P034 GB004, a novel gut-targeted prolyl hydroxylase inhibitor, induces HIF-1α target genes and is efficacious in mouse colitis
K. Taylor Meadows1, M. Kennedy2, Z. Naiman1, M. Sergeeva2, B. Paulson2, G. Opiteck3, D. Slee4, L. Carter1, L. Salter-Cid4
1Department of Biology, Gossamer Bio Inc., San Diego, USA, 2Department of Preclinical Research, Gossamer Bio Inc., San Diego, USA, 3Department of Clinical Development, Gossamer Bio Inc., San Diego, USA, 4Department of Research and Development, Gossamer Bio Inc., San Diego, USA
Background
GB004 is a small molecule prolyl hydroxylase inhibitor (PHDi) that stabilises hypoxia inducible factor (HIF-α), key transcription factors involved in the protective cellular responses at the intersection of hypoxia and inflammation. GB004 was selected based on its gut-targeted profile to limit systemic on-target effects associated with HIF-α stabilisation. GB004 is in clinical development for the treatment of ulcerative colitis.
Methods
Female wild-type C57BL/6 and immunodeficient B6.129S6-Rag2tm1FwaN12 ko/ko mice (Rag2) mice received either a single oral dose of GB004 or daily oral dosing for 7 days. Colitis was induced by administering 100 µg of anti-CD40 monoclonal antibody interperitoneally in Rag2 mice. GB004 oral dosing started on day 0 and continued once daily for 7 days. Body weight was measured daily. At termination, plasma was isolated for compound exposure and colons were excised, measured and weighed. Colon tissue was preserved in formalin for histology and 1 cm colon sections were snap-frozen for compound exposure and preserved with RNA for gene expression.
Results
A single oral administration or 7 days dosing of 10 mg/kg GB004 in healthy mice resulted in significantly higher exposure in the gastrointestinal tract (GI) (pylorus, duodenum, ileum and colon) than in plasma with colon to plasma ratio of ≥500. Target engagement in colon was demonstrated by induction of HIF-dependent genes (HIF1A), epithelial barrier genes (AKAP12, TFF3, NT5E) and anti-apoptotic genes (BNIP3). In colitis mice, GB004 plasma exposure was elevated compared with plasma concentrations in healthy mice, even so, GB004 exposure was still higher in the colon than plasma at a ratio of 90. Target engagement was demonstrated by an increase in NT5E, CLND1, BNIP3 and CA9 and a reduction in IL12B. In colitis mice, 1, 3 and 10 mg/kg GB004 demonstrated a dose-dependent reduction in colon inflammation and gland loss and 10 mg/kg GB004 showed a significant reduction in neutrophil score. Gene expression 4 h after the final GB004 dose demonstrated an increase in barrier genes AKAP12 and CLDN1 and a decrease in IL12B.
Conclusion
These studies demonstrate that oral GB004 has significantly higher exposure in the GI tract than in the plasma and induces HIF-1α-dependent genes in colon. In mouse colitis, GB004 has high colon exposure, induces target genes involved in barrier function and repair and demonstrates efficacy by reducing inflammation, gland loss and neutrophil inflammation. A clinical study of GB004 is ongoing in patients with ulcerative colitis to explore safety, PK and PD both systemically and in colon (NCT03860896). Sponsored by GB004, Inc., a wholly owned subsidiary of Gossamer Bio, Inc.