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

Saroj Vadhan-Raj, Rafat Abonour, Jonathan W. Goldman, David A. Smith, Christopher A. Slapak, Robert L. Ilaria, Ramon V. Tiu, Xuejing Wang, Sophie Callies, Joanne Cox, Jay L. Tuttle, Yiu Keung Lau, Eric J. Roeland

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article number73
JournalJournal of Hematology and Oncology
Volume10
Issue number1
DOIs
StatePublished - Mar 21 2017

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Hepcidins
Anemia
Iron
Monoclonal Antibodies
Neoplasms
Transferrin
Pharmacokinetics
Antibodies, Monoclonal, Humanized
Erythropoiesis
Hematology
Homeostasis
Bone Marrow
Safety
Serum

Keywords

  • Anemia
  • Cancer
  • Ferritin
  • Hepcidin
  • Iron

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia. / Vadhan-Raj, Saroj; Abonour, Rafat; Goldman, Jonathan W.; Smith, David A.; Slapak, Christopher A.; Ilaria, Robert L.; Tiu, Ramon V.; Wang, Xuejing; Callies, Sophie; Cox, Joanne; Tuttle, Jay L.; Lau, Yiu Keung; Roeland, Eric J.

In: Journal of Hematology and Oncology, Vol. 10, No. 1, 73, 21.03.2017.

Research output: Contribution to journalArticle

Vadhan-Raj, S, Abonour, R, Goldman, JW, Smith, DA, Slapak, CA, Ilaria, RL, Tiu, RV, Wang, X, Callies, S, Cox, J, Tuttle, JL, Lau, YK & Roeland, EJ 2017, 'A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia', Journal of Hematology and Oncology, vol. 10, no. 1, 73. https://doi.org/10.1186/s13045-017-0427-x
Vadhan-Raj, Saroj ; Abonour, Rafat ; Goldman, Jonathan W. ; Smith, David A. ; Slapak, Christopher A. ; Ilaria, Robert L. ; Tiu, Ramon V. ; Wang, Xuejing ; Callies, Sophie ; Cox, Joanne ; Tuttle, Jay L. ; Lau, Yiu Keung ; Roeland, Eric J. / A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia. In: Journal of Hematology and Oncology. 2017 ; Vol. 10, No. 1.
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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.",
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AU - Abonour, Rafat

AU - Goldman, Jonathan W.

AU - Smith, David A.

AU - Slapak, Christopher A.

AU - Ilaria, Robert L.

AU - Tiu, Ramon V.

AU - Wang, Xuejing

AU - Callies, Sophie

AU - Cox, Joanne

AU - Tuttle, Jay L.

AU - Lau, Yiu Keung

AU - Roeland, Eric J.

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N2 - 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.

AB - 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.

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