Summary Basis of Decision for Velphoro

Clinical Pharmacology

Velphoro (sucroferric oxyhydroxide) is a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water in sucroferric oxyhydroxide and the phosphate ions throughout the physiological pH range of the gastrointestinal tract. The bound phosphate is eliminated with feces. Both serum phosphorus levels and calcium-phosphorus product levels are reduced as a consequence of the reduced dietary phosphate absorption.

Given 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, etc.). The Phase I clinical program, therefore, focussed on measures of phosphate binding capacity, iron release and absorption, and drug-drug interactions.

A significant reduction in serum phosphorus levels was seen in chronic kidney disease patients treated with Velphoro 2,000 mg iron/day for 7 days, but not in healthy subjects. Similarly, no changes in serum phosphate were seen in a Phase I dose-ranging tolerability study in healthy subjects. Velphoro was well tolerated in both Phase I studies with mainly mild gastrointestinal adverse events reported (e.g., diarrhea and discoloured feces) and showed only minimal iron absorption.

Studies in healthy volunteers have shown a low risk of drug-drug interactions between Velphoro and some drugs commonly used in dialysis patients including losartan, furosemide, digoxin, warfarin, and omeprazole. However, a potential adsorption of levothyroxine, doxycycline and alendronate by Velphoro has been reported. Therefore, these potential drug-drug interactions have been highlighted in the Velphoro Product Monograph, with recommendations for administering alendronate, doxycycline and levothyroxine separately from Velphoro.

The clinical pharmacological data support the use of Velphoro for the specified indication.

For further details, refer to the Velphoro Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The ability of Velphoro to lower serum phosphorus in end-stage renal disease patients on dialysis was demonstrated in two pivotal clinical trials:

• Study PA-CL-03A, a Phase II, 6-week, open-label, randomized, active-controlled (sevelamer hydrochloride), parallel group, dose-finding study; and
• Study PA-CL-05A, a Phase III, 27-week, open-label, randomized, active-controlled (sevelamer carbonate), parallel group, safety and efficacy study, and its 28-week extension, Study PA-CL-05B, with a total duration of 55 weeks.

The open-label design of the trials conducted with Velphoro was necessitated by the chewed or crushed ingestion of Velphoro as compared to the whole tablet ingestion of the active comparators. In addition, fecal discolouration with the iron-based Velphoro precluded double blinding.

A total of 835 patients have been treated with Velphoro in the pivotal clinical trials at doses up to 3,000 mg iron/day (15 g/day sucroferric oxyhydroxide).

The efficacy endpoints included change from baseline in serum phosphorus levels at the end of treatment and at various time points.

The dose-finding Study PA-CL-03A enrolled a total of 154 adult patients with end-stage renal disease on hemodialysis and with serum phosphorus levels ≥1.78 mmol/L. The primary objective of Study PA-CL-03A was to investigate the ability of different doses of Velphoro (250 mg iron/day to 2,500 mg iron/day, equivalent to 1.25 g/day to 12.5 g/day sucroferric oxyhydroxide, as hereafter referred to) to lower serum phosphorus levels in patients with chronic kidney disease on maintenance hemodialysis. A priori assumption was that the lowest dose group (1.25 g/day) would be an inactive control group. The study demonstrated that the two highest doses of Velphoro (12.5 g/day and 10.0 g/day) were significantly (p<0.05) superior to the Velphoro low-dose control group (1.25 g/day) in lowering serum phosphorus levels from baseline to end of treatment. The 1.25 g/day dose of Velphoro was found to be ineffective. The phosphorus lowering effect of Velphoro appeared dose-related. The maximum response and the clinically relevant change of 0.65 mmol/L were achieved with the dose of 10.0 g/day.

The efficacy of Velphoro in lowering serum phosphorus levels has been further demonstrated and confirmed in the pivotal Phase III trial (Study PA-CL-05A) and its extension (Study PA-CL-05B). Study PA-CL-05A enrolled a total of 1,055 chronic kidney disease patients on hemodialysis or peritoneal dialysis, whose serum phosphorus levels were ≥1.94 mmol/L.

In Stage 1 of the Study PA-CL-05A, Velphoro was shown to be non-inferior to sevelamer carbonate in lowering serum phosphorus in chronic kidney disease patients (undergoing hemodialysis or peritoneal dialysis) after 12 weeks of treatment. The treatment difference (Velphoro versus sevelamer carbonate) was 0.08 mmol/L with 97.5% confidence interval (CI) upper limit of 0.15 mmol/L, which was below the 0.19 mmol/L predefined non-inferiority margin. The mean dose used after 12 weeks of treatment was 10.0 g/day for Velphoro and 8.2 g/day for sevelamer carbonate.

Stage 2 of the study was structured to establish the superiority of the Velphoro maintenance dose identified in Stage 1 versus a Velphoro low-dose control in maintaining the phosphorus lowering effect in patients undergoing hemodialysis. The low-dose control used in Stage 2 was the Velphoro 1.25 g/day dose that was found to be ineffective in Study PA-CL-03A. Switching to the ineffective Velphoro low dose (in patients in whom the effective dose was withdrawn following re-randomization) resulted in a rapid rise in mean serum phosphorus levels, confirming the long-term efficacy of Velphoro.

Maintenance of effect has been demonstrated after 24 weeks of treatment. Mean serum phosphorus levels in both the Velphoro group and the sevelamer carbonate group remained steady throughout the maintenance phase of Study PA-CL-05A, and throughout the extension Study PA-CL-05B. The phosphorus lowering effect of Velphoro was consistent and similar to the effect observed with sevelamer carbonate across all subgroups (dialysis type, sex, age, region, and race) over 52 weeks of treatment. The decrease in serum phosphorus levels seen in Stage 1 of Study PA-CL-05A was similar across subjects undergoing peritoneal dialysis and hemodialysis, when compared both within Velphoro-treated subjects, and between the Velphoro and sevelamer treatment groups. This was in line with studies of other phosphate binders where the efficacy of the drugs was found to be consistent, irrespective of the modality of dialysis.

For more information, refer to the Velphoro Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical development program of Velphoro included 1,112 subjects (chronic kidney disease patients and healthy volunteers) treated with Velphoro for up to 55 weeks. In the integrated data from Study PA-CL-05A and its extension, Study PA-CL-05B (described in Clinical Efficacy section), over 500 subjects treated with Velphoro have completed at least 24 weeks of treatment, and over 300 subjects have completed at least 52 weeks of treatment, with a total of 470.5 person-years of exposure. A total of 610 subjects (86.3%) were exposed to more than 7.5 g/day (1,500 mg iron/day), the proposed starting dose for Velphoro, for an average duration of 223.7 days.

The safety profile of Velphoro is primarily defined by gastrointestinal adverse events, which is to be expected, since the drug is practically insoluble and hardly absorbed. Most commonly reported gastrointestinal adverse events were diarrhea (23.6%) and discoloured feces (16.1%). The laxative action of Velphoro has been noted in all studies, including those conducted in healthy volunteers. In most subjects, diarrhea occurred early after starting treatment, it was mild in severity, and resolved with continued use of Velphoro. Diarrhea was the most common treatment-related adverse event causing discontinuation in the Velphoro group. The incidence of diarrhea in the Velphoro group was substantially lower in the extension Study PA-CL-05B, providing further support for the early onset and transient nature of these events. Discoloured feces is an expected event for an oral iron-based compound. The relatively low incidence of discoloured feces reported in the clinical program suggests that many patients do not consider this event to be of concern.

Constipation is a concern in chronic kidney disease patients on dialysis, occurring in over 60% of patients, and it is also commonly reported with the use of oral iron medications. Throughout the clinical development program, there has been no indication that constipation is a concern with the use of Velphoro. The incidence of constipation with Velphoro was low (5.1%) over 52 weeks in Studies PA-CL-05A and PA-CL-05B, and the majority of reported events were mild in severity.

Very few serious adverse events were related to treatment, and they were generally attributed to the gastrointestinal disorders. Although the incidence of serious adverse events was similar between Velphoro and sevelamer, a higher proportion of patients discontinued treatment due to treatment-emergent adverse events in the Velphoro group compared to the sevelamer group (number of patients [n] = 148; 20.9% versus n = 36; 10.3%, respectively, in the integrated data from Studies PA-CL-05A and PA-CL-05B). Gastrointestinal adverse events were the most common adverse events leading to withdrawal in both groups, accounting for 70 of 148 withdrawals (47.3%) in the Velphoro group and 11 of 36 (30.6%) in the sevelamer group. In the extension Study PA-CL-05B, discontinuation rates were markedly lower among the Velphoro-treated patients, but they remained higher compared to the sevelamer group.

Overall, there were 21 deaths in subjects treated with Velphoro during the Phase II and Phase III studies, none of which were considered related to treatment. In keeping with the end-stage renal disease patient population, most of the deaths involved cardiac or cardiorespiratory events, and the overall death rate was similar between the two treatment groups.

Velphoro is an iron-based phosphate binder and non-clinical studies have shown minimal release of iron from Velphoro in the gastrointestinal tract. No significant changes in iron parameters were noted in the Phase I studies or in the short-term Study PA-CL-03A. In Studies PA-CL-05A and PA-CL-05B, serum ferritin, serum iron and transferrin saturation for subjects receiving Velphoro showed increases, which occurred early during treatment and stabilized thereafter. No clinically meaningful changes in hemoglobin or hematocrit were noted. In current clinical practice, chronic kidney disease patients on dialysis are commonly administered intravenously significant amounts of iron averaging 5 to 7 mg per day. In a Phase I study, subjects on hemodialysis had a median uptake of 0.02% of iron from Velphoro. This would equate to absorption of 0.6 mg iron/day following administration of the maximum proposed daily dose of 1.5 g iron/day Velphoro. The iron status, including hemoglobin is regularly assessed in the chronic kidney disease patients on dialysis. Consequently, any increase in iron stores will be detected early, and adjustments to their intravenous iron treatment made accordingly. Therefore, the risk of potential iron accumulation with long-term treatment with Velphoro is minimal, and an appropriate wording has been included in the Warnings and Precautions section of the Velphoro Product Monograph.

No safety signals were detected with respect to clinical chemistry, hematological, or vitamin levels. Post hoc analyses from clinical studies demonstrated that Velphoro did not impact the intact parathyroid hormone lowering effect of oral vitamin D analogues. Vitamin D and 1,25-hydroxy vitamin D levels remained unchanged. No changes in electrocardiogram parameters or vital signs were seen. In Study PA-CL-05A and its extension, Study PA-CL-05B, there were significant decreases in fibroblast growth factor 23 (FGF-23) (responsible for phosphate and vitamin D metabolism) in both treatment groups, with no significant difference between treatment groups. Significant increases in bone-specific alkaline phosphatase were observed in both treatment groups, with a significantly higher increase in the sevelamer group. However, given that serum intact parathyroid hormone, calcium, and vitamin D levels remained relatively stable, the small changes in bone-specific alkaline phosphatase which occurred concurrently with the control of serum phosphorus levels during long-term treatment with Velphoro were not considered clinically relevant.

Overall, Velphoro has a comparable safety profile to sevelamer. No signs of increased numbers of adverse events related to Velphoro were seen in the post-marketing experience.

Appropriate warnings and precautions are in place in the approved Velphoro Product Monograph to address the identified safety concerns.

For more information, refer to the Velphoro Product Monograph, approved by Health Canada and available through the Drug Product Database.