ABX464 (obefazimod) up-regulates miR-124 to reduce pro-inflammatory markers in inflammatory bowel diseases

Abstract

Advanced therapies have transformed the treatment of inflammatory bowel disease; however, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. The first-in-class oral molecule ABX464 (obefazimod), which selectively upregulates miR-124, has demonstrated its ability to be a well-tolerated treatment with rapid and sustained efficacy in patients with ulcerative colitis (UC). Here, we provide evidence that ABX464 affects the immune system in vitro , in the murine model of inflammatory bowel disease, and in patients with UC. In vitro , ABX464 treatment upregulated miR-124 and led to decreases in proinflammatory cytokines including interleukin (IL) 17 and IL6, and in the chemokine CCL2. Consistently, miR-124 expression was upregulated in the rectal biopsies and blood samples of patients with UC, and a parallel reduction in Th17 cells and IL17a levels was observed in serum samples. In a mouse model of induced intestinal inflammation with dextran sulfate sodium, ABX464 reversed the increases in multiple proinflammatory cytokines in the colon and the upregulation of IL17a secretion in the mesenteric lymph nodes. By upregulating miR-124, ABX464 acts as “a physiological brake” of inflammation, which may explain the efficacy of ABX464 with a favorable tolerability and safety profile in patients with UC.

ABX464 (obefazimod) for patients with COVID-19 at risk for severe disease: miR-AGE, a randomized, double-blind placebo-controlled trial

“…6 The upregulation of the single miR-124 has been demonstrated in healthy subjects as well as in patients with HIV infection and patients with UC. 3 , 7 From a mechanistic perspective, obefazimod was shown to bind the cap binding complex (CBC), a protein complex at the 5' ends of RNAs involved in fueling cellular RNA integrity (eg, splicing). As a result, obefazimod enhances the splicing of a long noncoding RNA to upregulate miR-124, which is a modulator of inflammation and innate immunity and has an antiproliferative effect (by affecting some of the important cell cycle transcripts).…”

“… 14 Obefazimod affected the immune system in vitro and demonstrated a marked decrease in the inflammatory colitis in murine model of inflammatory bowel disease as well as in patients with UC. 7 These effects of obefazimod 15 , 16 were associated with the prevention of proliferation of T H 17 cells, which produce IL-17 in both peripheral blood and mesenteric lymph nodes. 7 …”

“… 7 These effects of obefazimod 15 , 16 were associated with the prevention of proliferation of T H 17 cells, which produce IL-17 in both peripheral blood and mesenteric lymph nodes. 7 …”