Background/Purpose: Macrophage migration inhibitory factor [MIF] is a cytokine secreted by activated T cells and macrophages that plays an important role in RA and autoimmune disease pathogenesis. MIF exerts its proinflammatory effects through its direct biological function and downstream signaling events following receptor engagement. The therapeutic utility in targeting MIF has been established, demonstrating preclinical efficacy in several RA and autoimmune disease models. Lead development efforts of several proprietary novel chemical scaffolds of the INV-88 portfolio of small molecule MIF inhibitors led to the identification of an INV-88 clinical compound candidate demonstrating potent in vitro pharmacological effects against proinflammatory effector 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-88 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-88 enabling p.o. dosing in this study. To assess the preclinical efficacy in a mouse CIA model, INV-88 was administered orally for 7 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 7-day dosing with INV-88 at 60 mg/kg (n=12) or comparator controls: Vehicle (n=11) or Dexamethasone [Dex] (n=9).

Results: Successful disease amelioration following INV-88 and Dex treatments was observed with statistically significant reduction of cumulative arthritis score of 3.72 +/- 0.36 [mean +/- SEM] (p<0.05) and 1.51 +/- 0.58 (p<0.001), respectively, in contrast to the vehicle group of 5.92 +/- 0.68. Significant rapid improvement in clinical disease scores in the INV-88 treated group was evident as early as arthritis day 2 (p=0.041) through end of study on arthritis day 7 (p=0.036). INV-88 was well tolerated and INV-88-treated mice were unremarkable with optimal body conditions.

Conclusion: The superior safety and therapeutic efficacy data following 7-day treatment of an orally bioavailable small molecule INV-88 MIF inhibitor provide the first compelling evidence ever reported of the preclinical utility of MIF inhibition and of a small molecule-based cytokine inhibitor. These profound findings support advancing INV-88 into further IND-enabling development and highlight the potential promise of INV-88 as a safe & efficacious novel RA DMARD treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-efficacy-of-a-novel-oral-small-molecule-macrophage-migration-inhibitory-factor-mif-inhibitor-a-promising-safe-efficacious-treatment-for-rheumatoid-arthritis/