Xueqing Liu1, Harry Dedman1, Robert O’Connell2, Alison Bendele2, Connor Ohlsen2, Steve Govek1, Johnny Nagasawa1, Karensa Douglas1, Angelica Milik1, Nhin Lu1, Jing Qian1, Alvaro Ortiz1, Kyoung-Jin Lee1, Nicholas Smith1, Brandee Wagner1, Ken Song1
1. Metacrine, San Diego, CA
2. Bolder BioPath, Inc., Boulder, CO
Introduction: Inflammatory bowel disease (IBD) is a debilitating disease in which most effective therapies are injectable biologics with immunosuppressive side effects. Targeting the farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids, represents a novel approach. FXR is a ligand-activated transcription factor highly expressed in the liver and gastrointestinal tract. Previous studies with FXR agonists have shown prophylactic efficacy in DSS and TNBS chemically induced IBD models. Unlike DSS and TNBS models, the adoptive T-cell transfer model is thought to be more representative of human IBD. Therefore, we examined the efficacy of M480, a potent non-bile acid FXR agonist, in therapeutic treatment mode in adoptive T-cell transfer colitis.
Methods: Colitis was induced by transplanting purified CD4+CD45RBhi T-cells to recipient C.B-17 SCID mice. Body weights of all mice were monitored throughout study duration. Treatments with vehicle (n=10), M480 (10 and 30 mg/kg p.o., n=10), anti-IL-12p40 (neutralizing both IL-12 and IL-23, 0.5mg/mouse, i.p., n=5) and cyclosporine A (CsA, 50 mg/kg p.o., n=10) were administered starting 21 days post T-cell transfer and maintained for 4 weeks. Terminal endpoints included colon weight to length ratio (W/L), colon histopathology and gene expression. Histopathology analysis included inflammation, erosion, gland loss and hyperplasia, each with a score of 0-5, and cumulative sum score of 0-20.
Results: CD4+CD45RBhi T-cell transfer led to a 12% (p<0.05) reduction in body weight from baseline, which was reversed by M480 (10 mg/kg), anti-IL-12p40 and CsA. A marker of colitis, colon W/L, was increased 2.8 fold (p<0.05) in the vehicle group, relative to control mice without T-cell transfer. As compared to vehicle, M480 treated mice showed 41% and 38% reduction in colon W/L at 10 mg/kg and 30 mg/kg respectively (p<0.01). Treatment with anti-IL-12/23 and CsA showed 52% and 34% improvement in colon W/L, respectively. The vehicle treated mice averaged histopathology scores of 4, 3 and 2 for inflammation, hyperplasia and gland loss, respectively, with little or no erosion, and an average histopathology sum score of 10. M480 at 10 and 30 mg/kg significantly reduced the sum score by 71% (p<0.01) and 74% (p<0.01), respectively, comparable to 78% reduction by anti-IL-12/23 (p<0.01). Both M480 and anti-IL-12/23 showed similar improvement across all histopathology endpoints. While CsA improved the colon W/L it failed to show significant improvement in histopathology parameters.
Conclusion: M480, a non-bile acid FXR agonist, is efficacious in reducing colitis in the adoptive T-cell transfer model with efficacy superior to CsA and comparable to anti-IL-12/23 treatment. M480 represents a novel class of oral agents that may offer an alternative treatment for IBD.