pre-clinical safety studies) at end of 2016-early 2017, and subject to successfully completion of IND enabling studies, the objective is to commence Phase I studies in 2017.

Nuevolution’s RORγt program may offer the promise for a next-generation tablet based and safer treatment of chronic inflammatory auto-immune diseases such as psoriasis, ankylosing spondylitis, multiple sclerosis and rhematoid arthritis.


RORγt – the master regulatory factor relevant to IL17A expression.

Pro-inflammatory interleukin 17A (herein after IL17A) acts as a potent cytokine mediator in delayed–type reactions by increasing chemokine production in various tissues leading to recruitment of monocytes and neutrophils to sites of inflammation. IL17A is produced by TH17 cells and acts synergistic with other pro-inflammatory cytokines like TNFα and IL1.

TH17 cells originate from CD4+ T helper precursor cells. Through the activation from antigenic stimulation, the process proceeds through a coordinated cytokine-signaling cascade leading to transcriptional activity modulated by specific transcription factors. The activation pathway in humans involves cytokines like IL6, IL21 and IL23 leading to differentiation of the precursor T-cells into TH17 cells and then production and release of IL17 from the TH17 cells.

IL6 stimulation activates the transcription factors STAT3 and RORγt, protein factors indispensable for TH17 cell differentiation, and exerting their function through directly binding at the IL17A gene promoter region. A variety of additional transcriptional factors are involved in the differentiation process as reviewed by Kurebayashi et al., however RORγt is the master regulatory factor relevant to IL17A expression.



RORγt belongs to a subfamily of nuclear receptors (NR1’s), and has the ability to bind DNA in a ligand-dependent manner to regulate the expression of multiple target genes. Thus, the term receptor in a classical definition is misleading, since the NR’s functionally are acting as transcription regulatory factors (regulating gene expression). Hydroxycholesterols are high-affinity natural ligands for RORγt.


The X-ray crystal structures of RORγt have revealed a clear binding mode of hydroxycholesterol ligands [2]. In addition, the active conformation of RORγt affirms the agonist nature of these hydroxycholesterol ligands. The concentration of hydroxycholesterols is high during the inflammation process making RORγt exhibit constitutive activity. Antagonizing RORγt activity with synthetic small molecules inhibits expression of IL17A as well as inhibits the differentiation into TH17 cells [3] offering a mode of action where both formation of new TH17 cells as well as their production of IL17 is blocked.



TH17 cells are a relatively novel (2005) defined class of CD4+ T helper cells, characterized by secreting interleukins IL17A/F, IL21 and IL22. TH17 cells are beneficial during host infection and is as such part of the adaptive immune response, however uncontrolled or inappropriate activation of TH17 cells is linked to a number of severe autoimmune diseases including psoriasis, rheumatoid arthritis and multiple sclerosis.


CD4+ T helper cells are important mediators of the adaptive immune response and consist of three major subsets; TH1, TH2 and TH17. The different T helper subsets differentiate from TH0 cells in response to different extracellular stimuli and serve different roles in the immune response as well as in human pathological conditions.


A group of secreted proteins acting as signalling molecules in the immune system. More than 35 different interleukins are known, serving various functions in coordinating the immune response by activating, stimulating and inhibiting cells of the immune system.


1. Y. Kurebayashi, S. Nagai, A. Ikejiri, and S. Koyasu, “Recent advances in understanding the molecular mechanisms of the development and function of Th17 cells.,” Genes Cells, vol. 18, no. 4, pp. 247–65, Apr. 2013.
2. L. Jin, D. Martynowski, S. Zheng, T. Wada, W. Xie, and Y. Li, “Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma.,” Mol. Endocrinol., vol. 24, no. 5, pp. 923–9, May 2010
3. L. A. Solt, N. Kumar, P. Nuhant, Y. Wang, J. L. Lauer, J. Liu, M. A. Istrate, T. M. Kamenecka, W. R. Roush, D. Vidović, S. C. Schürer, J. Xu, G. Wagoner, P. D. Drew, P. R. Griffin, and T. P. Burris, “Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.,” Nature, vol. 472, no. 7344, pp. 491–494, 2011.