Kymera Therapeutics announces first-in-human results for Phase 1 trial of KT-621

Kymera Therapeutics (KYMR) announced clinical results from the Phase 1 healthy volunteer study of KT-621, its first-in-class, oral STAT6 degrader medicine. The KT-621 Phase 1 healthy volunteer trial was a double-blind, placebo-controlled study that enrolled a total of 118 subjects. The trial consisted of single ascending dose and multiple ascending dose cohorts. The trial objective was to evaluate the safety and tolerability of escalating single and multiple ascending daily oral doses of KT-621. The trial also included pharmacokinetic measures as secondary endpoints. Exploratory endpoints included STAT6 protein levels in blood and skin and Th2 biomarkers. There were 48 healthy participants enrolled in SAD, with 8 per cohort randomized 6:2. The SAD doses, which were administered as a single dose, ranged from 6.25 to 800 mg. There were 70 healthy subjects enrolled in MAD, with 12 per cohort randomized 9:3 except for the 12.5 mg cohort which randomized 10 participants. The MAD doses, which were administered once daily for 14 days, ranged from 1.5 to 200 mg. 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. 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 greater than or equal to95% or when most subjects’ STAT6 levels are reduced below the Lower Limit of Quantification, 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 greater than90% across all SAD doses starting at 6.25 mg. All SAD cohorts at doses of 75 mg or greater achieved greater than95% 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 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 greater than or equal to50 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 for doses above 1.5 mg. Steady-state, complete degradation, associated with greater than or equal to95% mean STAT6 degradation with STAT6 levels below LLOQ in multiple subjects, was achieved at doses greater than or equal to50 mg. 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 patients even at 52 weeks. The safety profile of KT-621 was undifferentiated from placebo. There were no serious adverse events, no severe AEs, no treatment related adverse events in more than one subject, no TRAEs leading to discontinuation, and no clinically relevant changes in vital signs, laboratory tests and ECGs. 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.