Equillium NASDAQ: EQ Chief Scientific Officer Stephen Connelly outlined new preclinical data during a company webinar focused on the relationship between the aryl hydrocarbon receptor, or AhR, and miR-124, a microRNA implicated in inflammatory disease biology.
The presentation, titled “Insights to the Aryl Hydrocarbon Receptor and miR-124 Axis,” centered on Equillium’s effort to build a mechanistic framework linking ligand-dependent AhR signaling to miR-124 expression. Connelly said understanding that relationship has implications for interpreting mechanisms of action and developing therapies for inflammatory diseases, including ulcerative colitis.
Equillium Says AhR Activation Appears to Drive miR-124 Induction
Connelly described AhR as a ligand-activated transcription factor found largely in barrier tissues, where it can regulate pathways tied to detoxification, immune modulation, anti-inflammatory cytokines, antioxidant proteins, and barrier repair. He said different AhR ligands may produce different biological signatures, a concept he referred to as “biased agonism.”
A central question for the webinar was whether miR-124 is downstream of AhR activation. Connelly said Equillium’s experiments using its AhR modulator EQ504 and Abivax’s obefazimod, also known as ABX464, suggest that AhR modulation induces miR-124 in immune cells. He said the company observed miR-124 induction in multiple systems and that adding an AhR antagonist reduced that induction.
“This would be the first set of data that really highlights that miR-124 is downstream and dependent on AhR activation,” Connelly said while discussing experiments in isolated CD4-positive T cells.
Connelly also said the data showed reductions in several pro-inflammatory cytokines, including IL-17, IL-6, TNF-alpha, IL-23, IL-12 and IL-1 beta, depending on the cell system and compound tested. He noted that EQ504 appeared to be a strong inducer of IL-22 in activated PBMCs, consistent with prior Equillium interest in IL-22 as a biomarker of AhR-related biology.
ABX464 Identified as a Moderately Potent AhR Modulator
Connelly said Equillium used in silico modeling, docking simulations and an AhR luciferase reporter assay to test whether ABX464 could bind and activate AhR. According to Connelly, the modeling suggested ABX464 fits the canonical PAS-B binding domain of AhR, while reporter assays showed ABX464 is a “moderately potent AhR agonist” with an EC50 of about 400 nanomolar.
Equillium also tested the N-glucuronidated metabolite of ABX464. Connelly said that metabolite did not bind or activate AhR in the assays. He said the result may reflect reduced cellular entry, loss of molecular planarity, steric hindrance, or other effects of glucuronidation.
Connelly said those findings may help reconcile what he called the “obefazimod paradox,” in which miR-124 induction has been linked to anti-inflammatory effects despite prior literature suggesting miR-124 can negatively regulate AhR protein levels. He said Equillium’s model suggests miR-124 may be part of a regulatory feedback system within the broader AhR pathway.
Immune and Epithelial Cell Findings Differ
In immune-cell models, Connelly said AhR modulation by EQ504 and ABX464 induced CYP1A1, miR-124, IL-10 and IL-22, while AhR antagonism inhibited those downstream responses. He said Equillium also saw a reduction in AhR protein expression of roughly 20% to 30% in T regulatory cells, but did not believe that reduction eliminated the receptor’s ability to signal.
In intestinal epithelial cell lines, Connelly said Equillium did not see miR-124 induction, consistent with prior published work from Abivax. However, the company did observe AhR activation through CYP1A1 induction. Connelly said this suggests miR-124 may be more contextually relevant to immune cells than epithelial cells.
Equillium also presented epithelial wound-healing and barrier-function data. Connelly said EQ504 and ABX464 improved wound healing in T84 epithelial cell assays, while adding an AhR antagonist worsened healing. The company also reported reductions in claudin-2, a marker associated with impaired gut barrier function, following AhR modulation. Connelly said claudin-2 levels rose when AhR activity was blocked.
Analysts Press on Clinical Translation and Biomarkers
During the question-and-answer session, analysts asked how the mechanistic findings may translate to Equillium’s clinical development plans for EQ504. Connelly said the company’s approach is to deliver EQ504 directly to colon tissues, seeking high local tissue exposure and lower systemic exposure. He avoided describing the molecule as strictly “gut restricted,” saying the goal is to “tip the scales” toward colon-tissue activation rather than peripheral blood activation.
Asked by Thomas Smith of Leerink about clinical preparation, Connelly said Equillium’s guidance was unchanged and that the company expects to initiate a study around mid-year, which he said the company believes brings it into the third quarter.
In response to Alex Thompson of Stifel, Connelly said the phase 1 study is expected to focus on proof of mechanism. He said key readouts would include tissue concentrations in the expected EC50 to EC90 range and CYP1A1 induction in colon tissue, which he described as a canonical AhR biomarker. He added that IL-10, IL-22 and other markers may be explored, though they could be harder to detect in healthy volunteers because they may require activated cells.
Connelly said miR-124 may also be measured, but he cautioned that CYP1A1 is better characterized for dose response. “That’s why CYP1A1 is so widely studied and so widely relied on,” he said.
Next Steps Include Phase 1 Planning and Potential Publications
Connelly said Equillium may seek to publish the presented data through conferences or publications, including work comparing EQ504 with other AhR modulators such as tapinarof, indirubin and ABX464. He declined to discuss intellectual property strategy in detail.
He also said Equillium is working with an advisory board that includes Bruce Sands, Geert D’Haens, Florian Rieder, Simon Travis and Vipul Jairath as it considers development plans. Connelly said the company remains focused on starting the phase 1 study, demonstrating safety and tolerability, delivering drug to colon tissue, and showing AhR engagement through CYP1A1 induction.
Connelly closed the webinar by directing listeners to Equillium’s website for the full presentation deck, which he said would include additional data not covered during the event.
About Equillium NASDAQ: EQ
Equillium, Inc NASDAQ: EQ is a clinical-stage biopharmaceutical company focused on developing novel immunotherapies to treat severe autoimmune diseases and prevent organ transplant rejection. The company's lead therapeutic candidate, EQ001 (itolizumab), is a humanized monoclonal antibody that modulates T-cell activation by targeting the CD6 receptor. Equillium's pipeline also includes additional biologic candidates aimed at addressing indications such as acute graft-versus-host disease (GVHD) and lupus nephritis.
Founded in 2015 and headquartered in La Jolla, California, Equillium in-licensed itolizumab from Biocon Limited, leveraging the antibody's established safety profile in earlier clinical studies.
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