Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney DiseaseMartin E.R.a · Smith M.T.b · Maroni B.J.c · Zuraw Q.C.c · deGoma E.M.c
aSouth Florida Nephrology Associates, Lauderdale Lakes, FL, bNephrology Associates, PC, Augusta, GA, and cAkebia Therapeutics Inc., Cambridge, MA, USA
Emil M. deGoma, MD
Akebia Therapeutics Inc.
245 First Street Suite 1400
Cambridge, MA 02142 (USA)
Do you have an account?
Background: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD. Methods: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability. Results: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration. Conclusions: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.
© 2017 The Author(s) Published by S. Karger AG, Basel
- Jones M, Ibels L, Schenkel B, Zagari M: Impact of epoetin alfa on clinical end points in patients with chronic renal failure: a meta-analysis. Kidney Int 2004;65:757-767.
- Locatelli F, Pisoni RL, Combe C, Bommer J, Andreucci VE, Piera L, Greenwood R, Feldman HI, Port FK, Held PJ: Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the dialysis outcomes and practice patterns study (DOPPS). Nephrol Dial Transplant 2004;19:121-132.
Regidor DL, Kopple JD, Kovesdy CP, Kilpatrick RD, McAllister CJ, Aronovitz J, Greenland S, Kalantar-Zadeh K: Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 2006;17:1181-1191.
- Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584-590.
- Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK: Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008;74:791-798.
- Servilla KS, Singh AK, Hunt WC, Harford AM, Miskulin D, Meyer KB, Bedrick EJ, Rohrscheib MR, Tzamaloukas AH, Johnson HK, Zager PG: Anemia management and association of race with mortality and hospitalization in a large not-for-profit dialysis organization. Am J Kidney Dis 2009;54:498-510.
- Locatelli F, Barany P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, Horl W, London G, Vanholder R, Van Biesen W; ERA-EDTA ERBP Advisory Board: Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European renal best practice position statement. Nephrol Dial Transplant 2013;28:1346-1359.
- Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group: KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl 2012;2:279-335.
- Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098.
- Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-2084.
- Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; TREAT Investigators: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-2032.
- McCullough PA, Barnhart HX, Inrig JK, Reddan D, Sapp S, Patel UD, Singh AK, Szczech LA, Califf RM: Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease. Am J Nephrol 2013;37:549-558.
- Fishbane S, Besarab A: Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets. Clin J Am Soc Nephrol 2007;2:1274-1282.
- Lenihan CR, Winkelmayer WC: The dawning of a new day in CKD anemia care? J Am Soc Nephrol 2016;27:968-970.
- Semenza GL: Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 2009;24:97-106.
- Safran M, Kaelin WG Jr: HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest 2003;111:779-783.
Buch A, Maroni BJ, Hartman CS: Dose exposure relationship of vadadustat is independent of the level of renal function. J Am Soc Nephrol 2015;26:#SA-PO537.
Hartman C, Smíth MT, Flinn C, Shalwitz I, Peters KG, Haase VH: AKB-6548, a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia. J Am Soc Nephrol 2011;22:435A.
- Dunnett CW: A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 1955;50:1096-1121.
- Maxwell PH, Eckardt KU: HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol 2016;12:157-168.
- Windsor JS, Rodway GW: Heights and haematology: the story of haemoglobin at altitude. Postgrad Med J 2007;83:148-151.
- Klausen T, Poulsen TD, Fogh-Andersen N, Richalet JP, Nielsen OJ, Olsen NV: Diurnal variations of serum erythropoietin at sea level and altitude. Eur J Appl Physiol Occup Physiol 1996;72:297-302.
- Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH: Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int 2016;90:1115-1122.
- Gao L, Chen Q, Zhou X, Fan L: The role of hypoxia-inducible factor 1 in atherosclerosis. J Clin Pathol 2012;65:872-876.
- Li J, Thorne LN, Punjabi NM, Sun CK, Schwartz AR, Smith PL, Marino RL, Rodriguez A, Hubbard WC, O'Donnell CP, Polotsky VY: Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 2005;97:698-706.
- Ramakrishnan SK, Taylor M, Qu A, Ahn SH, Suresh MV, Raghavendran K, Gonzalez FJ, Shah YM: Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2α and regulation of bile acid homeostasis. Mol Cell Biol 2014;34:1208-1220.
- Jun J, Reinke C, Bedja D, Berkowitz D, Bevans-Fonti S, Li J, Barouch LA, Gabrielson K, Polotsky VY: Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 2010;209:381-386.
Haase VH, Chertow G, Block G, Pergola P, Zuraw Q, Khawaja Z, Sharma A, Maroni BJ, McCullough PA: Vadadustat Maintains Hemoglobin (Hb) Levels in Dialysis-Dependent Chronic Kidney Disease (DD-CKD) Patients Independent of Systemic Inflammation or Prior Dose of Erythropoiesis-Stimulating Agent (ESA): Kidney Week. Chicago, American Society of Nephrology, 2016, TH-PO960. http://www.akebia.com/wp-content/themes/ akebia/img/media-kit/abstracts-posters- presentations/20161117%20Ph2%200011%20ASN%202016_FINAL_v4_09Nov16.pdf.
Hartman CS, Farmer TM, Annis K, Kazazi F, Pollack P, Shalwitz R: Phase 2 Study of AKB-6548, A Novel Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor (HIF-PHI) in Patients with End Stage Renal Disease (ESRD) Undergoing Hemodialysis (HD). Philadelphia, Kidney Week, 2014, INFO25. http://akebia.com/wp-content/themes/akebia/img/media-kit/abstracts-posters-presentations/ 20141106_Akebia_ASN_Informational_Poster-FINAL.pdf.
Center for Drug Evaluation Research: FDA Drug Safety Communication: Modified Dosing Recommendations to Improve the Safe Use of Erythropoiesis-Stimulating Agents (ESAs) in Chronic Kidney Disease. Silver Spring, US Food and Drug Administration, 2011.
Haase VH, Hartman CS, Maroni B, Farzaneh-far R, McCullough PA: Vadadustat, A Novel, Oral Treatment for Anemia of CKD, Maintains Stable Hemoglobin Levels in Dialysis Patients Converting from Erythropoiesis-Stimulating Agents: National Kidney Foundation Spring Clinical Meeting. Boston, The National Kidney Foundation, 2016, abstr 171. http://akebia.com/wp-content/themes/akebia/img/media-kit/abstracts-posters- presentations/Akebia_NKF 2016 Poster_ FINAL.pdf.
Buch A, Maroni B, Hartman C: Dose exposure relationship of vadadustat is independent of the level of renal function. J Am Soc Nephrol 2015;26:747A.
Chandorkar GA, Jhee S, Han D, Schmelzer K, Sherman M, Manzur K, Sharma A, Zuraw Q: Pharmacokinetics, Pharmacodynamics, and Safety of Single and Multiple Oral Doses of Vadadustat in Healthy Japanese and Caucasian Subjects: American Society of Nephrology's Kidney Week. Chicago, American Society of Nephrology, 2016, SA-PO506.
Buch A, Farmer TM, Hartman C, Alcorn H, Shalwitz R: Hemodialysis has minimal impact on the pharmacokinetics of AKB-6548, a once-daily oral inhibitor of hypoxia-inducible factor prolyl-hydroxylases (HIF-PHs) for the treatment of anemia related to chronic kidney disease (CKD). In: ASN Kidney Week. Philadelphia, PA; 2014, FR-PO952. http://akebia.com/wp-content/themes/ akebia/img/media-kit/abstracts-posters-presentations/20141106_Akebia_ASN_PK_Poster-FINAL.pdf. (accessed December 12, 2016).
Chandorkar GA, Farzaneh-Far R, Buch A, Maroni B: A Drug-Drug Interaction Study to Evaluate the Effect of Vadadustat on the Pharmacokinetics of Celecoxib - a CYP2C9 Substrate - in Healthy Volunteers: ERA-EDTA Congress. Vienna, ERA-EDTA, 2016, SP322. http://akebia.com/wp-content/themes/akebia/img/media-kit/abstracts-posters-presentations/ 20160523%20ERA-EDTA%20Poster_FINAL.pdf.