IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial

Abstract

Toll-like receptor–driven and interleukin-1 (IL-1) receptor–driven inflammation mediated by IL-1 receptor–associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). 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 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600–1,600 mg and after 14 daily doses of ≥95% at 50–200 mg. 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: NCT04772885.

The oral IRAK4 inhibitors zabedosertib and BAY1830839 suppress local and systemic immune responses in a randomized trial in healthy male volunteers

“…Our data also suggested a similar level of pharmacological activity compared with an IRAK4 degrader, which suppressed TLR4-and TLR7/8-mediated cytokine release in peripheral blood mononuclear cells from healthy volunteers. 29 While the clinical relevance of the differences observed between BAY1834845 (zabedosertib) and BAY1830839 in the described suppression of cytokine release remains unclear and warrants further investigation, this indirect comparison with available data from other IRAK4-targeting molecules clearly suggests a competitive profile for zabedosertib and BAY1830839.…”

Rethinking Hidradenitis Suppurativa Management: Insights into Bacterial Interactions and Treatment Evolution

“…Out of 12 HS patients, 10 with moderate to severe disease and 2 with severe disease, 42–50% achieved HiSCR50. Results were observed across 28 days followed by a 2-week follow-up [ 48 ]. KT-474 is currently in phase II for its treatment of HS [ 49 ].…”

Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839

“…Finally, Kymera advanced IRAK4 degrader KT-474 to Phase 2 clinical trials for the treatment of atopic dermatitis and hidradenitis suppurativa (ClinicalTrials.gov Identifiers: NCT06058156 and NCT06028230, studies initiated by collaborator Sanofi). Results from the Phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT04772885) were recently published …”