Upstream cytokine inhibition shows statistically significant efficacy and clean safety through 12 weeks in a phase 2a trial.
Targeting IL-18 produced rapid, statistically significant and clinically meaningful improvements in moderate-to-severe atopic dermatitis, a phase 2a proof-of-concept trial has found.
Patients achieved placebo-adjusted EASI reductions as early as week four and sustained responses through week 12 after just two doses, the researchers say.
The randomised, double-blind, placebo-controlled study enrolled 70 adults with moderate-to-severe disease, assigning 48 patients to intravenous EVO301 at 5mg/kg on days one and 28, and 22 to placebo.
The trial met its primary endpoint, with 99.8% of the posterior distribution exceeding the prespecified threshold of at least an 8% improvement over placebo in percent change from baseline in the Eczema Area and Severity Index (EASI).
Differences versus placebo were statistically significant at weeks four, eight and 12 (p<0.01 at each time point).
Mean EASI reductions with active treatment reached 41% at week four, 50% at week eight and 55% at week 12, compared with 18%, 16% and 22%, respectively, in the placebo arm.
The placebo-adjusted improvements were 23%, 34% and 33% across the same time points.
At week 12, 23% of treated patients achieved validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD) scores of 0 or 1 with at least a two-point improvement from baseline, while no placebo-treated patients reached that endpoint.
Biomarker analyses demonstrated reductions across both Th2 and non-Th2 inflammatory mediators, including CCL-17 (TARC), CCL-22 and IL-22, supporting the rationale for upstream cytokine inhibition.
IL-18 functions as an alarmin and amplifier of inflammation, capable of driving Th1, Th2, Th17/22 and innate immune pathways.
Its upstream position in the inflammatory cascade has drawn interest as a strategy to address the heterogeneous immunologic signatures observed in atopic dermatitis.
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EVO301 is a long-acting SAFA-IL-18BP fusion protein designed to neutralise aberrantly upregulated IL-18.
By combining native human IL-18 binding protein with an anti-serum albumin Fab-associated domain, the molecule is engineered for extended half-life and enhanced tissue distribution.
Pharmacokinetic and target engagement findings in this trial were consistent with earlier phase 1 data and support once-monthly dosing.
The therapy was well tolerated, with no treatment-related serious or severe adverse events reported, no discontinuations due to adverse events and no meaningful differences in overall adverse event rates between active and placebo groups.
Full data are expected to be presented at an upcoming scientific meeting, while researchers are planning a phase 2b dose-ranging trial using a subcutaneous formulation, with additional evaluation in ulcerative colitis under consideration.
“These data underscore that impacting pathways beyond only Th2 biology can meaningfully contribute to AD disease activity. EVO301’s ability to target the novel IL-18 mechanism and show clinically relevant treatment activity, without side effects, could offer real benefit for patients in such a heterogeneous disease,” said Dr Mark G. Lebwohl, dean for Clinical Therapeutics and Chairman Emeritus of the Department of Dermatology at the Icahn School of Medicine at Mount Sinai.
“There is an urgent need for new treatment options for the growing number of patients suffering from AD.
“With rapid onset and durable responses, as evidenced by meeting the primary endpoint at weeks four, eight and 12 after only two doses, this trial supports the potential of EVO301 to become a front-line biologic treatment in AD, if approved.”
Luis Pena, president and CEO at Evommune, a clinical-stage biotechnology company developing innovative therapies that target key drivers of chronic inflammatory diseases, said it was an important development.
“This is a big milestone for Evommune and we are pleased to report unequivocally positive data that validate IL-18 inhibition and show significant activity of EVO301 in moderate-to-severe AD patients,” he said.
“These data support our plans to move EVO301 into a Phase 2b dose-ranging trial where we can optimise the dose and seek to further improve patient outcomes.”
