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 .
Subject(s)
Dermatitis, Atopic , Hidradenitis Suppurativa , Humans , Hidradenitis Suppurativa/drug therapy , Dermatitis, Atopic/drug therapy , Interleukin-1 Receptor-Associated Kinases , Treatment Outcome , Skin/pathology , Double-Blind Method , Severity of Illness IndexABSTRACT
OBJECTIVE: The aim of this study was to compare phenobarbital (PB) versus lorazepam (LZ) in the treatment of alcohol withdrawal in the emergency department (ED) and at 48 hours. METHODS: Prospectively, randomized, consenting patients were assessed using a modified Clinical Institute Withdrawal Assessment (CIWA) score and given intravenous PB (mean, 509 mg) or LZ (mean, 4.2 mg). At discharge, LZ patients received chlordiazepoxide (Librium), and PB patients received placebo. RESULTS: Of 44 patients, 25 received PB, and 19 LZ. Both PB and LZ reduced CIWA scores from baseline to discharge (15.0-5.4 and 16.8-4.2, P < .0001). There were no differences between PB and LZ in baseline CIWA scores (P = .3), discharge scores (P = .4), ED length of stay (267 versus 256 minutes, P = .8), admissions (12% versus 16%, P = .8), or 48-hour follow-up CIWA scores (5.8 versus 7.2, P = .6). CONCLUSION: Phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.
