Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Vifor Fresenius Medical Care Renal Pharma France, 100–101 Terrasse Boieldieu, Tour Franklin La Défense 8, 92042, Paris la Défense Cedex, France
Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia
ATC code: V03AE05
Velphoro contains sucroferric oxyhydroxide which is comprised of polynuclear iron(III)-oxyhydroxide (pn-FeOOH), sucrose and starches. Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water and the phosphate ions throughout the physiological pH range of the gastrointestinal tract.
Serum phosphorus levels are reduced as a consequence of the reduced dietary phosphate absorption.
One phase 3 clinical study has been performed in patients with CKD on dialysis to investigate the efficacy and safety of Velphoro in this population. This study was an open-label, randomised, activecontrolled (sevelamer carbonate), parallel group study for up to 55 weeks. Adult patients with hyperphosphataemia (serum phosphorus levels ≥1.94 mmol/L) were treated with sucroferric oxyhydroxide at a starting dose of 1,000 mg iron/day followed by an 8-week dose titration period. Non-inferiority to sevelamer carbonate was determined at week 12. Subjects were continued on their study medication from week 12 to week 55. From week 12 to 24, dose titrations were allowed for both tolerability and efficacy reasons. Treatment of patient sub-populations from week 24 to week 27 with maintenance dose of sucroferric oxyhydroxide (1,000 to 3,000 mg iron/day) or low dose (250 mg iron/day) of sucroferric oxyhydroxide demonstrated superiority of the maintenance dose.
In Study-05A, 1,055 patients on haemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus ≥1.94 mmol/L following a 2 – 4-week phosphate binder washout period, were randomised and treated with either sucroferric oxyhydroxide, at a starting dose of 1,000 mg iron/day (N=707), or active-control (sevelamer carbonate, N=348) for 24 weeks. At the end of week 24, 93 patients on haemodialysis whose serum phosphorus levels were controlled (<1.78 mmol/L) with sucroferric oxyhydroxide in the first part of the study, were re-randomised to continue treatment with either their week 24 maintenance dose (N=44 or a non-effective low dose control 250 mg iron/day, N=49) of sucroferric oxyhydroxide for a further 3 weeks.
Following completion of Study-05A, 658 patients (597 on haemodialysis and 61 on peritoneal dialysis) were treated in the 28-week extension study (Study-05B) with either sucroferric oxyhydroxide (N=391) or sevelamer carbonate (N=267) according to their original randomization.
Mean serum phosphorus levels were 2.5 mmol/L at baseline and 1.8 mmol/L at week 12 for sucroferric oxyhydroxide (reduction by 0.7 mmol/L). Corresponding levels for sevelamer carbonate at baseline were 2.4 mmol/L and 1.7 mmol/L at week 12 (reduction by 0.7 mmol/L), respectively.
The serum phosphorus reduction was maintained over 55 weeks. Serum phosphorus levels and calcium-phosphorus product levels were reduced as a consequence of the reduced dietary phosphate absorption.
The response rates, defined as the proportion of subjects achieving serum phosphorus levels within the Kidney Disease Outcomes Quality Initiative (KDOQI) recommended range were 45.3% and 59.1% at week 12 and 51.9% and 55.2% at week 52, for sucroferric oxyhydroxide and sevelamer carbonate, respectively.
The mean daily dose of Velphoro over 55 weeks of treatment was 1,650 mg iron and the mean daily dose of sevelamer carbonate was 6,960 mg.
A prospective, non-interventional, post-authorisation safety study (VERIFIE) has been conducted, evaluating the short- and long-term (up to 36 months) safety and effectiveness of Velphoro in adult patients on haemodialysis (N=1,198) or peritoneal dialysis (N=160), who were followed in routine clinical practice for 12 to 36 months (safety analysis set, N=1,365). During the study, 45% (N=618) of these patients were concomitantly treated with phosphate binder(s) other than Velphoro.
In the safety analysis set, the most common ADRs were diarrhoea and discoloured faeces, reported by 14% (N=194) and 9% (N=128) of patients, respectively. The incidence of diarrhoea was highest in the first week and decreased with duration of use. Diarrhoea was of mild to moderate intensity in most patients and resolved in the majority of patients within 2 weeks. Discoloured (black) faeces is expected for an oral iron-based compound, and may visually mask gastrointestinal bleeding. For 4 of the 40 documented concomitant gastrointestinal bleeding events, Velphoro-related stool discolouration was reported as causing an insignificant delay in diagnosis of gastrointestinal bleeding, without affecting patient health. In the remaining cases, no delay in diagnosis of gastrointestinal bleeding has been reported.
The results from this study showed that the effectiveness of Velphoro in a real-life setting (including concomitant use of other phosphate binders in 45% of patients), was in line with that observed in the phase 3 clinical study.
An open label clinical study investigated the efficacy and safety of Velphoro in paediatric patients 2 years of age and older with CKD, and hyperphosphatemia (CKD stages 4-5 (defined by a glomerular filtration rate <30 mL/min/l .73 m²) or with CKD on dialysis). Eighty-five subjects were randomised to Velphoro (N=66) or active control calcium acetate arm (N=19) for a 10-week dose titration (Stage 1), followed by a 24-week safety extension (Stage 2). Most patients were ≥12 years of age (66%). Eighty percent of patients were CKD patients on dialysis (67% on haemodialysis and 13% on peritoneal dialysis) and 20% were CKD patients not on dialysis.
The limited difference in reduction in mean serum phosphorus level from baseline to the end of Stage 1 in the Velphoro group (N=65) was not statistically significant with -0.120 (0.081) mmol/L (95% CI: -0.282, 0.043) based on the mixed model calculations with actual data showing a mean of 2.08 mmol/L at baseline and 1.91 mmol/L at the end of Stage 1 (reduction by 0.17 mmol/L). The effect was maintained during Stage 2, although some fluctuations in mean effect over time were noticed (0.099 (0.198) mmol/L (95% CI: -0.306, 0.504)).
The percentage of subjects with serum phosphorus levels within normal ranges increased from 37% at baseline to 61% at the end of Stage 1, and was 58% at the end of Stage 2, showing the sustainable phosphorus lowering effect of sucroferric oxyhydroxide. Among subjects whose serum phosphorus was above age-related normal ranges at baseline (N=40), serum phosphorus levels showed statistically significant decrease from baseline to the end of Stage 1, with the LS mean (SE) change -0.87 (0.30) mg/dL (95% CI: -1.47, -0.27; p=0.006). The safety profile of Velphoro in paediatric patients was generally comparable to that previously observed in adult patients.
Velphoro works by binding phosphate in the gastrointestinal tract and thus the serum concentration is not relevant for its efficacy. Due to the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out, e.g., determination of the distribution volume, area under the curve, mean residence time, etc.
In 2 Phase 1 studies, it was concluded that the potential for iron overload is minimal and no dose dependent effects were observed in healthy volunteers.
The active moiety of Velphoro, pn-FeOOH, is practically insoluble and therefore not absorbed. Its degradation product, mononuclear iron species, can however be released from the surface of pnFeOOH and be absorbed.
The absolute absorption studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that systemic absorption was very low (≤1% of the administered dose).
The iron uptake from radiolabelled Velphoro drug substance, 2,000 mg iron in 1 day was investigated in 16 CKD patients (8 pre-dialysis and 8 haemodialysis patients) and 8 healthy volunteers with low iron stores (serum ferritin <100 mcg/L). In healthy subjects, the median uptake of radiolabelled iron in the blood was estimated to be 0.43% (range 0.16–1.25%) on Day 21, in pre-dialysis patients 0.06% (range 0.008–0.44%) and in haemodialysis patients 0.02% (range 0–0.04%). Blood levels of radiolabelled iron were very low and confined to the erythrocytes.
The distribution studies in humans were not performed. Non-clinical studies in several species (rats and dogs) showed that pn-FeOOH is distributed from the plasma to the liver, spleen and bone marrow, and utilized by incorporation into red blood cells.
In patients, absorbed iron is expected to be also distributed to the target organs, i.e. liver, spleen and bone marrow, and utilized by incorporation into red blood cells.
The active moiety of Velphoro, pn-FeOOH, is not metabolised. However, the degradation product of Velphoro, mononuclear iron species, can be released from the surface of polynuclear iron(III)-oxyhydroxide and be absorbed. Clinical studies have demonstrated that the systemic absorption of iron from Velphoro is low.
In vitro data suggest that the sucrose and starch components of the active substance can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood.
In animal studies with rats and dogs administered 59Fe-Velphoro drug substance orally, radiolabelled iron was recovered in the faeces but not the urine.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Effects seen in the rabbit embryo-foetal development toxicity study (skeletal variations and incomplete ossificaton) are related to exaggerated pharmacology, and likely not relevant for patients. Other reproduction toxicity studies showed no adverse effects.
Carcinogenicity studies were performed in mice and rats. There was no clear evidence of a carcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was observed in the colon and caecum of mice after 2-years treatment, but this was considered a species-specific effect with no diverticula/cysts seen in long term studies in rats or dogs. In rats, there was a slightly increased incidence of benign C-cell adenoma in the thyroid of male rats given the highest dose of sucroferric oxyhydroxide. This is thought to be most likely an adaptive response to the pharmacological effect of the drug, and not clinically relevant.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
