Safety, tolerability and efficacy of repeated intravenous infusions of KHK4083, a fully human anti-OX40 monoclonal antibody, in Japanese patients with moderate to severe atopic dermatitis.

BACKGROUND: KHK4083, a fully human anti-OX40 monoclonal antibody, is a potential novel therapeutic option for moderate to severe atopic dermatitis (AD), targeting the immunopathogenic pathways. OBJECTIVE: Assess the safety and tolerability of repeated doses of KHK4083 in patients with moderate to severe AD, and investigate the pharmacokinetics and immunogenicity of KHK4083. Additionally, assess the clinical efficacy and pharmacodynamics as exploratory objectives. METHODS: In this phase 1, single-center, open-label, repeated-dose study, a total of 22 patients received KHK4083 10 mg/kg IV on Day 1, Day 15 and Day 29, and were followed until Day 155. RESULTS: There were no deaths, serious adverse events (SAEs), or discontinuations due to adverse events (AEs). Common treatment-emergent AEs were mild or moderate pyrexia (11 patients, 50.0 %), and chills (8 patients, 36.4 %). No clinically meaningful changes in the laboratory values, vital signs, and electrocardiogram recordings were observed. The Cmax was 267 ± 53 µg/mL and the t1/2 was 303 ± 88 h at Day 29. The overall assessment of antibodies against KHK4083 (immunogenicity) showed low positive responses. Continued improvement in the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA) scores were observed throughout the study. The mean and median percent changes in thymus and activation-regulated chemokine (TARC) continued to decrease over time to -70.4 and -78.8 % until Day 155. CONCLUSION: Repeated intravenous infusion of KHK4083 had an acceptable safety profile in patients with moderate to severe AD. Sustained improvement in the symptoms of AD was observed after completion of KHK4083 treatment.

Chills in 'early sepsis': good for you?

We evaluated the predictive value of chills, bacteraemia and endotoxaemia for in-hospital mortality and survival at 5-10 years long-term follow-up in a prospective cohort of 'early sepsis' patients presenting with fever resulting from community-acquired pneumonia or pyelonephritis. Febrile patients with chills had bacteraemia more often (RR 3.1, 95% CI 1.8-5.4) than those without chills. Neither chills nor bacteraemia were significantly related to in-hospital mortality, but patients with endotoxaemia had a higher in-hospital mortality rate than those without endotoxaemia. Patients with chills had a significantly higher survival rate at long-term follow-up than those without chills on admission: the estimated risk of dying was 0.644 (95% CI 0.43-0.95, P = 0.029) for an individual with chills, compared to a person without chills, adjusting for the other factors [age cohort, underlying disease and the pro-inflammatory response in the blood, i.e. tumour necrosis factor-alpha (TNF-alpha) and blood leucocyte number, as scored on hospital admission] in the Cox proportional hazards model. Chills may characterize a patient subpopulation that upon pulmonary and urinary tract infection is able to raise a more rapid and/or efficient host response.