D1.166 - REX-8756 is a First-in-Class Potent and Selective Orthosteric STAT6 Inhibitor That Demonstrates Efficacious Potential and Safety Differentiation in TH2-Mediated Inflammation

Biologics targeting IL-4 and IL-13 immunology have achieved clinically meaningful efficacy in type 2 (allergic) inflammatory and respiratory diseases. Binding of IL-4 or IL-13 to their cognate receptors triggers the intracellular JAK-STAT signaling cascade to propagate their inflammatory responses. However, the clinical utility of small molecule JAK inhibitors is confounded by their associated on-target safety signals, including dysregulated hematologic homeostasis (anemia, thrombocytopenia). Selective STAT6 inhibition therefore represents an opportunity to phenocopy the biologic efficacy of monoclonal antibodies targeting anti-IL-4/13 signaling pathways, while avoiding broad JAK-mediated immune suppression.

The SH2 domain is the exclusive mediator of STAT6 binding to the IL-4/13 cytokine receptors which triggers its dimerization and subsequent downstream transcriptional activity.  Orthosteric inhibition of the pTyr-binding site within the STAT6 SH2 domain therefore represents an optimal strategy for modulating activity of this attractive therapeutic target. 

Here we describe REX-8756, a reversible, SH2 domain-targeting STAT6 inhibitor that demonstrates sub-nanomolar potency in biochemical and primary human cellular assays, high selectivity across the SH2 family including other STAT proteins and inhibits IL-4/13 driven inflammation. We show that unlike JAK inhibition, reversible and selective STAT6 inhibition does not impair growth factor signaling critical for hematologic homeostasis. 

In preclinical studies, once daily dosing of REX-8756 is well tolerated, achieves complete inhibition of phosphorylation-mediated STAT6 activation translating to efficacy comparable to antibody-mediated blockade of anti-IL-4/13 pathways in both allergic asthma and dermatitis in vivo models. Preclinical in vivo efficacy is associated with a dose-dependent reduction of pSTAT6 across multiple tissue types as well as Th2 cytokines (IL-13, IL-5) within the immune compartment.