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P080 ADS024 attenuates weight loss and decreases disease activity in DSS-induced colitis

Chesnel, L.(1);Acton, S.(1);

(1)Adiso Therapeutics Inc, Research and Development, Concord- MA, United States;

Background

Ulcerative colitis (UC) is a chronic, idiopathic inflammatory disease characterised by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the perpetuation of colonic inflammation. ADS024 is an orally administered live biotherapeutic product (LBP), comprised of a single strain of Bacillius velezensis, being developed for potential application in the treatment of patients with UC.

Methods

Colitis was induced in 39 mice by exposure to 3% dextran sodium sulfate (DSS)-treated drinking water from Day 0 to Day 5; 6 control animals did not receive DSS. Animals were then dosed with vehicle (PBS; n=15) or ART24 (n=12) twice daily for 14 days via oral gavage or with comparator anti-p40 mAb (n=12) once daily (IP) on Days 6, 9, 12, 15. All animals were monitored daily for body weight loss, diarrhea, blood in stool, and activity level. Each of these parameters was individually scored according to the disease activity index (DAI) scoring scheme. Animals underwent video endoscopy on Day 19 to assess colitis severity and stool consistency was scored during endoscopy. Following endoscopy on Day 19, all surviving animals were sacrificed, and blood was collected and processed for serum and analysed for metabolomic profile.

Results

Animals in which colitis was induced by exposure to 3% DSS demonstrated significant weight loss, most profoundly from Days 8 to 11, an increase in the composite DAI and increased mean colon weight:length ratios as compared to control animals. Animals treated with ADS024 had improved body weight, starting at 72 hours post-treatment and decreased DAI scoring over the course of the study compared to the vehicle control group (p<0.01 and p<0.05 respectively), comparable to treatment with  anti-p40 mAb which has a mechanism of action similar to ustekinumab (Stelara®) approved for the treatment of UC. A trend towards a decrease in the mean colon weight:length ratio was observed in animals treated with ADS024, but there was no difference in mean endoscopy scoring compared to the vehicle control group. DSS treatment altered the serum biochemical profile at day 19 and ADS024 induced changes suggesting a reversion towards the control state.

Conclusion

Oral treatment with ADS024 improved body weight loss, reduced DAI, and resulted in a trend towards reduction in mean colon weight:length ratios in the DSS-induced mouse colitis model. In addition, ADS024 treatment led to a rebalancing of the systemic metabolomic shift caused by DSS exposure.

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