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Zabedosertib, the interleukin-1 receptor-associated kinase-4 (IRAK4) inhibitor, is in clinical development as an oral therapeutic for immune-mediated inflammatory diseases and was thoroughly investigated in several phase 1 studies in healthy male volunteers. Pharmacokinetics, safety, and tolerability of zabedosertib were characterized in two clinical phase 1 studies with single oral doses up to 480 mg and multiple oral doses up to 200 mg twice daily over 10 consecutive days. The absolute oral bioavailability was determined in a third study using the intravenous microtracer methodology. Zabedosertib showed good safety and tolerability without dose-limiting toxicities or severe infections. An under-proportional increase in exposure was observed with increasing dose. The observed mean accumulation ratios for the area under the concentration-time curve of 1.04-1.62 were lower than expected based on the dose-independent terminal half-life of 19-30 h. The absolute oral bioavailability was 74% at a dose of 120 mg. No food effect was observed. The pharmacokinetics could be described with a one-compartmental population-pharmacokinetic model with first-order elimination, dose-dependent bioavailability, and capacity-limited binding in plasma. The estimation of target occupancy, based on potency for IL-6 inhibition as a representative pro-inflammatory cytokine in a human whole-blood assay, target residence time, and unbound plasma pharmacokinetics, indicated ∼80% target occupancy over the dosing interval after the maximum feasible dose of 120 mg twice daily. This dose was the highest dose providing relevant exposure increases. Based on the projected target occupancy, favorable pharmacokinetics, and safety profile, as well as on distinct pharmacodynamic effects in a proof-of-mechanism study, zabedosertib 120 mg twice daily was selected for further clinical development in patient studies. https://clinicaltrials.gov/, identifier SAD: NCT03054402, MAD: NCT03493269 (part 1), FE/abs.BA study NCT03244462 (EudraCT numbers: 2016-002668-15, 2017-001817-10, and 2016-004393-18).

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.

PurposeTo determine the prevalence of and identify factors associated with visual impairment and blindness in institutionalized elderly in Germany.MethodsIn this prospective multicenter cross-sectional study, ophthalmic health care need and provision were investigated in institutionalized elderly in 32 nursing homes in Germany. All participants underwent a standardized examination including medical and ocular history, refraction, visual acuity testing, tonometry, biomicroscopy, and dilated funduscopy. A standardized questionnaire was used to identify factors associated with eye healthcare utilization, visual impairment and/or blindness.ResultsVisual acuity of 566 (94.3%; 413 women and 153 men) of a total of 600 institutionalized elderly was determined. Mean age of the included patients was 82.9 years (± 9.8). Of all participants, 30 (5.3%; 95% CI 3.4–7.2%) were blind and 106 (18.7%; 95% CI 15.5–21.9%) were moderately or severely visually impaired according to the World Health Organization definition. The 136 blind and moderately or severely visually impaired participants were older (OR, Odds Ratio = 1.1, 95% CI 1.0–1.1; p < 0.001), and more likely to have reduced mobility (OR = 12.6, 95% CI 2.8–57.6; p = 0.001).ConclusionA high proportion of blindness and visual impairment was found amongst nursing home residents. Age and reduced mobility were factors associated with an increased likelihood of blindness and visual impairment. Any surveys of blindness and visual impairment excluding nursing homes may considerably underestimate the prevalence of visual impairment and blindness.

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