Laurent Chesnel, PhD, Susan Acton, PhD Adiso Therapeutics, Concord, MA
Introduction: Colonic inflammation is a hallmark of ulcerative colitis (UC), a disease characterized by a dysregulated immune response to gut microbiota. ADS024, an orally administered single strain live biotherapeutic product (SS-LBP), was previously shown to reduce disease activity in mice exposed to dextran sodium sulfate (DSS). ADS024 is currently being developed for the treatment of patients with mild to moderate UC.
Methods: Colitis was induced in 90 mice by 3% DSS in drinking water from Day 0 to Day 5; 6 sham mice did not receive DSS. Mice were dosed by oral gavage with ADS024 (n=15 per group) twice daily for 7 days with either 5x108 CFU/dose or 5x104 CFU/dose, or once daily with ADS024 at 1x109 CFU/dose or 1x105 CFU/dose. Negative control mice were dosed with vehicle (PBS; n=20) and a comparator group was dosed with anti-p40 mAb (n=10) once daily (IP) on Days 6, 9, 12. All mice were monitored daily for weight loss, diarrhea, blood in stool, and activity level and individually scored using the Disease Activity Index (DAI) scheme. On Day 12, all mice were sacrificed, and colons collected. Colonic cytokines and myeloperoxidase levels were quantified by ELISA.
Results: DSS-exposed animals treated with ADS024 twice daily at high dose (5x108 CFU/dose) demonstrated significant attenuation of weight loss (p< 0.05) and decreased composite Disease Activity Index (DAI) (p< 0.01) compared to control (DSS only) animals. This ADS024 dosing regimen also decreased mean colon weight:length ratio, a measure of inflammation, as compared to controls (p< 0.005 respectively). The anti-p40 mAb, with a mechanism of action similar to ustekinumab, an approved treatment for UC, reduced DAI but did not significantly reduce colon weight:length ratio. Once daily dosing of ADS024 at high daily dose (1x109 CFU given in the morning) was ineffective, despite the same total daily dose as responding mice dosed BID. A much lower daily dose (1x105 CFU/day) was ineffective regardless of dosing schedule. In DSS-exposed mice treated twice daily with high dose ADS024, the inflammatory marker interleukin-6 (IL6) was significantly down in colons and both interleukin 1 beta (IL1b) and colonic myeloperoxidase (MPO), a measure of active neutrophils, trended down.
Discussion: Oral treatment with high dose ADS024 twice daily, but not once daily, improved disease activity index and reduced measures of inflammation including colon weight:length ratio and the inflammatory cytokine IL-6.
Disclosures:
Laurent Chesnel: Adiso therapeutics – Employee.
Susan Acton: Adiso therapeutics – Employee.
Laurent Chesnel, PhD, Susan Acton, PhD. A0379 - ADS024, a Single Strain Live Biotherapeutic Product, Reduces Colonic Inflammation in DSS-Induced Colitis When Dosed Twice Daily, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.
