Article Text

PDF
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 & Efficacious Novel Lupus Treatment
  1. A. Gaweco1,2,
  2. K. Matthews2,
  3. S. Palmer2,
  4. R. Shamilov2,
  5. K. Adam2,
  6. A. Elia2,
  7. C. Clybouw2,
  8. W. Windsor2,
  9. A. Nomeir2,
  10. T. Stouch2,
  11. E. Ginzler1,
  12. J. Tilley2
  1. 1SUNY Downstate Medical Center
  2. 2Innovimmune Biotherapeutics, Brooklyn, New York, United States

Abstract

Background 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 [TH17] cells and their production of TH17 cytokines (IL-17A, IL-17F) play a critical role in the pathogenesis of several autoimmune diseases including SLE and LN. Increased TH17 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 TH17 cells by acting as a control switch for TH17 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 in vitro pharmacological effects against TH17 cells and cytokines, optimal drug-likeness & pharmacokinetic properties and superior therapeutic efficacies in preclinical autoimmune models of rheumatoid arthritis and multiple sclerosis.1,2

Objectives The in vivo treatment efficacy of INV-17 was assessed in this initial pilot study prior to a larger study group in lupus-prone MRL/lpr mouse model to establish the preclinical Proof of Concept of a novel oral INV-17 RORgT inverse agonist.

Methods Lupus-prone MRL/lpr mice spontaneously develop disease. Upon disease-onset, mice with a proteinuria score >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).

Results 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.

Conclusions 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 & efficacious novel treatment for lupus.

References

  1. Gaweco et al. 2014 Arthritis Rheum. 66[11]: S137.

  2. Gaweco et al. 2013 J.Neurol.Sci. 333: 362-363.

Disclosure of Interest 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

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.