A randomized, double-blinded, phase 2 trial of EDP1815, an oral immunomodulatory preparation of Prevotella histicola, in adults with mild-to-moderate plaque psoriasis.

Background: Psoriasis is a chronic inflammatory skin disease. EDP1815 is an oral, gut-restricted preparation of non-live Prevotella histicola, the first of a new immunomodulatory therapeutic class targeting the small intestine to generate systemic anti-inflammatory responses. Objective: To evaluate safety and efficacy of EDP1815 in mild-to-moderate psoriasis in a proof-of-concept study. Methods: A phase 2, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study with a 16-week treatment period and up to 24 weeks of follow-up. Participants were randomized to receive 1, 4, or 10 capsules daily. Results: EDP1815 was well tolerated with comparable rates of treatment-emergent adverse events to placebo, and no drug-related serious adverse events. Clinically meaningful responses to EDP1815, defined as at least 50% reduction in Psoriasis Area and Severity Index (PASI-50) at week 16, were observed in all 3 cohorts, statistically significant in the 1-capsule (29.7%; P = 0.048) and 4-capsule (31.9%; P = 0.022) groups, compared with placebo (12.1%). Among EDP1815-treated PASI-50 responders at week 16, 60% (18/30) maintained or improved off-treatment responses at week 40. Limitations: Continued off-treatment improvement past 16 weeks shows potential for greater therapeutic benefit that was not assessed. Conclusion: EDP1815 was well-tolerated with a placebo-like safety profile, and had meaningful efficacy outcomes in psoriasis, validating this novel immunomodulatory approach. Clinical trial registration: https://www.clinicaltrials.gov/search?term=NCT04603027, identifier NCT04603027.

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

Introduction: EDP1815 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. Methods: Supported 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. Results: Preclinically, 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. Discussion: This 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.

Lesson of the month 2: Cauda equina in Cushing's syndrome.

We present the case of a 34-year old woman who initially presented with obesity and back pain. She was eventually diagnosed with Cushing's syndrome secondary to an adrenocortical carcinoma that had metastasised to her spine, causing cauda equina compression. The delays in reaching the correct diagnosis caused significant morbidity and exemplify the pitfalls of premature closing, a common cognitive error in diagnostic reasoning.

Do suncreens protect us?

Sunlight stimulates a multitude of important biological effects on skin, causing, amongst other pathological changes, photocarcinogenesis. Sunscreens are designed to provide protection against these harmful properties of ultraviolet radiation, and public health campaigns have been employed to encourage their use. Despite this, there has been a continued rise in the incidence and mortality of the most harmful skin cancer, malignant melanoma. This review article therefore looks at the role of ultraviolet radiation in causing skin cancer; summarizes the available evidence on both the beneficial and harmful effects of sunscreen use; and concludes with practical advice on how we might advise our patients to best protect themselves from photocarcinogenesis.