The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia

Geoffrey A Block, David P Rosenbaum, Andrew Yan, Peter J Greasley, Glenn M Chertow, Myles Wolf, Geoffrey A Block, David P Rosenbaum, Andrew Yan, Peter J Greasley, Glenn M Chertow, Myles Wolf

Abstract

Background: Elevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study.

Methods: After 1-3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study.

Results: After phosphate-binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430-2605 pg/mL before, to 2601-6294 pg/mL after washout (P < 0.001 for all patients analyzed as a single group)]. Serum FGF23 concentrations subsequently decreased in tenapanor-treated patients (2030-3563 pg/mL), whereas they increased further in placebo-treated patients (6930 pg/mL). In an analysis of covariance, FGF23 decreased by 9.1-27.9% in tenapanor-treated patients and increased by 21.9% in placebo-treated patients (P ≤ 0.001-0.04).

Conclusions: Following a marked increase in serum FGF23 in response to withdrawal of phosphate binders, tenapanor significantly decreased serum FGF23 in patients receiving hemodialysis with hyperphosphatemia. Further studies are required to explore the long-term effects of controlling FGF23 with tenapanor.

Figures

FIGURE 1
FIGURE 1
Serum FGF23 concentrations at screening, post-phosphate-binder washout and at the end of study treatment with tenapanor or placebo. Geometric means (CV, percentage) at post-washout reported previously [27]. b.i.d., twice daily; EOT/ET, end of treatment/early termination; q.d., once daily.
FIGURE 2
FIGURE 2
Forest plots of ratios of geometric mean of serum FGF23 concentration following treatment with tenapanor or placebo. Data are presented as ratios (with 95% confidence intervals), which can be converted to percentage changes from post-washout or placebo treatment. ANCOVA was performed on data for the change from post-washout in natural log-transformed FGF23 concentration at the end of treatment/early termination, with treatment as a fixed factor and post-washout FGF23 (natural log-transformed) as a covariate. Ratios for change from post-washout reported previously [27]. b.i.d., twice daily; CI, confidence interval; EOT/ET, end of treatment/early termination; q.d., once daily.
FIGURE 3
FIGURE 3
Scatter plot of changes in serum FGF23 (natural log transformed) and phosphate concentrations from post-phosphate-binder washout to the end of treatment/early termination for all study participants. The change in serum FGF23 concentrations from post-phosphate-binder washout to the end of treatment correlated with concomitant changes in serum phosphate (Pearson correlation coefficient, ρ  =  0.48; P  < 0.001). b.i.d., twice daily; q.d., once daily.

References

    1. Hruska KA, Mathew S, Lund R. et al. Hyperphosphatemia of chronic kidney disease. Kidney Int 2008; 74: 148–157
    1. Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int 2012; 82: 737–747
    1. Gutierrez O, Isakova T, Rhee E. et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16: 2205–2215
    1. Shimada T, Hasegawa H, Yamazaki Y. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19: 429–435
    1. Shigematsu T, Kazama JJ, Yamashita T. et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 2004; 44: 250–256
    1. David V, Martin A, Isakova T. et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 2016; 89: 135–146
    1. Farrow EG, Yu X, Summers LJ. et al. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci USA 2011; 108: E1146–E1155
    1. Larsson T, Nisbeth U, Ljunggren O. et al. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 2003; 64: 2272–2279
    1. Palmer SC, Hayen A, Macaskill P. et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 2011; 305: 1119–1127
    1. Faul C, Amaral AP, Oskouei B. et al. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121: 4393–4408
    1. Gutierrez OM, Mannstadt M, Isakova T. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359: 584–592
    1. Isakova T, Xie H, Yang W. et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 2011; 305: 2432–2439
    1. Scialla JJ, Xie H, Rahman M. et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol 2014; 25: 349–360
    1. Mehta R, Cai X, Lee J. et al. Association of fibroblast growth factor 23 with atrial fibrillation in chronic kidney disease, from the chronic renal insufficiency cohort study. JAMA Cardiol 2016; 1: 548–556
    1. Xie J, Yoon J, An SW. et al. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J Am Soc Nephrol 2015; 26: 1150–1160
    1. Bacchetta J, Sea JL, Chun RF. et al. Fibroblast growth factor 23 inhibits extrarenal synthesis of 1, 25-dihydroxyvitamin D in human monocytes. J Bone Miner Res 2013; 28: 46–55
    1. Rossaint J, Oehmichen J, Van Aken H. et al. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest 2016; 126: 962–974
    1. Chonchol M, Greene T, Zhang Y. et al. Low vitamin D and high fibroblast growth factor 23 serum levels associate with infectious and cardiac deaths in the HEMO study. J Am Soc Nephrol 2016; 27: 227–237
    1. Bansal S, Friedrichs WE, Velagapudi C. et al. Spleen contributes significantly to increased circulating levels of fibroblast growth factor 23 in response to lipopolysaccharide-induced inflammation. Nephrol Dial Transplant 2017; 32: 960–968
    1. Shalhoub V, Shatzen EM, Ward SC. et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J Clin Invest 2012; 122: 2543–2553
    1. Kalantar-Zadeh K, Gutekunst L, Mehrotra R. et al. Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease. Clin J Am Soc Nephrol 2010; 5: 519–530
    1. Isakova T, Ix JH, Sprague SM. et al. Rationale and approaches to phosphate and fibroblast growth factor 23 reduction in CKD. J Am Soc Nephrol 2015; 26: 2328–2339
    1. Block GA, Rosenbaum DP, Leonsson-Zachrisson M. et al. Effect of tenapanor on interdialytic weight gain in patients on hemodialysis. Clin J Am Soc Nephrol 2016; 11: 1597–1605
    1. Johansson S, Rosenbaum DP, Knutsson M. et al. A phase 1 study of the safety, tolerability, pharmacodynamics, and pharmacokinetics of tenapanor in healthy Japanese volunteers. Clin Exp Nephrol 2017; 21: 407–416
    1. Spencer AG, Labonte ED, Rosenbaum DP. et al. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med 2014; 6: 227–236
    1. Labonte ED, Carreras CW, Leadbetter MR. et al. Gastrointestinal inhibition of sodium-hydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKD. J Am Soc Nephrol 2015; 26: 1138–1149
    1. Block GA, Rosenbaum DP, Leonsson-Zachrisson M. et al. Effect of tenapanor on serum phosphate in patients receiving hemodialysis. J Am Soc Nephrol 2017; 28: 1933–1942
    1. Merck Millipore. EZHFGF23-32K Human FGF-23 ELISA Kit (7 March 2018, date last accessed)
    1. Isakova T, Barchi-Chung A, Enfield G. et al. Effects of dietary phosphate restriction and phosphate binders on FGF23 levels in CKD. Clin J Am Soc Nephrol 2013; 8: 1009–1018
    1. Oliveira RB, Cancela AL, Graciolli FG. et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 2010; 5: 286–291
    1. Iguchi A, Kazama JJ, Yamamoto S. et al. Administration of ferric citrate hydrate decreases circulating FGF23 levels independently of serum phosphate levels in hemodialysis patients with iron deficiency. Nephron 2015; 131: 161–166
    1. Gonzalez-Parra E, Gonzalez-Casaus ML, Galan A. et al. Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients. Nephrol Dial Transplant 2011; 26: 2567–2571
    1. Cancela AL, Oliveira RB, Graciolli FG. et al. Fibroblast growth factor 23 in hemodialysis patients: effects of phosphate binder, calcitriol and calcium concentration in the dialysate. Nephron Clin Pract 2011; 117: c74–c82
    1. Chue CD, Townend JN, Moody WE. et al. Cardiovascular effects of sevelamer in stage 3 CKD. J Am Soc Nephrol 2013; 24: 842–852
    1. Moe SM, Chertow GM, Parfrey PS. et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the evaluation of cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) trial. Circulation 2015; 132: 27–39
    1. Block GA, Bushinsky DA, Cheng S. et al. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: a randomized clinical trial. JAMA 2017; 317: 156–164
    1. Francis C, David V.. Inflammation regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens 2016; 25: 325–332
    1. Chertow GM, Levin NW, Beck GJ. et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010; 363: 2287–2300
    1. Moe SM, Zidehsarai MP, Chambers MA. et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6: 257–264
    1. Block GA, Rosenbaum DP, Korner P. et al. Gastrointestinal tolerability of tenapanor to treat hyperphosphatemia in patients on hemodialysis [Abstract]. J Am Soc Nephrol 2017; 28: 373
    1. Smith ER. The use of fibroblast growth factor 23 testing in patients with kidney disease. Clin J Am Soc Nephrol 2014; 9: 1283–1303
    1. Ardelyx. An 8-Week, Multicenter, Randomized, Double-Blind, Parallel Group Study With A 4-Week, Placebo-Controlled, Randomized Withdrawal Period To Evaluate The Efficacy, Safety, And Tolerability Of Tenapanor To Treat Hyperphosphatemia In End-Stage Renal Disease Patients On Hemodialysis (ESRD-HD) identifier: NCT02675998. (7 March 2018, date last accessed)

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