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.

由 IL-1 受体相关激酶 4 (IRAK4) 介导的 Toll 样受体驱动和白细胞介素 1 (IL-1) 受体驱动的炎症参与化脓性汗腺炎 (HS) 和特应性皮炎 (AD) 的病理生理学。 KT-474 (SAR444656) 是一种 IRAK4 降解剂，在一项随机、双盲、安慰剂对照 1 期试验中进行了研究，其主要目标是安全性和耐受性。次要目标包括中度至重度 HS 患者和中度至重度 AD 患者的药代动力学、药效学和临床活性。 KT-474 在 105 名健康志愿者 (HV) 中以单剂量给药，然后每天给药 14 天，然后在由 21 名患者组成的开放标签队列中给药 28 天。在 HV 血液中观察到 IRAK4 降解，单剂量 600-1,600 mg 后平均降低 ≥93%，14 日剂量 50-200 mg 后平均降低 ≥95%。在患者中，血液中也实现了类似的 IRAK4 降解，并且 IRAK4 在皮肤病变中正常化，相对于 HV 而言，IRAK4 过度表达。 HS 和 AD 患者的血液和皮肤中与疾病相关的炎症生物标志物减少，并且与皮肤病变和症状的改善相关。没有发生与药物相关的感染。据我们所知，这些结果是首次发表的使用异双功能降解剂的临床试验，为 KT-474 在 HS 和 AD 中的概念提供了初步证明，并将在更大规模的试验中得到进一步证实。 ClinicalTrials.gov 标识符：NCT04772885。