Background/Purpose: Interleukin-1 (IL-1) is highly active pro-inflammatory cytokine, which is responsible for clinical and laboratory findings in hereditary and acquired auto-inflammatory disorders. Blocking IL-1 activity in these conditions results in a rapid and sustained reduction in inflammatory activity and disease severity. RPH-104, a novel heterodimeric fusion protein containing IL-1R1 and IL-1RAcP linked to immunoglobulin heavy chains, highly selectively binds IL-1β, but can also bind IL-1α and IL-1Ra with lower affinity.  In this First-in-Human study, we aimed to evaluate safety as well as pharmacokinetic (PK) and pharmacodynamic (PD) parameters of RPH-104. Methods: A total of 35 healthy volunteers (HV) were enrolled in this randomized, double-blind, placebo-controlled, single-dose study. Five different dosages (4 mg, 20 mg, 40 mg, 80 mg and 160 mg) were tested in cohorts consisted of 7 HV in each. Each HV was hospitalized for 72 hours and followed up to 60 days after subcutaneous (SC) injection of RPH-104. Evaluation of safety data after each subgroup was performed by the Independent Data Monitoring Committee; and the next subgroup could be dosed when the previous dose results did not reveal any risk safety concern. Results: Totally 35 HV were dosed, 5 HV were administered RPH104 and 2 HV were administered placebo (saline) in each cohort; All 35 HV were included in the safety analysis but 33 HV were included in PK analysis (2 drop outs). Totally 70 adverse events (AE) were reported, none of them were serious. None of the AE was related to the study drug nor leaded to subject withdrawal. All AE were of mild intensity. RPH-104 was safe and well tolerated in terms of AE and other clinical and laboratory parameters at all dose levels. PK parameters of RPH-104 are summarized at Table 1 and Figure 1. Mean terminal elimination half-life (t_1/2 ) was similar in all cohorts.  Initial results suggest linear PK for RPH-104 at all dose levels. PD analysis are ongoing. However, according to the PD analysis of the first 2 cohorts, administration of RPH-104 resulted in a decrease in Serum Amyloid A levels starting from the first hour post-dose in 20 mg cohort, and they remained suppressed throughout the study which may suggest the first biologic activity of RPH-104. Conclusion: RPH-104 was administered first time in humans, and it was considered safe and well tolerated following single dose SC administration at different dose levels. A linear PK was observed.