Recludix Pharma presented promising data for its selective STAT6 inhibitor at the American Thoracic Society (ATS) International Conference in San Francisco, demonstrating efficacy comparable to biologic treatments in preclinical asthma models. The company's novel approach could potentially offer a first-in-class oral alternative to injectable biologics for treating type 2 inflammatory diseases.
The poster presentation, titled "Highly Selective and Reversible STAT6 Inhibition Demonstrates Potential for Differentiated Efficacy and Safety Profile in Type 2 Allergic Inflammation," revealed that the company's reversible, non-degrading STAT6 inhibitor achieved significant, dose-dependent reduction of airway inflammation in an in vivo asthma model. Notably, the efficacy was on par with anti-IL-4/IL-13 treatment in both prophylactic and therapeutic dosing paradigms.
"What we have demonstrated in vivo is that our reversible STAT6 inhibitor has the potential to meet or exceed the efficacy of clinically validated biologics without needing to degrade STAT6 protein, while likely avoiding the hematologic safety concerns observed with JAK inhibitors," said Ajay Nirula, M.D., Ph.D., executive vice president and head of research and development at Recludix.
Mechanism and Selective Targeting
The STAT6 inhibitor targets the SH2 domain and demonstrated highly selective, picomolar potency for inhibiting STAT6 activation driven by IL-4 in biochemical and primary human cellular assays. This selective approach disrupted TARC (thymus and activation-regulated chemokine) production, a known biomarker for type 2 inflammatory diseases, following stimulation of human PBMCs with IL-4 or IL-13.
Importantly, the molecule replicated the selectivity of IL-4/IL-13 biologics by preventing differentiation of Th2 (T helper 2) cells without impacting other immune pathways. Unlike JAK inhibitors, which can cause broad immunosuppression, the reversible and selective STAT6 inhibition did not impair growth factor signaling critical for hematologic homeostasis.
Preclinical Efficacy Data
In the preclinical model of allergic asthma, blocking STAT6 activation prevented lung inflammation with efficacy comparable to antibody-mediated blockade of anti-IL-4/13 pathways. The STAT6 inhibitor suppressed phosphorylated STAT6 activity in the blood, spleen, and lung with repeat dosing without any impact on total STAT6 protein levels.
This approach represents a significant advancement in targeting the STAT6 pathway, which is a key nodal transcription factor that selectively mediates downstream signaling of IL-4 and IL-13 - dominant cytokines in the pathophysiology of type 2 inflammatory diseases.
Potential Clinical Applications
Recludix is focusing on developing this STAT6 inhibitor for multiple type 2 inflammatory diseases, including asthma, COPD, atopic dermatitis, and other IL-4/IL-13-dependent conditions. The company is working with its partner Sanofi to advance a STAT6 inhibitor into clinical trials.
"We are very excited about the potential of selective STAT6 inhibition for the treatment of asthma, COPD, atopic dermatitis, and other IL-4/IL-13-dependent diseases," added Dr. Nirula.
Recludix's Platform Approach
The STAT6 inhibitor was discovered using Recludix's proprietary drug discovery platform, which integrates custom-generated DNA-encoded libraries, massively parallel determination of structure-activity relationships, and a proprietary screening tool to ensure selectivity.
This platform approach has enabled Recludix to develop inhibitors for challenging protein targets, with a focus on SH2 domain inhibitors. Beyond STAT6, the company is also advancing potential first-in-class BTK SH2 domain inhibitors for B cell or mast cell-driven inflammatory diseases and STAT3 SH2 domain inhibitors for Th17-mediated inflammatory diseases.
The company's management team includes industry veterans with experience from Seagen, Blueprint Medicines, and Lilly, and Recludix was named a 2024 Fierce 15 biotech company, highlighting its innovative approach to drug discovery in the inflammatory disease space.
