RESUMEN
This study evaluated and characterized the pharmacological activity of the orally administered interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment. The inflammatory response was evaluated by laser speckle contrast imaging (skin perfusion) and multispectral imaging (erythema). At Day 7, participants received 1 ng/kg intravenous lipopolysaccharide (LPS). Circulating inflammatory proteins, leukocyte differentiation, acute phase proteins, and clinical parameters were evaluated before and after the systemic LPS challenge. Treatment with BAY1834845 significantly reduced the mean IMQ-induced skin perfusion response (geometric mean ratio [GMR] vs. placebo: 0.69 for BAY1834845, 0.70 for prednisolone; both p < 0.05). Treatment with BAY1834845 and BAY1830839 significantly reduced IMQ-induced erythema (GMR vs. placebo: 0.75 and 0.83, respectively, both p < 0.05; 0.86 for prednisolone, not significant). Both IRAK4 inhibitors significantly suppressed the serum TNF-α and IL-6 responses (≥80% suppression vs. placebo, p < 0.05) and inhibited C-reactive protein, procalcitonin, and IL-8 responses to intravenous LPS. This study demonstrated the pharmacological effectiveness of BAY1834845 and BAY1830839 in suppressing systemically and locally induced inflammatory responses in the same range as prednisolone, underlining the potential value of these IRAK4 inhibitors as future therapies for dermatological or other immune-mediated inflammatory diseases.
Asunto(s)
Indazoles , Quinasas Asociadas a Receptores de Interleucina-1 , Lipopolisacáridos , Piridinas , Humanos , Masculino , Eritema , Prednisolona , Imiquimod , Inmunidad , VoluntariosRESUMEN
Given the introduction of new therapies targeting specific immune pathways for atopic dermatitis (AD), information on the economic burden of AD patients is needed. Direct costs (medication use and healthcare resource utilization) and costs of productivity loss were studied in 90 adult patients with AD indicated for systemic treatment. Costs were calculated for patients with controlled (Investigator Global Assessment (IGA) 0-2) and uncontrolled (IGA 3-5) disease at inclusion. Mean (95% confidence interval (95% CI)) total direct costs were 5,191 (4,382-6,019) per patient per year (PPY), 4,401 (3,695-5,215) for patients with controlled AD vs. 6,993 (5,552-8,406), mean difference 2,593 (820-4,282) (p=0.014) for patients with uncontrolled AD. Costs of productivity loss were 10,040 (6,260-14,012) PPY for the total group, 6,886 (4,188-10,129) PPY for patients with controlled AD vs. 13,702 (6,124-22,996) for patients with uncontrolled AD, mean difference 6,816 (-1,638-16,677; p=0.148). Total costs (direct costs+costs of productivity loss) were 15,231 (11,487-19,455) PPY for the total group, 11,287 (7,974-15,436) for patients with controlled AD vs. 20,695 (14,068-34,564), mean difference 9,408 (-119-19,964) (p=0.077) for patients with uncontrolled AD. Patients with AD using systemic immunosuppressive treatment incur considerable direct costs and costs of productivity loss.