KT-474 is a first-in-class IRAK4 degrader in development for the treatment of immune-inflammatory diseases with significant patient need, such as hidradenitis suppurativa and atopic dermatitis.

Kymera Therapeutics, Inc. KT-474 (SAR444656), a potent, highly selective, orally bioavailable IRAK4 degrader, is showing early promise in Hidradenitis Suppurativa (HS) and Atopic Dermatitis (AD), according to a Phase 1 Trial published online in Nature Medicine.

There was a reduction of disease-relevant inflammatory biomarkers in the blood and skin of HS and AD patients that was associated with improvement in skin lesions and symptoms, the study  showed. Kymera’s partner Sanofi conducting Phase 2 clinical trials of KT-474 (SAR444656) in HS and AD. 

The data show that KT-474 administered to HS and AD patients had safety, pharmacokinetics and pharmacodynamics similar to healthy volunteers (HVs), achieved robust IRAK4 degradation in blood and skin lesions associated with a systemic anti-inflammatory effect, and showed activity in HS and AD. 

“The Phase 1 results published in Nature Medicine highlight the transformative potential of IRAK4 degradation in TLR/IL-1R-driven, high unmet need inflammatory diseases, with KT-474 demonstrating a favorable safety profile, broad anti-inflammatory effect including downregulation of disease-relevant gene transcripts in skin lesions, and promising impact on skin lesions and symptoms in HS and AD patients after only 28 days of dosing,” says Jared Gollob, MD, Chief Medical Officer, Kymera Therapeutics, in a news release. “These positive data show TPD’s unique ability to unlock this critical pathway, and we look forward to sharing additional updates as our partner Sanofi advances the Phase 2 clinical trials of KT-474 in HS and AD.”

KT-474 (SAR444656) was studied in a Phase 1 randomized, placebo-controlled, single and multiple ascending dose trial to assess safety, pharmacokinetics, pharmacodynamics and clinical activity (NCT04772885). 105 healthy volunteers (HVs) were enrolled in the placebo-controlled single and multiple ascending dose escalation cohorts (SAD and MAD) and 21 HS and AD patients were enrolled into an open-label patient cohort. KT-474 was administered as a single dose and then daily for 14 days in the fasted state in HVs followed by dosing for 28 days in the fed state in patients with HS or AD. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600–1600 mg and after 14 daily doses of ≥95% at 50–200 mg. In patients treated with 75 mg of KT-474, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. 

Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of HS and AD patients associated with improvement in skin lesions and symptoms. KT-474 was well-tolerated with no drug-related infections. These results from the first published clinical trial using a heterobifunctional degrader provide initial proof of concept for KT-474 in HS and AD to be further confirmed in placebo-controlled Phase 2 trials.