Regulatory Decision Summary for Veltassa
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
A New Drug Submission (NDS) for Veltassa (Patiromer sorbitex calcium) was filed to seek approval for the treatment of hyperkalemia in adults.Upon review, Health Canada approved the following indication: Veltassa (patiromer as patiromer sorbitex calcium) is indicated for the treatment of hyperkalemia in adults with chronic kidney disease (estimated glomerular filtration rate [eGFR] ≥15 mL/min/1.73 m2).
Hyperkalemia refers to an elevated concentration of potassium in the plasma (serum K+ levels >5.0 mmol/L), and represents a serious condition that can cause life-threatening cardiac arrhythmias, and increase the risk of mortality.
Why was the decision issued?
The safety and efficacy of Veltassa was primarily supported by a phase 3 pivotal study with 243 subjects and a phase 2 long-term (1 year) dose-ranging study with 304 subjects. Subjects enrolled in both trials were adults with chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] ≥15 and <60 mL/min/1.73m2) who had chronic hyperkalemia (serum potassium of 5.1 to <6.5 mmol/L), on a stable dose of at least one renin-angiotensin-aldosterone system inhibitor (RAASi), and may have had heart failure, type 2 diabetes, and hypertension. They were enrolled throughout Europe, and were mostly elderly (mean age of 65-66 years) and Caucasian. The pivotal trial was conducted in two sequential parts; part A consisted of a 4 week period that assessed the extent that Veltassa reduced serum potassium levels, after which the responders were randomized to continue Veltassa treatment or placebo in part B. The primary endpoints were mainly the serum potassium changes from baseline to week 4.
In the pivotal trial, Veltassa at a titrated dose of 8-37 g/day patiromer caused a clinically relevant mean reduction in serum potassium from baseline of -1.07 mmol/L [95% CI: -1.07; -0.95; p<0.001] in the overall study population. Furthermore, 76% [95% CI: 70%; 81%] of subjects were within the serum potassium target range at week 4 (3.8 to <5.1 mmol/L). In subjects that progressed into part B of the study, continued treatment with Veltassa caused no change in serum potassium (0 mmol/L [95% CI: -0.3; 0.3]) in the active treatment group, whereas there was an increase of 0.72 mmol/L [95 CI: 0.46; 0.99] in the group switched to placebo (p<0.001). Fewer subjects discontinued or reduced the dose of their RAASi in the Veltassa compared to placebo group throughout part B (RAASi adjustment; patiromer: 16%; placebo: 62%; p<0.001). The results of the phase II dose-ranging study showed that Veltassa caused a mean change from baseline in serum potassium at week 4 of -0.47 mmol/L and -0.92 mmol/L in subjects with a baseline serum potassium of 5.0 to 5.5 mmol/L and >5.5 to 6.0 mmol/L, respectively. Serum potassium was within the target range for approximately 80% of the long-term maintenance period (up to 44 weeks). Efficacy was consistent across age, gender, region, assessed CKD stages, and subjects with and without diabetes.
Throughout all the studies in the clinical development program, Veltassa was well tolerated at the proposed doses. The safety profile of Veltassa was primarily defined by gastrointestinal (GI) adverse events (AEs). In the overall safety pooled population consisting of 666 subjects in all clinical trials, the most common drug-related AEs were constipation (6.2%), hypomagnesemia (5.3%), diarrhea (3.0%), abdominal pain (2.9%), flatulence (1.8%), and hypokalemia (1.5%). Gastrointestinal events tended to occur within the first 30 to 60 days of Veltassa treatment, were typically mild and moderate in nature, and could be managed effectively. Hypokalemia was mild to moderate in nature (<3.0 to 3.5 mmol/L), and the frequency reported in the overall safety pooled population (4.7%) was based on clinical trials that used fixed-dose regimens (higher hypokalemia frequency of ~7%) as well as individualized dose titrations (lower hypokalemia frequency of ~1.5-2.5%). In order to mitigate potential risks of developing hypokalemia, the Dosing Considerations and Cautions and Warnings sections of the Product Monograph recommend the monitoring of serum potassium levels; the dose of Veltassa should be down-titrated if serum potassium levels decrease below 3.5 mmol/L or the desired target range.
Based on mechanism of action, there is a concern for its interaction with other medications taken orally. According to drug-drug interaction studies conducted with 12 medications commonly used by hyperkalemic patients, Veltassa had clinically meaningful interactions with ciprofloxacin, levothyroxine and metformin. However, there were no interactions observed when these medications were taken 3 hours apart from Veltassa. As a precaution, the Product Monograph states in the Dosing Considerations section that Veltassa should be separated by 3 hours from other orally administered drugs, and details outlining all pertinent in vitro and clinical drug interaction studies are outlined in the Drug-Drug Interactions section.
Veltassa has shown clinically meaningful reductions of serum potassium in hyperkalemic patients with CKD with a majority of patients achieving normal serum potassium levels within 4 weeks of treatment. As an additional benefit, Veltassa treatment allowed fewer hyperkalemic patients to discontinue or reduce the dose of their RAASi, thereby promoting the therapeutic benefits of RAAS inhibition in the target population. The safety profile of Veltassa was primarily defined by gastrointestinal AEs, hypomagnesemia, and hypokalemia. Warnings on the product monograph and patient monitoring can help mitigate these safety risks. Overall, the clinical studies demonstrated that Veltassa has a favourable benefit/risk profile which offers a new option for the treatment of hyperkalemia in adult patients with CKD (eGFR ≥15 mL/min/1.73m2).
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.
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