BENEVOLENTAI DRUG PIPELINE

Ulcerative Colitis

GASTROENTEROLOGY

BEN-8744 is our novel PDE10 inhibitor under development for ulcerative colitis. The novel target was not previously linked to the disease, and BEN-8744 was nominated as a clinical candidate only 2 years after programme initiation.

Substantial unmet need in a complex disease

Ulcerative colitis (UC) is a chronic disease that causes inflammation and ulceration of the inner lining of the colon and rectum, but the exact cause of UC is unknown. Current treatments can have severe side effects1,2 so there is a high unmet need for an alternative oral small molecule treatment with disease-modifying efficacy and improved safety for patients who do not respond to the current standard of care options.

Rapid identification of a target with no previous linkage to UC

Drug discovery scientists used the Benevolent Platform™ to surface phosphodiesterase 10 (PDE10) as an intriguing and novel therapeutic target for UC, despite the fact that there were no direct connections between PDE10 and UC in the scientific literature. Within 2 years of validating PDE10 as a target, the team generated a potent, selective and peripherally restricted candidate inhibitor, BEN-8744. We plan to submit a Clinical Trial Application (CTA) by the end of 2022, and we anticipate the Phase I trial to start in the UK in 2023. We are actively taking a precision medicine approach, using patient-derived molecular descriptors to optimise trial design and identify efficacy biomarkers.

PDE10 biology and BEN-8744 expected mechanism of action

PDE10 reduces intracellular levels of the signalling molecule cGMP. Low levels of cGMP are directly associated with increased inflammation in UC,3 so inhibition of PDE10 with BEN-8744, and restoration of cGMP levels, should have a direct anti-inflammatory and disease modifying benefit.

Preclinical validation of PDE10 inhibition in UC

PDE10 was experimentally validated in an ex vivo system that uses colon tissue from patients with UC; the assay is translational in that it replicates pharmacological efficacy of known standard of care agents.4 We demonstrated a robust anti-inflammatory effect with a PDE10 inhibitor in this system.

“Our UC programme demonstrates BenevolentAI's unique ability to uncover novel targets not previously linked to a disease. The programme unites the best of human and machine intelligence to build confidence in the early discovery phase, with the aim of ultimately providing new therapeutic options for patients.”

Nikki Robas  —  VP Drug Discovery, BenevolentAI
References

1) Kobayashi et al. Nat Rev Dis Primers 6, 74 (2020)
2) US FDA Drug Safety Communication (2021)
3) Brenna et al. Scand J Gastroenterol 50, 1241-1252 (2015)
4) Crowe et al. Sci Rep 8, 4941 (2018)

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