KT-621 Shows Strong Phase 1 Results as First-in-Class Oral STAT6 Degrader

At the 2025 European Academy of Dermatology & Venereology (EADV) Congress in Paris, France, Kymera Therapeutics presented new clinical and preclinical findings for KT-621, a first-in-class oral degrader of STAT6. Data from the phase 1 healthy volunteer trial, alongside preclinical work comparing KT-621 with dupilumab, highlighted the compound’s potential as an oral systemic therapy for common Th2-driven immuno-inflammatory diseases, including atopic dermatitis (AD).¹

Mechanism of Action and Rationale
KT-621 employs targeted protein degradation (TPD), a therapeutic modality designed to eliminate disease-causing proteins rather than inhibit them. This approach leverages the ubiquitin-proteasome system to selectively degrade STAT6, a transcription factor that mediates IL-4 and IL-13 signaling. This pathway is central to Th2 inflammation and validated by existing biologics, such as dupilumab, which block IL-4/IL-13 receptors.² Unlike conventional inhibitors, KT-621 acts catalytically, with a single molecule capable of degrading multiple STAT6 proteins, thereby enabling deep and continuous pathway blockade similar to injectable biologics but in an oral formulation.

Study Design and Pharmacokinetics
The phase 1 trial was a randomized, double-blind, placebo-controlled study conducted in healthy volunteers. It comprised single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. In the SAD arm, 48 participants received doses ranging from 6.25 mg to 800 mg. In the MAD arm, 70 participants received once-daily dosing from 1.5 mg to 200 mg over 14 days. The primary endpoint was safety and tolerability, with pharmacokinetics (PK), pharmacodynamics (PD), and biomarker analyses as secondary and exploratory endpoints.

KT-621 exhibited rapid absorption with a time-to-maximum concentration of 2 to 4 hours and a half-life of 9 to 36 hours depending on dose. Steady-state levels were achieved by day 4 of daily dosing.

STAT6 Degradation in Blood and Skin
KT-621 achieved >90% mean STAT6 degradation in blood at all doses above 1.5 mg. Complete degradation, defined as >95% reduction or below assay detection levels, was observed at single doses ≥75 mg and all MAD doses ≥50 mg. Importantly, similar degradation was demonstrated in skin biopsies, confirming systemic and tissue-level activity. Degradation persisted up to several days after dosing, with recovery occurring within 1 to 2 weeks post-treatment

Biomarker Modulation
Th2-relevant biomarkers were significantly reduced. Median TARC (a chemoattractant for Th2 cells) decreased by up to 37%, while Eotaxin-3 (an eosinophil chemoattractant) was reduced by up to 63% at day 14. These reductions were consistent with or exceeded effects observed in dupilumab studies, despite the short treatment duration and the fact that participants were healthy volunteers with low baseline biomarker levels.

Safety and Tolerability
KT-621 was generally well tolerated, with a safety profile comparable to placebo. No serious or severe adverse events were reported, and mild adverse events did not lead to discontinuations. No clinically relevant changes were seen in vital signs, laboratory values, or ECGs.

Preclinical Data
Complementary preclinical findings presented at EADV demonstrated that KT-621 modulated AD-relevant gene expression in IL-4-stimulated keratinocytes in a manner comparable to dupilumab. In mouse and non-human primate models, oral dosing achieved complete STAT6 degradation and inhibition of Th2 inflammation, further validating the mechanism of action.

Next Steps in Development
The ongoing BroADen phase 1b open-label trial is evaluating KT-621 in patients with moderate to severe AD, with results anticipated in Q4 2025. Kymera also plans to initiate phase 2b studies in AD and asthma in late 2025 and early 2026, respectively. These trials are designed to accelerate development toward parallel Phase 3 programs across multiple Th2-driven dermatologic, respiratory, and gastrointestinal indications.

Conclusion
The phase 1 results suggest KT-621 is the first oral agent capable of fully degrading STAT6, producing biomarker changes comparable to biologics, and maintaining a favorable safety profile. If confirmed in patient studies, KT-621 could offer an oral alternative to injectable therapies for chronic Th2-driven conditions, potentially broadening access and convenience for patients.

References

1. Kymera Therapeutics announces late-breaking oral presentations on KT-621, a first-in-class, oral STAT6 degrader, at the European Academy of Dermatology & Venereology and European Respiratory Society Congresses. News release. Kymera Therapeutics. Published September 18, 2025. Accessed September 18, 2025. https://investors.kymeratx.com/news-releases/news-release-details/kymera-therapeutics-announces-late-breaking-oral-presentations
2. Simpson EL, Silverberg JI, Worm M, et al. Dupilumab treatment improves signs, symptoms, quality of life, and work productivity in patients with atopic hand and foot dermatitis: Results from a phase 3, randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2024;90(6):1190-1199. doi:10.1016/j.jaad.2023.12.066