Oral STAT6 Degrader KT-621 Delivers Biologics-Like Efficacy in Moderate to Severe AD

Kymera Therapeutics presented late-breaking phase 1b data at the 2026 American Academy of Dermatology Annual Meeting in Denver, Colorado, demonstrating that KT-621, a first-in-class oral STAT6 degrader, produced deep target engagement, broad suppression of type 2 inflammatory biomarkers, and meaningful clinical improvements in adults with moderate to severe atopic dermatitis (AD), all with a favorable safety profile across both doses studied.¹

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Background and Mechanism

Presenter Mahta Mortezavi, MD, explained that KT-621 exploits targeted protein degradation, a mechanistic approach that uses the E3 ubiquitin-proteasome system to eliminate target proteins rather than merely blocking their function. As Mortezavi noted, unlike conventional small-molecule inhibitors, which require continuous high drug exposure to maintain pharmacodynamic effects, degraders act catalytically—a single molecule can sequentially degrade multiple copies of the target protein, enabling sustained pathway blockade at low doses.¹ Mortezavi is a physician-scientist at Kymera Therapeutics and an assistant professor of medicine at the University of Pittsburgh in Pennsylvania. She is triple board-certified in allergy/immunology, rheumatology, and internal medicine.

The target, STAT6, is the obligate transcription factor downstream of both IL-4 and IL-13 signaling, the same pathway validated clinically by dupilumab (Dupixent; Regeneron and Sanofi) across multiple type 2 diseases, including AD, asthma, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Despite this well-established biology, no oral therapy has previously achieved selective STAT6 inhibition in patients.¹

“If you don’t have STAT6, you can’t signal through IL-4, IL-13—that’s been clearly shown. So if you can get rid of STAT6, you can phenocopy what drugs like [dupilumab] can do, but potentially do it with an oral drug,” said Jared Gollob, MD, chief medical officer at Kymera Therapeutics, in an interview with Dermatology Times.²

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Study Design

The open-label, single-arm phase 1b BroADen trial (NCT03431610) enrolled 22 adults with moderate to severe AD (Eczema Area and Severity Index [EASI] ≥ 16; Validated Investigator Global Assessment scale for Atopic Dermatitis [vIGA-AD] ≥ 3; ≥ 10% body surface area involvement, documented topical corticosteroid failure) across 2 sequential cohorts. Ten patients received KT-621 100 mg once daily, and 12 received 200 mg once daily, each for 28 days, with a 14-day follow-up period. Prior biologic use was permitted after washout.¹

Biomarker Results

Median STAT6 degradation reached 98% in peripheral blood in both dose cohorts and was sustained throughout the 28-day treatment period. In lesional skin biopsies, median degradation was 94% across both groups, with multiple patients’ STAT6 levels falling below the lower limit of quantification by targeted mass spectrometry.¹

Gollob described the 94% STAT6 degradation as closely mirroring pharmacodynamic effects seen in the healthy volunteer cohort, and a "really nice translation from healthy volunteers into patients."²

Downstream biomarker effects were equally compelling, the presenters noted. TARC (CCL17), a validated circulating marker of type 2 inflammation, decreased by a median of up to 74% in patients with higher baseline levels. Eotaxin-3 (CCL26), a highly specific IL-4/IL-13 pathway cytokine, declined by 62% to 73% across the cohorts.

Investigators reported what they described as the "first known demonstration of IL-31 reduction in blood of AD patients in response to IL-4/IL-13 pathway inhibition," with serum IL-31 decreasing by approximately 54% to 56% at the end of treatment. IgE showed modest reductions of 5% to 14%, which the study authors noted is expected given the extended timeline required to deplete IgE-switched B cells and plasma cells.¹

Clinical Efficacy

Mean EASI scores declined by 63% from baseline by day 29 across both dose groups, with reductions apparent as early as day 8 and no plateau observed during the treatment window, suggesting continued improvement with longer therapy. Overall, 76% of patients achieved EASI 50, and 29% achieved EASI 75. A total of 19% reached a vIGA-AD score of 0 or 1 (clear or almost clear) at 4 weeks. Total body surface area involvement fell by a mean of up to 55%, peak pruritus Numerical Rating Scale improved by up to 47%, and patient-reported disease burden, as determined by Patient-Oriented Eczema Measure, surpassed the minimum clinically important difference threshold of a 4-point change.¹

Safety

There were no serious, severe, or treatment-emergent adverse events related to KT-621 or leading to discontinuation. Critically, there were no cases of conjunctivitis or any ocular disorder, herpes infections, or arthralgias—adverse events associated with existing IL-4/IL-13-targeted biologics. No clinically meaningful changes were observed in vital signs, laboratory values, or electrocardiograms.¹

Looking Ahead

The phase 2b BROADEN2 trial (NCT07217015) is currently enrolling approximately 200 adult and adolescent patients aged 12 to 75 years with moderate to severe AD in a randomized, double-blind, placebo-controlled, dose-ranging design across 16 weeks of treatment, followed by a 52-week open-label extension. Data are expected by mid-2027, with the aim of selecting a dose to support phase 3 studies across dermatological and gastrointestinal indications.^1,2

“KT-621 presents a potential opportunity for a biologic-like efficacy in a pill form that will be attractive to many patients, including children and adolescents who may be afraid of needles. We are eager to see long-term studies of safety and efficacy to prove this for our patients in need of oral medications,” said Emma Guttman-Yassky, MD, PhD, dermatologist and chair of the Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York, New York, in a statement to Dermatology Times.

References

1. Gollob J, Paleczny H, Blankinship M, et al. Clinical activity and safety of KT-621, an oral STAT6 degrader, in moderate-to-severe atopic dermatitis: phase 1b trial results. Presented at: 2026 American Academy of Dermatology Annual Meeting; March 27-31, 2026; Denver, CO.
2. Hebebrand M, Gollob J. 85% of biologic-eligible AD patients left behind — can KT-621 reach them. Dermatology Times. April 1, 2026. Accessed May 13, 2026. https://www.dermatologytimes.com/view/85-of-biologic-eligible-ad-patients-left-behind-can-kt-621-reach-them-