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A First-in-Human Phase I Study to Evaluate the Safety, Tolerability, Pharmacokine�cs and Pharmacodynamics of a Novel An�-Interleukin 1 Biologic Agent, Rph-104, in Healthy Subjects Ahmet Gul 1 , Sibel Ulker 2 , Recep Selim Senturk 2 , Ugur Onsel Turk 2 , Cemil Gurgun 2 , Yan Lavrovsky 3 , Mikhail Samsonov 4 , Sebnem Ozen 5 , Serdar Al�nel 5 1 Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey. 2 Ege University Drug Development and Pharmacokine�cs Research and Applica�on Centre (ARGEFAR),İzmir, Turkey. 3 R-Pharm Overseas, Inc., San Diego, USA. 4 R-Pharm JSC, Moscow, Russia. 5 TRPHARM ilac A.S. , Istanbul, Turkey. BACKGROUND Figure 1. RPH-104 serum concentra�ons (mean, linear scale) CONCLUSION: Table 2. Overview of adverse event profile: Adverse events - Safety popula�on Table 1. Pharmacokinetic (PK) parameters of RPH-104 at 4 mg, 20 mg, 40 mg, 80 mg and 160 mg dose levels METHODS RESULTS Interleukin-1 (IL-1) is highly ac�ve pro-inflammatory cytokine, which is responsible for clinical and laboratory findings in hereditary and acquired auto-inflammatory disorders. Blocking IL-1 ac�vity in these condi�ons results in a rapid and sustained reduc�on in inflammatory ac�vity and disease severity. RPH-104, a novel heterodimeric fusion protein containing IL-1R1 and IL-1RAcP linked to immunoglobulin heavy chains, highly selec�vely 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 pharmacokine�c (PK) and pharmacodynamic (PD) parameters of RPH-104. A total of 35 healthy volunteers (HVs) 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 HVs in each. Each HVs was hospitalized for 72 hours and followed up to 60 days a�er subcutaneous (SC) injec�on of RPH-104. Evalua�on of safety data a�er each subgroup was performed by the Independent Data Monitoring Commi�ee (IDMC); and the next subgroup could be dosed when the previous dose results did not reveal any risk safety concern. Totally 35 HVs were dosed, 5 HVs were administered RPH104 and 2 HVs were administered placebo (saline) in each cohort; All 35 HVs were included in the safety analysis but 33 HVs 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 (Table 2). All AE were of mild intensity. The most frequent AEs both in RPH104 and placebo group were headache (44%-30%), nausea (12%-30%) and nasopharyngi�s (8%-20%) respec�vely. 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 elimina�on half-life (t1/2z) was similar in all cohorts. Ini�al 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, administra�on of RPH-104 resulted in a decrease in Serum Amyloid A levels star�ng from the first hour post-dose in 20 mg cohort, and they remained suppressed throughout the study which may suggest the first biologic ac�vity of RPH-104. *Units: Cmax (ng /mL); AUC (0-t) (hr*ng /mL); AUC (0-∞) (hr*ng /mL); t1/2 (hr); AUC Ext (%); tmax (hr). Group Treatment Variable N Mean SD Min Median Max Cohort 1 (4 mg) RPH-104 C max 5 198 89.1 116 158 318 t max 5 115 43.0 94.4 96.0 192 AUC (0-t) 5 74500 24700 50600 64800 107000 AUC (0-∞) 5 88100 28300 62200 76300 127000 t 1/2z 5 245 9.50 235 242 256 Cohort 2 (20 mg) RPH-104 C max 5 1280 402 904 1060 1830 t max 5 86.4 21.5 48.0 96.0 96.2 AUC (0-t) 5 430000 95700 302000 436000 531000 AUC (0-∞) 5 505000 105000 360000 517000 621000 t 1/2z 5 249 6.08 240 251 255 Cohort 3 (40 mg) RPH-104 C max 3 1650 257 1360 1730 1860 t max 3 136 49.9 96.0 120 192 AUC (0-t) 3 661000 158000 545000 597000 840000 AUC (0-∞) 3 804000 196000 684000 697000 1030000 t 1/2z 3 255 43.1 218 244 302 Cohort 4 (80 mg) RPH-104 C max 5 5120 1410 4130 4560 7600 t max 5 96.0 17.0 72.0 96.0 120 AUC (0-t) 5 1610000 317000 1210000 1580000 1990000 AUC (0-∞) 5 1850000 353000 1380000 1890000 2190000 t 1/2z 5 235 22.8 220 221 273 Cohort 5 (160 mg) RPH-104 C max 5 10300 4770 4490 11200 17000 t max 5 106 21.5 72.0 120 120 AUC (0-t) 5 3390000 1450000 1600000 3420000 5330000 AUC (0-∞) 5 3990000 1810000 1910000 3810000 6520000 t 1/2z 5 243 40.4 194 242 292 * RPH-104 was administered first �me in humans, and it was considered safe and well tolerated following single dose SC administra�on at different dose levels. A linear PK was observed. Poster Presenta�on at 2017 ACR/ARHP Annual Mee�ng, San Diego, California, USA - November 4–8, 2017 - This study was sponsored by TRPHARM İlaç A.Ş., Istanbul, Turkey – Disclosures: None.
