Intestinal microbe-preparation: Modest activity but safe for mild psoriasis

A phase 2 study has shown robust activity of a gut-restricted commensal microbe in patients with mild-to-moderate psoriasis. Although the efficacy is modest compared with modern biologics, this novel treatment option may be an interesting addition to the present treatment armamentarium due to its excellent safety profile.

The immune system of the small intestine is connected to the rest of the body via mesenteric lymph nodes in the small intestinal axis (SINTAX). Gut-restricted medicines that harness SINTAX could thus enfold anti-inflammatory actions throughout the body. An example of such an approach is EDP1815. EDP185 is a non-living preparation of a strain of Prevotella histicola resourced from a human duodenal biopsy. It targets the small intestine but does not modify or colonise the microbiome and entails no systemic absorption. Preclinically, this preparation has already demonstrated anti-inflammatory effects in models that cover multiple pathways of inflammation (i.e. Th1, Th2, and Th17). Thus, SINTAX medicines have the potential to down-regulate multiple inflammatory pathways which have been validated with targeted antibody therapies, but without the side effects seen with antibody therapeutics or broadly acting oral kinase inhibitors.

Dr Douglas Maslin (Evelo Biosciences, MA, USA) presented the double-blind, randomised, placebo-controlled, phase 2 trial (NCT04603027), in which 249 participants with mild-to-moderate psoriasis (i.e. PASI scores of ≥6 and ≤15) were treated with either 1, 4, or 10 capsules of EDP1815 or placebo for 16 weeks, followed by a treatment-free, 24-week follow-up period.

At week 16, robust PASI50 responses were seen with the microbe across all 3 groups. A PASI50 response was achieved by 31.9% of participants taking 4 capsules (P<0.05 versus placebo). The 10-capsule group had a worse response compared with the 1-capsule cohort, so there was no evidence of a dose-response. Clinical pictures demonstrated the clinically meaningful responses in the trial.

In the 24-week post-treatment period, the response was maintained by 18 of 30 participants and 9 out of 20 participants even deepened the response post-treatment, achieving a PASI75 response or more at the end of the follow-up period.

The adverse event profile, including gastrointestinal symptoms or infections, was similar between EDP1815 and placebo, both for drug responders (i.e. those who achieved a PASI50 response or more) and non-responders. No serious adverse events were observed.

Dr Maslin concluded that EDP1815 has the potential to be a foundational psoriasis treatment for all stages of the disease. With this first SINTAX medicine, a significant and clinically meaningful improvement was achieved in PASI50 and PGA 0/1 response with a placebo-like safety and tolerability. “In my opinion, there seems to be some longevity in this result because EDP1815 influences regulatory T cells,” Dr Maslin said.

In the discussion, Prof. Andrew Blauvelt (Oregon Medical Research Center, OR, USA) commented that “this is an incredible result; we need something that tweaks the immune system.” SINTAX medicines have the advantage to be oral, extremely safe, and affordable. They offer a coordinated reduction of disease-relevant inflammatory cytokines and might play a future role in psoriasis treatment; for example, in combination with more potent agents.

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   1. Maslin D. A phase 2 study investigating the effect of EDP1815, an orally-delivered, anti-inflammatory, gut-restricted commensal microbe in the treatment of mild and moderate plaque psoriasis. S026, AAD 2022 Annual Meeting, 25–29 March, Boston, MA, USA.

 

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Posted on 17 May, 202223 April, 2024