B-102 Results from a First-In-Human study with BNZ-1, a novel, selective inhibitor of IL-2, IL-9, and IL-15 at the common gamma-chain receptor, in clinical development for the treatment of HAM/TSP and T-cell malignancies

Aberrant signaling of IL-2, IL-9, and IL-15, members of the γγγc cytokine family, is involved in multiple human diseases (eg, T-cell malignancies, GvHD, HAM/TSP) that are not effectively or safely treated by the currently available anti-cytokine approaches. BNZ-1 is a selective inhibitor of IL-2, IL-9 and IL-15 signaling through γγc, without altering IL-4, -7, or -21. In this open-label, single-dose study (NCT03046459), 18 healthy adults (n = 3/dose) received a single IV dose of 0.2, 0.4, 0.8, 1.6, 3.2 or 6.4 mg/kg and were monitored for 30 days. BNZ-1 was well-tolerated with a good safety profile (no serious/severe AEs, no DLTs, and no clinically-significant changes on labs, vital signs or ECGs). BNZ-1 exposure was dose proportional with an elimination t1/2 of ∼5 days, supporting weekly or every other week dosing. PD activity was characterized by flow cytometry of Tregs (IL-2), NK cells (IL-15) and CD8+ central memory T-cells (Tcm; IL-2 & IL-15) in PBMCs from days 4, 15 and 31. Tregs were decreased by 50%–60% after doses of 0.4–1.6 mg/kg on day 4 and by 80%–93% at 3.2 and 6.4 mg/kg on day 15. On day 4 NK cells decreased by 20%, 40% and 60% at 0.2, 0.4 and 0.8 mg/kg, respectively, and plateaued at 70%–80% decreases at doses a1.6 mg/kg. Tcm were decreased at day 4 for the top 3 doses that continued to decline to day 15 when all doses, except 0.2 mg/kg, showed a mean decrease ranging from 10% to 81% that trended with dose. Tregs, NK cells, and Tcm returned to/toward baseline by day 31. CD4+ and CD8+ T-cells, B-cells, and monocytes were unchanged at all time points. These clinical data suggest that BNZ-1 is a highly-active, selective immunomodulator that safely decreases Tregs, NKs and Tcm, while sparing the major leukocyte populations.