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KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14\u2009d in 105 healthy volunteers (HVs), followed by dosing for 28\u2009d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of \u226593% at 600\u20131,600\u2009mg and after 14 daily doses of \u226595% at 50\u2013200\u2009mg. In patients, 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 patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is 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 larger trials. ClinicalTrials.gov identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04772885\">NCT04772885<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41591-023-02635-7","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T17:02:08Z","timestamp":1699894928000},"page":"3127-3136","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 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