Regulatory Decision Summary for Renvela

Two clinical trials were submitted in the present submission to support the equivalence of previously approved Renagel tablets to a new powder form of Renvela, and for the use of Renvela powder and tablets in pediatrics with hyperphosphatemia from chronic kidney disease (CKD). Hyperphosphatemia refers to an elevated concentration of phosphate in the blood (serum PO₄³- levels ≥1.46 mmol/L), which can increase the risk of bone mineralization defects, arterial calcification, and mortality in adult and pediatric patients with end-stage renal kidney disease (ESRD) who are on dialysis.

The equivalence between the efficacy of Renvela powder and Renagel tablets was evaluated in an open-label, cross-over clinical trial in 21 adults with ESRD and hyperphosphatemia on hemodialysis. The primary endpoint was averaged serum phosphate levels over the 4-week randomized treatment period for each dosage form. The study showed that Renagel tablets and Renvela powder were equivalent in controlling serum phosphorus levels in the population studied.

The safety and efficacy of Renvela tablets and powder in pediatric patients with hyperphosphatemia secondary to CKD was supported by one pivotal multi-centre study in 101 patients (6-18 years old). The study had a 2-week randomized, double-blind, placebo-controlled, fixed dose period followed by a 6-month, single-arm, open-label, dose titration period. Most patients were 13 to 18 years of age (73%), had a body surface area (BSA) ≥1.2 m² (84%), and were in ESRD (78%) undergoing dialysis (77%).

For the primary efficacy endpoint, Renvela powder or tablets at a fixed dose of 2.4 g/day (BSA ≥0.75 to <1.2 m²) or 4.8 g/day (BSA ≥1.2 m²) significantly reduced serum phosphate during the 2-week randomized period by a least squares mean difference of -0.29 (SE 0.087) mmol/L compared to placebo (p=0.001). No treatment response was observed in patients that had mild baseline hyperphosphatemia (<2.26 mmol/L). A similar treatment response was observed in patients who received titrated doses of Renvela during the 6-month open-label period. Although only 27% of patients on Renvela reached their age-appropriate normal serum phosphate level by the end of that period, most had a meaningful reduction in phosphate (based on clinical experience in adults). As there was a lack of efficacy in patients with mild hyperphosphatemia, the revised Product Monograph (PM) indicates that Renvela is not recommended for children who have mild hyperphosphatemia.

Renvela was well tolerated in pediatric patients, and most adverse events likely related to treatment were gastrointestinal (GI) in nature. In general, the adverse event profile for pediatric patients was similar to the profile observed in adults, with no new identified safety signals. This was expected as Renvela is not absorbed in the body. Following review, the PM was revised to mitigate the potential risks of hypophosphatemia and GI disturbances, to clarify the dosing, administration and titration practices, and to reduce choking hazard in small children. Uncertainty remains about the long-term developmental effects of Renvela in pediatric patients as the pediatric study was short and no data from juvenile animal studies was available to Health Canada. As Renvela could impact serum levels of nutrients essential for proper development, the PM recommends the monitoring of serum levels of vitamins and minerals and advises supplementation, as necessary.

An EU Risk Management Plan (RMP) Version 8.2 and Canadian Addendum Version 1.0 for Renvela was submitted by the Sponsor to Health Canada, Marketed Health Product Directorate which upon review was acceptable.

In summary, Renvela powder and Renagel tablets were equivalent in controlling serum phosphorus levels in hyperphosphatemic adults with ESRD. Renvela tablets and the new powder form in hyperphosphatemic pediatric patients with ESRD showed a meaningful reduction in serum phosphate. According to the population studied, an indication was granted in children ≥6 years of age with a BSA ≥0.75 m² who have ESRD and are undergoing dialysis. The safety profile of Renvela in the pediatric population studied was consistent with its known profile in adults. Since the long-term effects of Renvela in pediatric patients are uncertain, careful monitoring of serum levels of vitamins and minerals are recommended in the PM. Overall, Renvela has a favourable benefit-risk-uncertainty profile and represents a new option for the control of hyperphosphatemia in pediatric patients (≥6 years and BSA ≥0.75 m²) with ESRD undergoing dialysis. A Notice of Compliance, pursuant to section C.08.004 of the Food and Drug Regulations is recommended.