Late Breaking Abstract - Safety, pharmacokinetics and pharmacodynamics of KT-621, an oral STAT6 degrader, in healthy adults

KT-621 is a selective degrader of signal transducer and activator of transcription 6 (STAT6), an essential transcription factor in the IL-4/IL-13 pathway. Targeting STAT6 in inflammatory pulmonary diseases with a once daily (QD) oral drug has high clinical potential. KT-621 was studied in a first-in-human, randomized, double-blind, placebo-controlled Phase 1 trial (<ext-link>NCT06673667</ext-link>) assessing safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple (QD x 14 days) ascending doses (SAD/MAD) in healthy volunteers (HV). 48 HV were enrolled in SAD (doses of 6.25-800 mg) and 70 in MAD (1.5-200 mg). KT-621 was well tolerated with a safety profile undifferentiated from placebo. There were no serious or severe adverse events (AEs), very few treatment-related AEs that were mild, no treatment-related discontinuations, and no clinically relevant changes in vital signs, laboratory tests or electrocardiograms. Plasma PK showed rapid absorption after oral dosing and dose-proportional increase in exposure. Rapid, robust and durable >90% mean STAT6 degradation in blood, measured using mass spectrometry, was achieved in SAD across all dose cohorts. In MAD, complete STAT6 degradation for a cohort, defined as either a mean reduction of ≥95% or most subjects with levels falling below the lower limit of quantification, or both, was achieved in blood and skin at doses ≥50mg. KT-621 had a robust effect on Eotaxin-3, a highly specific chemokine downstream of IL-4/IL-13 pathway activation, with median reduction of up to 63% at Day 14. These data are the first to demonstrate the potential of STAT6 degradation for treatment of Th2 driven diseases such as asthma or eosinophilic COPD.