P294 AMT-101, a gut selective oral IL-10 fusion: results from a Phase 1b study in patients with active Ulcerative Colitis

Abstract

Abstract Background IL-10 is a pleiotropic anti-inflammatory cytokine that restores mucosal homeostasis. Genetic deficiencies in IL-10 cause intestinal inflammation in mice and are associated with early onset IBD in humans. In mice, this can be reversed by addition of exogenous IL-10. Subcutaneous use of recombinant human IL-10 treatment in patients with Crohn’s Disease led to symptomatic and endoscopic improvement, but dose limiting systemic toxicity including anemia and thrombocytopenia was observed and appeared to be mediated by induction of gamma-interferon. AMT-101 is an oral, gut selective, fusion protein of IL-10 and a carrier protein that mediates transcytosis through intestinal enterocytes into the lamina propria (LP). Pre-clinical studies demonstrated that AMT-101 efficiently transits the epithelial cell barrier, targets mucosal immune cells in the LP, and results in improved colitis disease severity without systemic exposure. Methods A multiple ascending dose Ph1b POC trial was conducted in 16 patients with active UC where patients were randomized 3:1 to receive AMT-101 at doses of 1, 3, 10, or 30 mg or PBO, orally, once daily for 14 days. Primary and secondary outcome measures included safety and PK. Exploratory endpoints included changes in fecal calprotectin, histology, and stool microbiome. Results AMT-101 was safe and well tolerated; all AEs were mild to moderate and self limiting. No systemic toxicities associated with prior administration of IL-10 (e.g.anemia or thrombocytopenia) were observed. Systemic levels of AMT-101 were below limit of quantitation, given the GI restricted design. 1 mg and 3 mg AMT-101 led to placebo-adjusted mean reductions of FCP of 44% and 27%, respectively, in patients with baseline FCP>150 μg/g. Paired biopsy samples were centrally read in a blinded manner using the Geboes scoring system. Improvements were observed in 60% (6/10) of patients on AMT-101, compared with 0% (0/2) patients treated with placebo. Microbiome analyses revealed changes in phyla abundance in the 1mg and 3mg treatment cohorts (Bacteroidetes: 28.3% ± 31.4 to 51.3% ± 21.6; Firmicutes: 21.8% ± 12.7 to 30% ± 7.3), including Roseburia hominis and Faecalibacterium prausnitzii species. Conclusion The results of this Phase 1b study confirm that once daily, oral AMT-101 was safe and well tolerated without SAEs previously observed with systemic IL-10 and without systemic exposure, by design. Doses at 10 mg or less suggest potential clinical efficacy paired with an enhancement of favorable enteric commensal bacteria after only 14 days of treatment. These findings support AMT-101 as actively exerting an immunomodulatory effect in the intestinal lamina propria and support ongoing Ph2 trials of AMT-101.