A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia

Abstract

Background: Hepcidin plays a central role in iron homeostasis and erythropoiesis. Neutralizing hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. This multicenter, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anemia.

Methods: Thirty-three patients with hepcidin levels ≥5 ng/mL received LY2787106 either every 3 weeks (19 patients, dose range 0.3-10 mg/kg) (part A) or weekly (14 patients, dose 10 mg/kg) (part B). LY2787106 PK/PD markers of iron and hematology biology were measured.

Results: LY2787106 clearance (32 mL/h) and volume of distribution (7.7 L) were independent of dose and time, leading to a dose-proportional increase in concentration with dose. Consistent dose-dependent increases in serum iron, and transferrin saturation were seen at the 3 and 10 mg/kg dose levels, typically peaking within 24 h after LY2787106 administration and returning to baseline by day 8.

Conclusions: Our findings indicate that LY2787106 was well tolerated in cancer patients with anemia and that targeting the hepcidin-ferroportin pathway by neutralizing hepcidin resulted in transient iron mobilization, thus supporting the role of hepcidin in iron regulation.

Trial registration: ClinicalTrial.gov, NCT01340976.

Keywords: Anemia; Cancer; Ferritin; Hepcidin; Iron.

Figures

Fig. 1

Study flow diagram

Fig. 2

Percent change in hemoglobin level from baseline to end of cycle 4 (week 12). Values shown are for evaluable patients in study part B who received 10 mg/kg LY2787106 weekly (QW) without and with oral iron (cohorts B1 [n = 6] and B2 [n = 7], respectively). Only patients with a baseline and postbaseline result are included; for patients who did not reach week 12, their final assessment was used

Fig. 3

LY2787106 concentration-versus-time profile (a) and clearance-versus-dose scatter plot (b)

Fig. 4

Change in serum iron level (expressed as ratio relative to baseline) versus time course following (a) a single dose and (b) multiple weekly doses (after 5th dose). Relative_Nominal_Time (h) is the protocol-scheduled time after last dose in hours presented on a log scale for greater clarity and better presentation of the earlier time point, where 168 h = 7 days = 1 week and 336 h = 14 days = 2 weeks. Data are displayed as mean ± SD

Fig. 5

Change in ferritin level (expressed as ratio relative to baseline) versus time course following (a) a single dose and (b) multiple weekly doses (after 5th dose). Relative_Nominal_Time (hr) is the protocol-scheduled time after last dose in hours presented on a log scale for greater clarity and better presentation of the earlier time point, where 168 h = 7 days = 1 week and 336 h = 14 days = 2 weeks. Data are displayed as mean ± SD

Fig. 6

Transferrin saturation (percentage) concentration-versus-time profile following (a) a single dose and (b) multiple weekly doses (after 5th dose). Relative_Nominal_Time (hr) is the protocol-scheduled time after last dose in hours presented on a log scale for greater clarity and better presentation of the earlier time point, where 168 h = 7 days = 1 week and 336 h = 14 days = 2 weeks. Data are displayed as mean ± SD

Fig. 7

Hepcidin (ng/mL) concentration-versus-time profile following (a) a single dose and (b) multiple weekly doses (after 5th dose). Relative_Nominal_Time (hr) is the protocol-scheduled time after last dose in hours presented on a log scale for greater clarity and better presentation of the earlier time point, where 168 h = 7 days = 1 week and 336 h = 14 days = 2 weeks. Data are displayed as mean ± SD