BenevolentAI S.A. announced positive safety data from its Phase Ia, first-in-human, clinical study of BEN-8744 in healthy volunteers. BEN-8744 is an orally administered, peripherally-restricted PDE10 inhibitor being developed as a potential first-in-class treatment for patients with moderate to severe ulcerative colitis (UC). The Phase Ia study met its primary objective.

BEN-8744 was safe and well tolerated, with no Serious Adverse Events (SAEs) reported in any dose cohorts. Importantly, given the liabilities associated with PDE10 inhibitors previously in clinical development for other central nervous system (CNS) indications, there was no evidence of CNS-associated adverse events. The pharmacokinetic profile of BEN-8744 generated in the study suggested that twice daily dosing should achieve the desired PDE10 target coverage to elicit a potential therapeutic effect in subsequent clinical studies in UC patients.

PDE10 was identified using the Benevolent PlatformTM as a novel drug target for the treatment of UC with potential for meaningful differentiation versus existing standard-of-care treatments. BenevolentAI, using the Benevolent PlatformTM, identified PDE10 inhibition as a potential novel approach to treat UC, but was aware of CNS side effects with PDE10 inhibitors in development for CNS indications that limited their further clinical development. As a result, BenevolentAI?s scientists designed BEN-8744 to be not only a potent PDE10 inhibitor, but also a peripherally-restricted molecule, i.e. with very limited CNS penetration, to minimise the chances of these side effects occurring.

The Phase Ia study results support this profile, showing no evidence of CNS-associated adverse events at any dose level. It is anticipated that the full results from this study will be presented in a peer-reviewed forum at a later date. Phase II-enabling extended regulatory toxicology studies and biomarker qualification studies are underway to permit the extended dosing envisaged for further drug development.

The Benevolent PlatformTM has been developed to rapidly identify novel potential drug targets for further evaluation. In the case of this programme, there was no previously published data in all available biomedical literature establishing PDE10 in the disease pathology of UC. Having validated the target hypothesis ex-vivo, BenevolentAI?s scientists were then able to quickly design a lead molecule that, after rapid lead optimisation, resulted in BEN-8744.

BEN-8744 was then nominated as a development candidate in September 2021, only two years from programme initiation. As such, BEN-8744, like all programmes within the BenevolentAI pipeline, is a wholly-owned asset of the Company. PDE10 is a dual phosphodiesterase that can function to reduce intracellular levels of both the signalling molecules cAMP and cGMP.

Restoration of cAMP and cGMP levels by PDE10 inhibition is anticipated to have a direct anti-inflammatory and potential disease-modifying benefit through improvement of barrier integrity. The therapeutic potential of PDE10 inhibition has been well studied in the central nervous system as its highest level of expression is in the brain. However, clinical trials for PDE10 inhibitors have revealed substantial side effects, thought to be attributable to PDE10 inhibition in the brain.

BEN-8744 has been intentionally designed to be peripherally restricted to avoid the CNS side effects and more selectively target PDE10 expression in the periphery. Initial signs of the potential pharmacological efficacy of BEN-8744 were observed in ex-vivo patient-derived colonic biopsies, where treatment with BEN-8744 was shown to reduce the release of pro-inflammatory cytokines such as IL6, IL8 and TNFa, in a dose dependent manner. The magnitude of the response was comparable to standard of care agents such as JAK inhibitors and steroids.

With a differentiated mechanism of action and potentially disease modifying efficacy, BEN-8744 could also be investigated further in wider inflammatory bowel disease indications, with the Company already having preclinical data indicative of a robust anti-inflammatory response in ex-vivo Crohn?s patient biopsies, allowing for the possibility of indication expansion.