Oral selective STAT3 inhibitors including REX-7117 showed efficacy and safety potential in preclinical models of Th17-mediated skin inflammation, according to data presented in an oral plenary session at the Society for Investigative Dermatology (SID) Annual Meeting in Dallas, TX.
Data demonstrated that REX-7117 achieves deep, durable, and selective STAT3 inhibition and exhibits similar efficacy to biologics targeting IL-17 in in vivo models of plaque psoriasis. Unlike Janus kinase inhibitor (JAK) 1/2 and tyrosine kinase 2 (TYK2) inhibitors, REX-7117 does not impair broader immune responses, such as interferon-dependent anti-viral immunity or growth factor signaling critical for hematologic homeostasis.
“These exciting data on our oral STAT3 inhibitors demonstrate that deep STAT3 inhibition has the potential to drive potent efficacy — such as that seen with clinically validated biologics but with improved convenience as an orally-administered medication, while high selectivity for the downstream STAT3 target may avoid some of the safety concerns observed with JAK and TYK2 inhibitors,” says Ajay Nirula, MD, PhD, executive vice president and head of research and development at Recludix Pharma, in a news release. “Inhibiting STAT3 could be a favorable and effective approach to treating Th17- and Th1-mediated diseases, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel disease.”
Both REX-7117 and REX-5376 are highly potent and selective orally-available STAT3 inhibitors, as demonstrated across biochemical and cellular assays, which have the potential to:
- Impair inflammatory Th17 cell function, while sparing activation of other cytokine pathways which play critical roles in the defense against viruses, bacteria, extra cellular pathogens, and parasites
- Spare STAT1 mediated-signaling, in contrast to the impact on STAT1 signaling seen with baricitinib (Olumiant, Eli Lilly), (JAK1/2) and deucravacitinib (Sotyktu, Bristol Myers Squibb), (TYK2)
- Not impair either type I or type II interferon (IFN)-mediated antiviral activity, as shown in in vitro models
- Not impair STAT5-mediated signaling by hematopoietic growth factors, unlike some JAK inhibitors which have the risk of inducing anemia, thrombocytopenia, and neutropenia
In a murine IL-23 induced psoriasis model, REX-7117 achieved efficacy responses similar to an anti-IL-17A antibody surrogate treatment and was more efficacious than an estimated clinically relevant dose of deucravacitinib.
