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Pharmacology: Pharmacodynamics: Mechanism of Action: 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 (GI) tract. The bound phosphate is eliminated with faeces.
Both serum phosphorus levels and calcium-phosphorus product levels are reduced as a consequence of the reduced dietary phosphate absorption.
Clinical Efficacy and Safety: The ability of Velphoro to lower serum phosphorus in ESRD patients on dialysis was demonstrated in 2 randomised clinical trials: one 6-week open-label, randomised, active-controlled (sevelamer hydrochloride), parallel-group, dose-finding study; and one 55-week, open-label, randomised, active-controlled (sevelamer carbonate), parallel-group, safety and efficacy study.
6-Week, Open-label, Randomised, Active-control, Parallel-group, Dose-finding Study in Haemodialysis Patients with Hyperphosphataemia (PA-CL-03A): A randomised, open-label, active-controlled dose-ranging Phase 2 study over 6 weeks was performed in 154 ESRD patients on haemodialysis who were hyperphosphatemic (serum phosphorus > 1.78 mmol/L but <2.50 mmol/L) following a 2-week phosphate binder washout period. These patients were randomized to receive Velphoro at 250mg iron/day, 1,000mg iron/day, 1,500 mg iron/day, 2,000mg iron/day or 2,500mg iron/day or active-control (sevelamer hydrochloride). Velphoro treatment was divided across meals, depending on dose. No dose titration was allowed. Within each of the groups, the serum phosphorus level at the end of treatment was compared to baseline value. Velphoro was shown to be efficacious (p≤0.016) for all doses except 250mg iron/day. There were no patient-reported dose limiting treatment emergent adverse events (AEs).
Mean changes in iron parameters (ferritin, TSAT and transferrin) and vitamins (A, D, E and K) were generally not clinically meaningful and showed no apparent trends across the treatment groups.
Velphoro had a similar gastrointestinal AE profile to sevelamer hydrochloride and no dose-dependent trend in gastrointestinal events was observed.
27-Week, Open-label, Randomised, Active-controlled, Parallel-group Safety and Efficacy Study (PA-CL-05A) followed by 28-week Safety Extension Study (PA-CL-05B) in Dialysis Patients with Hyperphosphataemia: 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, active controlled (sevelamer carbonate), parallel group study for up to 55 weeks. Adult patients with hyperphosphataemia (serum phosphorus levels ≥1.94 mmol/L) were treated with Velphoro at a starting dose of 1,000mg 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 Velphoro (1,000 to 3,000mg iron/day) or low dose (250mg iron/day) of Velphoro demonstrated superiority of the maintenance dose.
In Study PA-CL-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 Velphoro at a starting dose of 1,000mg iron/day (N=707) or active control (sevelamer carbonate, N=348) for 24 weeks.
At the end of week 24, 93 patients on hemodialysis whose serum phosphorus levels were controlled (<1.78 mmol/L) with Velphoro in the first part of the study, were re-randomized to continue treatment with either their week 24 maintenance dose (N=44 or a non-effective low dose control 250mg iron/day, N=49) of Velphoro for a further 3 weeks. Following completion of PA-CL-05A, 658 patients (597 on haemodialysis and 61 on peritoneal dialysis) were treated in the 28-week safety extension study (Study 05B) with either Velphoro (N=391) or sevelamer carbonate (N=267) according to their original randomisation.
Mean serum phosphorus levels were 2.5 mmol/L at baseline and 1.8 mmol/L at week 12 for Velphoro (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 (see Figure 1).
Click on icon to see table/diagram/imageSerum 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 Velphoro and sevelamer carbonate, respectively.
The mean daily dose of Velphoro over 55 weeks of treatment was 1,650mg iron and the mean daily dose of sevelamer carbonate was 6,960mg.
Serum phosphorus levels declined rapidly during the first few weeks of the titration phase, remaining relatively constant thereafter. The phosphorus lowering effect of Velphoro was consistently maintained through 12 months of treatment (see Figure 2).
Click on icon to see table/diagram/imagePost-authorisation data: 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.
Pharmacokinetics: Velphoro works by binding phosphate in the GI 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.
Absorption: 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 pn-FeOOH and be absorbed.
The iron uptake from radiolabelled Velphoro active substance, 2,000mg iron in 1 day was investigated in 16 chronic kidney disease (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 0.43% on Day 21. In CKD patients, the median uptake was minimal, 0.04% on Day 21. Blood levels of radiolabelled iron were very low and confined to the erythrocytes.
Distribution: Due to the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out. Therefore, there is no data to determine the distribution of the drug.
Biotransformation: 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.
Elimination: In animal studies with rats and dogs administered 59Fe-Velphoro active substance orally, radiolabelled iron was recovered in the faeces but not the urine.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
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. The observed epithelial hyperplasia, which is also observed in rats, is postulated to be due to chronic local irritation from high amounts of intraluminal Velphoro in the GI tract. Epithelial hyperplasia was not observed in chronic dog studies. In rats, there was a slightly increased incidence of benign C-cell adenoma in the thyroid of male rats given the highest dose of PA21. This is thought to be most likely an adaptive response to the pharmacological effect of the medical product and not clinically relevant.
