Clinical translation of anti-inflammatory effects of Prevotella histicola in Th1, Th2, and Th17 inflammation

Abstract

IntroductionEDP1815 is a non-colonizing pharmaceutical preparation of a single stain of Prevotella histicola isolated from the duodenum of a human donor. We report here preclinical and clinical studies showing that the action of EDP1815, an orally delivered and gut restricted single strain of commensal bacteria can regulate inflammatory responses throughout the body.MethodsSupported by evidence for anti-inflammatory activity in three preclinical mouse models of Th1-, TH2-, and Th17-mediated inflammation, EDP1815 was tested clinically in three Phase 1b studies in patients with psoriasis, patients with atopic dermatitis, and healthy volunteers in a KLH skin challenge model.ResultsPreclinically, EDP1815 was efficacious in all three mouse models of inflammation, showing reduction in skin inflammation as well as related tissue cytokines. In the Phase 1b studies, EDP1815 was found to be well tolerated by participants, with a safety profile comparable to placebo, including no severe or consistent side-effects reported, and no evidence of immunosuppression with no opportunistic infection occurring in these studies. In psoriasis patients, signs of clinical efficacy were seen after 4 weeks of treatment, which continued beyond the treatment period in the higher-dose cohort. In atopic dermatitis patients, improvements were seen throughout the key physician-and patient-reported outcomes. In a healthy-volunteer study of a KLH-induced skin inflammatory response, consistent anti-inflammatory effects were seen in two cohorts through imaging-based measures of skin inflammation.DiscussionThis is the first report demonstrating clinical effects from targeting peripheral inflammation with a non-colonizing gut-restricted single strain of commensal bacteria, providing proof of concept for a new class of medicines. These clinical effects occur without systemic exposure of EDP1815 or modification of the resident gut microbiota, and with placebo-like safety and tolerability. The breadth of these clinical effects of EDP1815, combined with its excellent safety and tolerability profile and oral administration, suggests the potential for a new type of effective, safe, oral, and accessible anti-inflammatory medicine to treat the wide range of diseases driven by inflammation.Clinical Trial Registration: EudraCT # 2018-002807-32; EudraCT # 2018-002807-32; NL8676; https://clinicaltrials.gov/ct2/show/NCT03733353; http://www.trialregister.nl.

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents

“…Rather, EDP1815 is believed to interact with innate immune cells in the small intestine, causing them to activate and migrate into nearby mesenteric lymph nodes, communicating with T-lymphocytes and priming them to promote a systemic anti-inflammatory response. This proposed mechanism is supported by data confirming the interaction of EDP1815 with toll-like receptor (TLR) 2 as well as studies demonstrating attenuated anti-inflammatory responses following the blockade of signaling by α4β7 and L-selectin, integrins that mediate dendritic cell migration to mesenteric lymph nodes [97][98][99]. The efficacy of EDP1815 in reducing systemic inflammation has been demonstrated in several preclinical studies in which the drug successfully reduced ear skin thickness in Th1-and Th17-driven mouse models of inflammation [99].…”

“…This proposed mechanism is supported by data confirming the interaction of EDP1815 with toll-like receptor (TLR) 2 as well as studies demonstrating attenuated anti-inflammatory responses following the blockade of signaling by α4β7 and L-selectin, integrins that mediate dendritic cell migration to mesenteric lymph nodes [97][98][99]. The efficacy of EDP1815 in reducing systemic inflammation has been demonstrated in several preclinical studies in which the drug successfully reduced ear skin thickness in Th1-and Th17-driven mouse models of inflammation [99]. When investigated in a phase I trial for psoriasis, participants treated with high-dose and low-dose EDP1815 saw greater reductions in Lesion Severity Score (LSS) at 4 weeks compared to those who received the placebo with no significant differences in adverse events reported between groups [99].…”

“…EDP1815 is a non-live pharmaceutical preparation of a single strain of the bacterium Prevotella histicola developed by Evelo Biosciences [ 97 , 98 , 99 , 100 ]. The agent is gut-restricted, non-colonizing, and does not alter the host gut microbiota [ 97 , 98 , 99 ].…”

“…EDP1815 is a non-live pharmaceutical preparation of a single strain of the bacterium Prevotella histicola developed by Evelo Biosciences [ 97 , 98 , 99 , 100 ]. The agent is gut-restricted, non-colonizing, and does not alter the host gut microbiota [ 97 , 98 , 99 ]. Rather, EDP1815 is believed to interact with innate immune cells in the small intestine, causing them to activate and migrate into nearby mesenteric lymph nodes, communicating with T-lymphocytes and priming them to promote a systemic anti-inflammatory response.…”

“…The efficacy of EDP1815 in reducing systemic inflammation has been demonstrated in several preclinical studies in which the drug successfully reduced ear skin thickness in Th1- and Th17-driven mouse models of inflammation [ 99 ]. When investigated in a phase I trial for psoriasis, participants treated with high-dose and low-dose EDP1815 saw greater reductions in Lesion Severity Score (LSS) at 4 weeks compared to those who received the placebo with no significant differences in adverse events reported between groups [ 99 ]. Most recently, the results from a larger phase II trial were presented (NCT04603027) [ 100 ].…”