Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: T helper 17 [TH17] cells and its production of TH17 cytokines IL-17A and IL-17F play a critical role in the pathogenesis of RA and collagen-induced arthritis [CIA]. Retinoic acid receptor-related orphan receptor gamma t [RORgT] is a nuclear hormone receptor that specifically regulates TH17 cells by acting as a control switch for TH17 differentiation, function and cytokine production. Lead development efforts of several proprietary novel chemical scaffolds of the INV-17 portfolio of small molecule RORgT inverse agonists led to the identification of an INV-17 clinical compound candidate demonstrating potent in vitro pharmacological effects against TH17 cells and cytokines coupled with optimal druggable properties. To establish the preclinical Proof of Concept in RA prior to advancing to IND-enabling development, the in vivotreatment efficacy of INV-17 was assessed in the mouse CIA model.
Methods: Disease was induced in DBA1 mice according to a standard protocol. Prior mouse in vivopharmacokinetic [PK] studies determined the optimal oral bioavailability and drug exposure of INV-17 enabling p.o. dosing in this study. To assess the preclinical efficacy in a mouse CIA model, INV-17 was administered orally for 28 days as a therapeutic treatment regimen following chicken collagen CII/CFA disease induction on day 0 and CII/IFA booster immunization on day 15 in DBA1 mice. Upon disease-onset, mice with a clinical arthritis score > 1 (Scale: 0-16) were randomized to receive 28-day dosing with INV-17 at 30 mg/kg (n=10) or comparator controls: Vehicle (n=11) or Dexamethasone [Dex] (n=9).
Results: Successful disease amelioration following INV-17 and Dex treatments was observed with statistically significant reduction of cumulative arthritis score of 6.02 +/- 0.26 [mean +/- SEM] (p<0.001) and 0.42 +/- 0.2 (p<0.001), respectively, in contrast to the vehicle group of 8.81 +/- 0.43. Significant improvement in clinical disease scores in INV-17 treated mice was evident starting on arthritis day 13 (p=0.04) with maximal therapeutic effects observed on arthritis day 16 (p=0.0007) through day 26 (p=0.0003) until end of study (p=0.01). INV-17 drug levels were assessed in peripheral blood and hind joints confirming optimal INV-17 pharmacokinetic exposures and oral bioavailability. INV-17 was well tolerated and INV-17-treated mice were unremarkable with optimal body conditions.
Conclusion: The superior safety and therapeutic efficacy data following 28-day treatment of an orally bioavailable small molecule INV-17 clinical candidate compound provide the first report establishing the preclinical POC in RA with pharmacological intervention of RORgT inverse agonism. 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 RA DMARD treatment.
Disclosure:
A. Gaweco,
Innovimmune Biotherapeutics Holding, LLC,
3;
S. Palmer,
Innovimmune Biotherapeutics Holding, LLC,
3;
R. Shamilov,
Innovimmune Biotherapeutics Holding, LLC,
3;
C. Stremnitzer,
Innovimmune Biotherapeutics Holding, LLC,
3;
K. Matthews,
Innovimmune Biotherapeutics Holding, LLC,
3;
M. Fisher,
Innovimmune Biotherapeutics Holding, LLC,
3;
W. Windsor,
Innovimmune Biotherapeutics Holding, LLC,
3;
J. Blinn,
Innovimmune Biotherapeutics Holding, LLC,
3;
E. M. Ginzler,
Innovimmune Biotherapeutics Holding, LLC,
5;
J. Tilley,
Innovimmune Biotherapeutics Holding, LLC,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/superior-therapeutic-efficacy-of-a-novel-oral-small-molecule-retinoic-acid-receptor-related-orphan-receptor-gamma-t-rorgt-inverse-agonist-inv-17-a-promising-safe-efficacious-treatment-for-rh/