Pharmacokinetics (PK)

KT-621 demonstrated a favorable plasma PK profile after single and multiple doses. Rapid absorption was demonstrated with a median tmax of 2-4 hours and a mean half-life of 9-36 hours. There was a dose-proportional increase in exposure after multi-dosing and steady-state was achieved by Day 4.

Pharmacodynamics (PD)

KT-621 demonstrated rapid, deep and prolonged STAT6 degradation in blood after single doses of KT-621 and in blood and skin after multiple doses of KT-621.

STAT6 levels in blood and skin were measured using a highly sensitive and quantitative mass spectrometry assay. Complete degradation within a cohort is defined as either a mean reduction of ≥95% or when most subjects' STAT6 levels are reduced below the Lower Limit of Quantification (LLOQ), or both.

In SAD, maximal degradation was achieved in blood as quickly as the first collected timepoint of 4 hours after a single dose, with mean STAT6 degradation reaching >90% across all SAD doses starting at 6.25 mg. All SAD cohorts at doses of 75 mg or greater achieved >95% mean STAT6 degradation with STAT6 levels below LLOQ in multiple subjects.

In MAD, robust STAT6 degradation was observed in blood at the first timepoint measured (8 hours) for doses above 1.5 mg. Steady-state, complete degradation, associated with STAT6 reductions below the LLOQ in the majority of subjects, was achieved at doses ≥50 mg with recovery starting as early as 4 days post-last dose.

In MAD, robust STAT6 degradation was observed in skin at the first timepoint measured (Day 7) for doses above 1.5 mg. Steady-state, complete degradation, associated with ≥95% mean STAT6 degradation with STAT6 levels below LLOQ in multiple subjects, was achieved at doses ≥50 mg.

Th2 Biomarkers

The impact of STAT6 degradation on Th2 biomarkers was assessed in the MAD cohorts, despite the low baseline levels typically seen in healthy volunteers. TARC reduction was observed for all KT-621 dose groups, with median reduction of up to 37% at Day 14. We believe these results are comparable or superior to what was seen in the dupilumab healthy volunteer study. In line with the dupilumab study in healthy volunteers, minimal IgE reductions were observed given the low levels of IgE at baseline and the short duration of treatment. Eotaxin-3, a highly specific downstream cytokine of the IL-4/IL-13 pathway, was also measured. Eotaxin-3 reduction was observed for all KT-621 dose groups with a median reduction of 63% at Day 14. These results are superior to what has been reported with dupilumab in asthma or chronic rhinosinusitis with nasal polyps (CRSwNP) patients even at 52 weeks.

Safety and Tolerability

The safety profile of KT-621 was undifferentiated from placebo. There were no serious adverse events (SAEs), no severe AEs, no treatment related adverse events (TRAEs) in more than one subject, no TRAEs leading to discontinuation, and no clinically relevant changes in vital signs, laboratory tests and ECGs.

Next Steps

The Company's KT-621 BroADen Phase 1b trial in moderate to severe AD patients is ongoing, with data expected to be reported in the fourth quarter of 2025. Two parallel Phase 2b trials in AD and asthma are planned to start in 4Q25 and 1Q26, respectively. These studies are intended to accelerate KT-621 development and enable dose selection for subsequent parallel Phase 3 registration studies across multiple Th2 dermatology, gastroenterology and respiratory indications.