– REX-7117 found to have superior efficacy to a clinically-relevant dose of deucravacitinib in a preclinical model of psoriasis
– REX-7117, as a highly selective STAT3 inhibitor, demonstrates favorable in vivo preclinical safety profile
SAN DIEGO, CA, October 31, 2023 – Recludix Pharma, a leader in platform approaches to discover inhibitors of challenging targets for inflammatory disease and cancer, announced that in a presentation given today at the 7th Annual Dermatology Drug Development Summit titled “Finding the New Ground Between Safety & Efficacy in Drug Development,” Recludix’s senior vice president of biology, Paul Smith, Ph.D., reviewed the challenges associated with inhibition of the JAK/STAT pathway through TYK2 and JAK inhibitors and presented preclinical data with Recludix’s STAT3 inhibitor REX-7117, which potently and selectively targets the STAT3 Src Homology 2 (SH2) domain. The presentation is available on the company’s website under the section titled “Events.”
“We are excited by these data demonstrating that our STAT3 inhibitor REX-7117 is efficacious in Th17-driven diseases and has shown greater efficacy than deucravacitinib in a preclinical model of psoriasis,” said Nancy Whiting, PharmD, CEO of Recludix. “Importantly, other approaches to inhibiting the JAK/STAT pathway by targeting TYK2 or JAK have resulted in undesirable safety consequences, such as increased risk of infections or altered hematopoiesis. Recludix’s approach targeting downstream STAT3 has been shown in preclinical models to be safer, as cytokines critical to anti-viral immunity and hematologic homeostasis do not utilize STAT3 signaling.”
REX-7117 is a highly potent and selective STAT3 inhibitor. It provides durable STAT3 inhibition and maintains in vivo selectivity against other STAT proteins, even after the administration of multi-day oral dosing in a preclinical model. In the same model, a single dose of TYK2 inhibitor deucravacitinib or JAK inhibitor baricitinib results in significant inhibition of STAT1, an off-target effect that may interfere with an effective immune response to infection.
STAT transcription factors are downstream regulators in the JAK/STAT pathway, and selective STAT inhibition provides a more focused impact on the immune system with fewer side effects than other modalities currently employed to inhibit this pathway. In contrast to JAK family inhibitors, STAT3 targeting with REX-7117 specifically inhibited disease-modifying Th17 cell function, but spared T cell subsets known to be important for defense against viruses, bacteria, extra cellular pathogens, and parasites.
In a translational Th17 preclinical model of psoriasis, once daily REX-7117 (300 mg/kg) was superior to a clinically-relevant dose of deucravacitinib (1 mg/kg). Moreover, twice daily REX-7117 (300 mg/kg) was comparable to deucravacitinib at a supra-clinical dose (30 mg/kg), reinforcing the rationale of STAT3 targeting as a potential disease-modifying opportunity.
The interleukin cytokines IL-23 and IL-6 signal through STAT3 and promote the generation and function of pathogenic T helper type-17 (Th17) cells, a type of immune cell that is pro-inflammatory. Th17 cells are considered pivotal players in certain inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease and others. Inhibiting STAT3 can also offer potential efficacy beyond Th17 / IL-17 driven diseases in clinical indications where blocking the IL-6 pathway is clinically validated. Furthermore, clinical trials inhibiting oncostatin M (OSM) and IL-22, both STAT3 dependent cytokines, have been reported as efficacious in inflammatory disease.
A selective, oral STAT3 inhibitor has potential to replace JAK/TYK2 inhibitors and biologics for multiple inflammatory diseases.
STAT3 inhibitors may also have significant opportunity in cancer settings, as STAT3 is activated in greater than 70% of human cancers.
Recludix is a leader in developing platform approaches to discover potent and selective inhibitors of challenging protein targets. The company’s management team includes industry veterans with a track record of success, including former leaders and founding scientific team members of Seagen and Blueprint Medicines. Recludix has developed a unique drug discovery platform that integrates custom generated DNA-encoded libraries, massively parallel determination of structure activity relationships, and a proprietary screening tool to ensure selectivity. The company is employing this approach first in the development of SH2 domain inhibitors. Recludix’s most advanced programs are focused on STAT (signal transducer and activator of transcription) proteins where abnormal activation is found in inflammatory diseases, such as rheumatoid arthritis, asthma, atopic dermatitis, and inflammatory bowel disease, as well as numerous cancer types, such as multiple leukemias and lymphomas. The company has a strategic partnership with Sanofi for the development and commercialization of a STAT6 inhibitor. Recludix is also advancing STAT3 inhibitors for Th17-mediated I&I diseases and oncology indications, as well as additional programs. For more information, please visit the company’s website at https://recludixpharma.com.