Exo Therapeutics Showcases Efficacy of Exosite-targeted TBK1/STING Inhibitor at FOCIS 2024

Exo Therapeutics, Inc., a firm dedicated to the creation of drug candidates targeting unique small-molecule binding pockets known as exosites, showcased groundbreaking research at the 24th Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS 2024) in San Francisco. The company presented both a poster and an oral presentation focusing on its preclinical program aimed at the TBK1/STING interaction within the cGAS-STING pathway.

The data revealed that Exo Therapeutics has discovered potent and highly selective TBK1/STING inhibitors. These inhibitors have shown efficacy across various preclinical models and have optimized properties leading towards the nomination of a development candidate. The exceptional quality of this research was recognized by FOCIS, which awarded Exo the 2024 Annual Meeting Award for outstanding research and commendable posters.

Mary K. Crow, M.D., an esteemed Physician-in-Chief Emeritus at the Hospital for Special Surgery and a Professor of Medicine at Weill Cornell Medical College, praised Exo’s approach. She emphasized the significance of defining the TBK1/STING pathway's role in conditions such as Systemic Lupus Erythematosus (SLE) and other autoimmune diseases, expressing hope that Exo’s drug development program would soon transition to clinical trials.

Exo Therapeutics aims to broaden the therapeutic landscape with molecules specifically designed to target exosites, thus allowing for a more tailored and precise approach to enzyme modulation. Traditional active-site inhibitors have often faced challenges due to their lack of selectivity, leading to undesirable off-target effects and limited therapeutic indices. In contrast, exosite inhibitors focus on specific portions of enzymes to minimize these off-target effects while maintaining therapeutic benefits.

The presentations highlighted the company’s innovative TBK1 exosite inhibitors, which interrupt the recruitment of TBK1 by STING, leading to downstream activation of type-1 interferon and NF-κB responses. These inhibitors are selective for the TBK1-STING axis, preserving the non-disease related housekeeping functions of the kinase. This selectivity promises to deliver superior efficacy and a better therapeutic window compared to conventional methods.

The company provided insights into its drug discovery efforts, showcasing the identification of a series of TBK1 exosite inhibitors with strong binding affinities, resulting in nanomolar inhibition of interferon-beta in THP1 cells and primary human cell types. These inhibitors are orally bioavailable and have been evaluated in both in vivo and ex vivo models, demonstrating significant inhibition of pharmacodynamic markers upon stimulation with STING agonists. In a pathway-driven model, such as the TREX-1 null mouse, treatment with these inhibitors led to a notable reduction in pro-inflammatory cytokines like IFNβ, CXCL-10, CXCL-9, and IFIT1.

Moreover, TBK1 exosite inhibitors have shown substantial effects in patient samples from those suffering from SLE and Scleroderma. When tested on SLE patient-derived human blood and PBMC, these inhibitors effectively suppressed pathway activation. They also inhibited cytokine production in disease-relevant skin inflammatory models, including fibroblasts and keratinocytes, upon activation of the cGAS-STING-TBK1 pathway.

Exo Therapeutics was co-founded by renowned professors David R. Liu, Alan Saghatelian, and Juan Pablo Maianti. The company leverages its proprietary ExoSight™ platform to develop a robust pipeline of drug candidates targeting exosites. This approach allows for the reprogramming of enzyme activity, opening new avenues for treatments in areas such as inflammation and oncology. The company's team of top-tier researchers continues to push the boundaries of pharmaceutical development, aiming to unlock breakthrough therapeutic solutions for a wide range of diseases.