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



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.



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.



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.



ClinicalTrial.gov, NCT01340976.
UT M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 450, Houston, TX, 77030, USA. svadhanr@mdanderson.org.
Saroj
S
Vadhan-Raj
Indiana University Simon Cancer Center, Indianapolis, IN, USA.
Rafat
R
Abonour
David Geffen School of Medicine at the University of California, Los Angeles, Santa Monica, CA, USA.
Jonathan W
JW
Goldman
Compass Oncology, Vancouver, WA, USA.
David A
DA
Smith
Eli Lilly and Company, Indianapolis, IN, USA.
Christopher A
CA
Slapak
Eli Lilly and Company, Indianapolis, IN, USA.
Robert L
RL
Ilaria
Eli Lilly and Company, Indianapolis, IN, USA.
Ramon V
RV
Tiu
Eli Lilly and Company, Indianapolis, IN, USA.
Xuejing
X
Wang
Eli Lilly and Company, Neuilly-sur-Seine, France.
Sophie
S
Callies
Eli Lilly and Company, Surrey, UK.
Joanne
J
Cox
Eli Lilly and Company, Indianapolis, IN, USA.
Jay L
JL
Tuttle
Eli Lilly and Company, Indianapolis, IN, USA.
Yiu-Keung
YK
Lau
Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Eric J
EJ
Roeland
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006454:Hemoglobins / Q000032:analysis / Q000187:drug effects; D064451:Hepcidins / Q000276:immunology*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications*; D013997:Time Factors; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D006454:Hemoglobins; D064451:Hepcidins; C000625126:LY2787106; D007501:Iron
Anemia; Cancer; Ferritin; Hepcidin; Iron