Long-Term Safety and Efficacy of a Novel Iron-Containing Phosphate Binder, JTT-751, in Patients Receiving Hemodialysis

doi:10.1053/j.jrn.2014.03.006

Journal of Renal Nutrition

Volume 24, Issue 4, July 2014, Pages 261-267

https://doi.org/10.1053/j.jrn.2014.03.006 Get rights and content

Abstract

Objective

JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. This study investigated long-term safety and efficacy of JTT-751 for hyperphosphatemia in patients receiving hemodialysis.

Design and Methods

This was 52-week, phase 3, multicenter, open-label, dose titration, long-term study. All patients were receiving thrice-weekly hemodialysis for ≥3 months before the initiation of the study. JTT-751 was given at titrated doses between 1.5 and 6.0 g/day.

Main Outcome Measures

Safety endpoints were adverse events and adverse drug reactions. Efficacy outcomes were the change in serum phosphate, corrected serum calcium, and intact parathyroid hormone. Changes in ferritin, transferrin saturation, and doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron formulations were additional outcomes.

Results

One hundred and eighty patients were included in the trial. Dose-titrated JTT-751 decreased mean serum phosphate after administration and satisfactorily maintained serum phosphate concentrations throughout the entire duration of the 52-week trial. Mean serum phosphate concentrations were kept lower than 5.5 mg/dL from weeks 5 to 52. The most common adverse events were gastrointestinal disorders, which were mild to moderate in intensity. Serum ferritin concentrations rose to a peak around week 28 and stabilized thereafter. The mean intravenous iron dose decreased from 57.3 mg/4 weeks (weeks 0-12) to 3.6 mg/4 weeks (weeks 28-52); weekly ESA dose declined by 25% over the same time frame, while mean hemoglobin concentrations remained stable.

Conclusion

JTT-751 1.5-6.0 g/day controls serum phosphorus concentrations and reduces the need for ESAs and intravenous iron in patients receiving hemodialysis.

Introduction

In patients with end-stage renal disease, hyperphosphatemia contributes to secondary hyperparathyroidism and can lead to skeletal complications including fracture and extraskeletal (ectopic) calcification of soft tissues. Vascular calcification and resultant vascular stiffness have been linked to changes in ventricular structure and function and cardiovascular events, including heart failure and sudden death.1, 2, 3, 4 Control of hyperphosphatemia is recommended by clinical practice guidelines worldwide. The Japanese Society for Dialysis Therapy Chronic Kidney Disease-Mineral and Bone Disorders guidelines advise that serum phosphate concentrations 3 days after the last hemodialysis session be kept within the range of 3.5-6.0 mg/dL⁵; the Kidney Disease Improving Global Outcomes guidelines suggest lowering serum phosphate concentrations toward the normal range.⁶

Currently employed phosphate binders include calcium carbonate, acetate and citrate, sevelamer carbonate and hydrochloride, and lanthanum carbonate. Although these agents are effective at binding orally ingested phosphates, they vary in safety, potency, and off-target effects, some of which may be salutary (e.g., low-density lipoprotein and uric acid lowering with sevelamer) and others adverse (low turnover bone disease and progressive vascular calcification with calcium).⁷ There remains a large unmet need for safe and effective phosphate binders with favorable off-target effects.

JTT-751 is a novel phosphate binder containing ferric citrate as an active ingredient.⁸ Ferric citrate is designated as a ‘Generally Recognized as Safe’ chemical by the United States Food and Drug Administration and has been used as a food additive. JTT-751 has a larger surface area and faster dissolution rate than ferric citrate.⁹ The efficacy and safety of JTT-751 have been confirmed in a phase 2 dose–response study in patients on hemodialysis with hyperphosphatemia.¹⁰

The study presented here was a phase 3 trial designed to evaluate the long-term safety and efficacy of JTT-751 in Japanese patients on hemodialysis with hyperphosphatemia. In addition to examining the effects of JTT-751 on serum phosphate concentrations and other parameters of chronic kidney disease mineral bone disorder, we aimed to determine the effects of JTT-751 on the use of erythropoiesis-stimulating agents (ESAs) and intravenous iron.

Section snippets

Subjects

Patients who were recruited were ≥20 years of age with end-stage renal disease receiving hemodialysis (including hemodiafiltration) 3 times a week and had received hemodialysis for ≥12 weeks before the initial screening date.

The inclusion criteria were as follows: serum phosphate within 3.5-10.0 mg/dL for patients who were receiving medication for hyperphosphatemia, and 6.1-10.0 mg/dL if patients were not on any treatment. The exclusion criteria included the following: (1) any gastrointestinal

Study Participants

Figure 1 shows the patient disposition in this trial. Written informed consent was obtained from 206 patients, of whom 180 met the criteria and were included in the trial. A total of 128 patients (71%) completed the 52-week trial. All of the 180 patients who were given JTT-751 were included in efficacy analyses. Demographic and baseline characteristics of the efficacy analysis population are shown in Table 1.

Throughout the study period, adherence of JTT-751 was 97.4%. Patients were asked to

Discussion

Herein, we describe an open-label trial in which dose-titrated JTT-751 controlled serum phosphate concentrations throughout a 52-week study period without attenuation of efficacy. Serum calcium and PTH concentrations were also maintained without significant changes in the use of vitamin D derivatives and cinacalcet, and with no clinically meaningful changes in markers of bone turnover. In addition, we found JTT-751 to markedly reduce the need for intravenous iron and to be ESA sparing. The

Practical Applications

These data suggest that JTT-751 1.5-6.0 g/day controls serum phosphorus concentrations and shows well tolerability in patients receiving hemodialysis. Also, the need for ESAs and intravenous iron were reduced after administration of JTT-751.

Acknowledgment

We thank all of the physicians, nurses, and patients of the participating centers for their support. Financial support for this study was provided by the Japan Tobacco Inc. We also acknowledge the support of Emedits Global Ltd. for editorial support during the preparation of this article (www.emedits.com).

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: Support and Financial Disclosure: K.Y. is an Advisory Board member and has received research funding and consulting fees from Japan Tobacco Inc. T.A., M.F., M.N., K.S., Y.K., and H.H. are Advisory Board members and have received consulting fees from Japan Tobacco Inc. G.M.C. has received consulting fees from Japan Tobacco Inc. Trial registration number: CTI-111437 (The Japan Pharmaceutical Information Center at: http//www.clinicaltrials.jp). Also see Acknowledgments on page 267.

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Original ResearchLong-Term Safety and Efficacy of a Novel Iron-Containing Phosphate Binder, JTT-751, in Patients Receiving Hemodialysis

Abstract

Objective

Design and Methods

Main Outcome Measures

Results

Conclusion

Introduction

Section snippets

Subjects

Study Participants

Discussion

Practical Applications

Acknowledgment

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Clin Biochem

Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder

Ther Apher Dial

KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)

Kidney Int Suppl

Phosphate binders in CKD: past, present, and future

J Indian Acad Clin Med

The safety and tolerability of ferric citrate as a phosphate binder in dialysis patients

Nephron Clin Pract

Ferric citrate hydrate, a new phosphate binder, prevents the complications of secondary hyperparathyroidism and vascular calcification

Am J Nephrol

Effect of oral JTT-751 (ferric citrate) on hyperphosphatemia in hemodialysis patients: results of a randomized, double-blind, placebo-controlled trial

Am J Nephrol

Interpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual

J Clin Pathol

Original Research
Long-Term Safety and Efficacy of a Novel Iron-Containing Phosphate Binder, JTT-751, in Patients Receiving Hemodialysis