Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD.
Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD.



The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events.



Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported.



In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.
St. John Hospital and Medical Center, Detroit, Michigan.
Robert
R
Provenzano
FibroGen, Inc., San Francisco, California.
Anatole
A
Besarab
Apex Research of Riverside, Riverside, California.
Chao H
CH
Sun
San Antonio Kidney Disease Center, San Antonio, Texas.
Susan A
SA
Diamond
Palmetto Nephrology, Professional Association, Orangeburg, South Carolina.
John H
JH
Durham
Nephrology Private Practice, San Juan, Puerto Rico.
Jose L
JL
Cangiano
Mountain Kidney and Hypertension Associates, Professional Association, Asheville, North Carolina; and.
Joseph R
JR
Aiello
Division of Nephrology, Henry Ford Hospital, Detroit, Michigan.
James E
JE
Novak
FibroGen, Inc., San Francisco, California.
Tyson
T
Lee
FibroGen, Inc., San Francisco, California.
Robert
R
Leong
FibroGen, Inc., San Francisco, California.
Brian K
BK
Roberts
FibroGen, Inc., San Francisco, California.
Khalil G
KG
Saikali
FibroGen, Inc., San Francisco, California.
Stefan
S
Hemmerich
FibroGen, Inc., San Francisco, California.
Lynda A
LA
Szczech
FibroGen, Inc., San Francisco, California.
Kin-Hung Peony
KP
Yu
FibroGen, Inc., San Francisco, California.
Thomas B
TB
Neff
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins / Q000097:blood; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000150:complications*
D004791:Enzyme Inhibitors; D006454:Hemoglobins; D064451:Hepcidins; D007546:Isoquinolines; D002097:C-Reactive Protein; D002784:Cholesterol; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine; C584543:roxadustat
C-Reactive Protein; Erythropoiesis; Hemoglobins; Hepcidins; Humans; Iron; Renal Insufficiency, Chronic; anemia; chronic kidney disease; clinical trial