OP0137 Complete Survival and Disease Amelioration in MRL/LPR Mice Following Therapeutic Administration of an Oral Retinoic Acid Receptor-Related Orphan Receptor Gamma T [RORGT] Inverse Agonist INV-17: A Promising Safe &amp; Efficacious Novel Lupus Treatment
Authors: A. Gaweco, K. Matthews, S. Palmer, R. Shamilov, K. Adam, A. Elia, C. Clybouw, W. Windsor, A. Nomeir, T. Stouch, E. Ginzler, J. Tilley
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> There are limited treatment options currently available for patients with systemic lupus erythematosus [SLE] and lupus nephritis [LN] providing modest therapeutic benefit in some patients associated with substantial toxicities. T helper 17 [T<sub>H</sub>17] cells and their production of T<sub>H</sub>17 cytokines (IL-17A, IL-17F) play a critical role in the pathogenesis of several autoimmune diseases including SLE and LN. Increased T<sub>H</sub>17 cytokine expression is observed in lupus-prone mouse models and in lupus patients associated with worsening disease. RORgT is a nuclear hormone receptor that specifically regulates T<sub>H</sub>17 cells by acting as a control switch for T<sub>H</sub>17 differentiation, function and cytokine production. Successful drug development efforts led to the discovery of several proprietary novel chemical scaffolds of the INV-17 portfolio of small molecule RORgT inverse agonists. Select INV-17 compounds demonstrate potent <i>in vitro</i> pharmacological effects against T<sub>H</sub>17 cells and cytokines, optimal drug-likeness &amp; pharmacokinetic properties and superior therapeutic efficacies in preclinical autoimmune models of rheumatoid arthritis and multiple sclerosis.<sup>1,2</sup> <h3>Objectives</h3> The <i>in vivo</i> treatment efficacy of INV-17 was assessed in this initial pilot study prior to a larger study group in lupus-prone MRL/<i>lpr</i> mouse model to establish the preclinical Proof of Concept of a novel oral INV-17 RORgT inverse agonist. <h3>Methods</h3> Lupus-prone MRL/<i>lpr</i> mice spontaneously develop disease. Upon disease-onset, mice with a proteinuria score &gt;2 (Scale: 0-3) were randomized to receive 6-wk of therapeutic treatment dosing with INV-17 per oral gavage at 2 mg/kg (n=4) versus controls receiving vehicle alone (n=7). <h3>Results</h3> Complete survival was observed in 100% of INV-17 treated mice compared to only 57% survival in vehicle-treated mice after 6-wk of dosing [Figure]. Successful disease amelioration following INV-17 treatment was observed as early as treatment day 11 with a significant reduction in mean proteinuria score (1.25±0.5; p=0.03) versus vehicle controls (2.17±0.8). Lower mean proteinuria area under the curve [AUC] score of 17.3 in the INV-17 group contrasted to those in the vehicle group with 22.1. INV-17 was well tolerated and INV-17-treated mice were unremarkable with optimal body condition scores of Grade BCS3. <h3>Conclusions</h3> The superior safety and therapeutic efficacy data following 6-wk treatment of an oral small molecule INV-17 clinical candidate compound provide the first report establishing the therapeutic efficacy in lupus following pharmacological intervention with an RORgT inverse agonist. This compelling evidence supports advancing INV-17 into IND-enabling development stage and highlights the potential promise of INV-17 as a safe &amp; efficacious novel treatment for lupus. <h3>References</h3> Gaweco et al. 2014 Arthritis Rheum. 66[11]: S137. Gaweco et al. 2013 J.Neurol.Sci. 333: 362-363. <h3>Disclosure of Interest</h3> A. Gaweco Employee of: Innovimmune Biotherapeutics, K. Matthews Employee of: Innovimmune Biotherapeutics, S. Palmer Employee of: Innovimmune Biotherapeutics, R. Shamilov Employee of: Innovimmune Biotherapeutics, K. Adam Employee of: Innovimmune Biotherapeutics, A. Elia Employee of: Innovimmune Biotherapeutics, C. Clybouw Employee of: Innovimmune Biotherapeutics, W. Windsor Employee of: Innovimmune Biotherapeutics, A. Nomeir Employee of: Innovimmune Biotherapeutics, T. Stouch Employee of: Innovimmune Biotherapeutics, E. Ginzler Consultant for: Innovimmune Biotherapeutics, J. Tilley Employee of: Innovimmune Biotherapeutics