Drug Evaluation Sprague, Marcuccilli & Rakov Clinical rationale of sucroferric oxyhydroxide for controlling hyperphosphatemia in patients with CKD 5 Drug Evaluation Clinical rationale of sucroferric oxyhydroxide for controlling hyperphosphatemia in patients with chronic kidney disease Clin. Invest. (Lond.) Sucroferric oxyhydroxide (Velphoro®; Vifor Fresenius Medical Care Renal Pharma Ltd) Stuart M Sprague*,1, is an iron-based phosphate binder approved for the control of serum phosphorus Morgan Marcuccilli2 concentrations in chronic kidney disease patients receiving dialysis. Clinical data & Viatcheslav Rakov3 1 indicate that sucroferric oxyhydroxide has similar efficacy to sevelamer carbonate in NorthShore University Health System, University of Chicago Pritzker School of lowering serum phosphorus levels; however, with a substantially lower pill burden with Medicine, Evanston, IL, USA on average three to four pills/day versus eight to nine pills/day of sevelamer carbonate. 2University of Colorado School of Sucroferric oxyhydroxide is associated with discolored feces, as expected for oral Medicine, Denver, CO, USA iron-based compounds. Some patients reported mild and transient diarrhea, mostly 3Vifor Pharma, Glattbrugg, Switzerland at the start of treatment, which did not require any interventions. There is minimal *Author for correspondence: [email protected] iron absorption, without risk of iron overload. Overall, sucroferric oxyhydroxide is an effective, well-tolerated new treatment for managing hyperphosphatemia in dialysis patients. Keywords: adherence • chronic kidney disease • dialysis • PA21 • phosphate binder • serum phosphorus • sevelamer • sucroferric oxyhydroxide Background is associated with a significant reduction in Chronic kidney disease (CKD) has an esti- mortality [2,8,9]. 10.4155/CLI.14.110 mated worldwide prevalence of 8−16%; com- Properties of an ideal phosphate binder mon causes of CKD include hypertension, include a high phosphate-binding capac- diabetes, and glomerulonephritis [1] . Hyper- ity across the wide pH range found in the phosphatemia is a universal consequence of gastrointestinal (GI) tract, low pill burden, Stage 5 CKD and, if left untreated, is asso- good safety and tolerability profile, and min- ciated with cardiovascular morbidity, and imal absorption [10] . The presently available 1 mortality [2]. Sources of phosphate include phosphate binders include sevelamer, lantha- dietary protein, polyphosphates that are num carbonate, and compounds containing added to foods as preservatives, and com- either aluminum, calcium, magnesium [2,9], mon beverages [3–5]. An association between iron [11,12], or colestilan [13] . It is challeng- 2015 the consumption of such beverages high in ing to find an established phosphate binder phosphate content and hyperphosphate- that possesses all the ideal properties. For mia in dialysis patients has been reported example, aluminum-based binders are asso- [4,6]. Because dietary phosphate restriction ciated with significant hematologic and neu- and conventional dialysis treatment alone rologic toxicity, as well as an increased risk of are often insufficient to adequately man- fractures [9,14,15]. Although oral aluminum- age hyperphosphatemia, administration of containing phosphate binders may have a oral phosphate binders to limit phosphorus direct toxicological effect, it has also been absorption from ingested food is necessary in suggested that exposure to aluminum in dial- most patients [7]. Several studies have dem- ysis fluid was the primary cause of the toxic- onstrated that control of hyperphosphate- ity [16] . Evidence indicates that calcium-based mia, including the use of phosphate binders, phosphate binders, such as calcium carbonate part of 10.4155/CLI.14.110 © 2015 Future Science Ltd Clin. Invest. (Lond.) (2015) 5(1), 9–21 ISSN 2041-6792 9 Drug Evaluation Sprague, Marcuccilli & Rakov or calcium acetate, affect the calcium balance [17], and was minimal, particularly in dialysis patients [27]. At are associated with hypercalcemia [18] and vascular cal- 21 days, iron uptake was slightly lower in hemodialy- cification [9,19]. Concerns have also been raised over sis patients (median: 0.02%; range: 0–0.04%) than the mortality rate associated with calcium-containing in non-dialysis CKD patients (median: 0.06%; range: phosphate binders versus their non-calcium-based 0.008–0.44%). Median uptake was approximately ten- counterparts [20]. Although inconclusive results have fold lower across both CKD subgroups, compared with been obtained from clinical studies (including the healthy subjects with low iron stores (0.43%; range: RIND study and DCOR study) [21], a meta-analysis 0.16–1.25%). Phase I data in healthy volunteers also indicated that calcium-based phosphate binders were showed that there was a low risk of drug−drug interac- associated with increased risk of all-cause mortality tions, based on systemic exposure, between sucrofer- versus non-calcium-based phosphate binders [20]. The ric oxyhydroxide and selected drugs commonly taken use of calcium-based phosphate binders is questionable by dialysis patients, including losartan, furosemide, when there is a positive calcium balance [22]. Finally, digoxin, warfarin, and omeprazole [28]. the majority of available phosphate binders are associ- This article provides an overview of the clinical data ated with a high pill burden, which might compromise from Phase II and III trials of sucroferric oxyhydroxide a dialysis patient’s ability to take the prescribed medi- in patients with CKD receiving dialysis. cation [2,9]. Pill burden is a particularly important con- sideration, because patients receiving dialysis are often Efficacy required to take a large number of concomitant tablets The efficacy of sucroferric oxyhydroxide in dialy- each day [23]. Indeed, lower pill burden is associated sis patients was examined in a Phase II clinical trial with increased adherence to phosphate binders, and (NCT00824460), the purpose of which was to deter- high levels of medication adherence are associated with mine the effect of varying doses of the compound increased control of serum phosphorus [24]. on serum phosphorus levels [29]. In this international Sucroferric oxyhydroxide (Velphoro®, Vifor Fre- open-label study, 154 adult patients who had been senius Medical Care Renal Pharma Ltd), previously receiving maintenance hemodialysis three times a known as PA21, is a novel, non-calcium-, iron-based week for a minimum of 3 months before screening, phosphate binder, which has received US FDA approval with stable calcium content in dialysate for at least and EU marketing authorization for the control of 1 month before screening, were included in the study. serum phosphorus levels in CKD patients undergo- After a 2-week washout period, patients were random- ing dialysis. Sucroferric oxyhydroxide is a stabilized ized in equal proportions to one of five doses of sucro- polynuclear iron(III)-oxyhydroxide-based compound, ferric oxyhydroxide (low dose: 250 mg iron/day; active composed of approximately 33% m/m iron(III) oxy- doses: 1.0, 1.5, 2.0 and 2.5 g iron/day) or to sevelamer hydroxide, 30% m/m sucrose, 28% m/m starch and hydrochloride (HCl; 4.8 g/day). A fixed dose of the ≤10% m/m water (Figure 1) [25]. Similar to other phos- study treatment was maintained for 6 weeks, with phate binders, sucroferric oxyhydroxide binds dietary dosing three-times a day with meals (the highest dose phosphate in the GI tract, preventing its absorption was taken with the largest meal[s] of the day). Patients into the blood. The bound phosphate is subsequently who received 250 mg iron/day took one tablet per day eliminated in the feces [26]. with the largest meal. The primary end point of the In vitro data demonstrate that sucroferric oxyhy- study was the change in serum phosphorus concentra- droxide has a high phosphate-binding capacity over the tion from baseline to end of treatment. All patients entire physiologically relevant pH range found in the remained on a phosphate-restricted diet throughout GI tract. Assuming 1 mg of iron binds 0.26 mg of phos- the study. Demographics and baseline characteristics phate, three sucroferric oxyhydroxide tablets contain- were similar across all five sucroferric oxyhydrox- ing a total of 1.5 g of iron are expected to bind 390 mg ide treatment groups and the sevelamer HCl control of phosphate [25] . In vitro data also support minimal group. Mean age of patients was 60.4 years across the iron absorption following sucroferric oxyhydroxide five sucroferric oxyhydroxide treatment groups and administration. Under conditions representative of a 61.6 years for the sevelamer HCl control group, and full stomach (i.e., in the presence of phosphate) and the majority of patients were male (63.5 and 58.3%, during passage through the GI tract (i.e., over the respectively). A significant decrease in serum phos- pH range of 2.5−8.0), iron release was ≤0.35% [25]. phorus concentrations was observed in all four active Data from a subsequent Phase I absorption, distribu- sucroferric oxyhydroxide dose groups (p < 0.05), thus tion, metabolism and excretion study demonstrated meeting the primary end point. In patients who pro- that iron uptake into the blood following oral admin- vided at least one post-baseline efficacy assessment (the istration of 59Fe-labeled sucroferric oxyhydroxide efficacy population; n = 150), the mean magnitude 10 Clin. Invest. (Lond.) (2015) 5(1) future science group Clinical rationale of sucroferric oxyhydroxide for controlling hyperphosphatemia in patients with CKD Drug Evaluation OH OH OH O O O O Fe3+ OH OH OH O O O OH- CH OH OH CH OH 2- 2 2 O O O Starch H2O OH O Hydrogen bond CH2OH HO HO OH O HO OH O OH O HO Sucrose HO HO OH O HO HO OH O O OH HO HO HO HO OH HO HO O O OH O HO O HO OH OH O O OH HO OH HO OH OH Sucrose OH HO O OH O HO HO CH2OH O OH O HO HO OH O O CH OH OH 2 CH2OH O O O OH OH OH O O O O OH OH OH Starch Figure 1. Structure of sucroferric oxyhydroxide.