S. Lee, A. Minnich, D. D. Desai, Y. Shen, H. Tang, J. Postelnek, W. L. Trigona, R. Townsend, B. Murthy, R. L. Parsons; Bristol-Myers Squibb, Princeton, NJ

BACKGROUND: BMS-938790 is a pegylated adnectin targeting human IL-23 which is being developed for the treatment of inflammatory diseases. The present study was intended to assess the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, safety and tolerability of BMS-938790 in healthy subjects.
METHODS: A single, ascending dose, randomized, placebo-controlled, double blind study was conducted in 56 healthy subjects. The tested dose levels ranged from 4 through 100 mg as a subcutaneous (SC) administration along with 50 and 100 mg as an intravenous (IV) administration.
RESULTS: Exposure to BMS-938790 (Cmax and AUCs) was dose proportional with a half-life of ~200 hours. Absolute bioavailability of BMS-938790 was ~50% following a SC administration. BMS-938790 inhibited the phosphorylation of STAT3 (pSTAT3) stimulated by ex-vivo IL-23 in a dose-dependent manner. PK/PD analysis showed the BMS-938790 concentration-dependent inhibition of pSTAT3 (IC50 of ~500 ng/mL) with a hysteresis loop, suggesting time-dependent changes in the effect of BMS-938790 on pSTAT3. Further mechanistic PK/PD modeling demonstrated that the time-dependent changes could be associated with increase in free IL-23 following the administration of BMS-938790. Approximately 10% of subjects developed the positive immunogenicity. No deaths, serious adverse events, or adverse events leading to discontinuation were observed in any of the treatment groups.
CONCLUSION: A single administration of BMS-938790 in healthy subjects up to doses of 100 mg was well tolerated without dose-limiting toxicity. The mechanistic PK/PD model adequately described the relationship between the concentration of BMS-938790 and pSTAT3 responses along with changes in free IL-23.