Clinical Trials

Date: 2016-06-27

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in Kidney International

Company: Relypsa (USA - CA)

Product: patiromer

Action mechanism: Patiromer (RLY5016 for Oral Suspension) is a high capacity non-absorbed, non-metal oral potassium binder being developed for the treatment of hyperkalemia. The compound has been evaluated in CKD patients with hyperkalemia, including a two part Phase 3 study, a 12-month Phase 2 trial and a 48-hour short-term Phase 1 onset-of-action study. In all of those studies, patiromer met its efficacy endpoints and the treatment was well tolerated.

Disease: hyperkalemia

Therapeutic area: Cardiovascular diseases - Metabolic diseases

Country: USA

Trial details: The two-part Phase 3 clinical trial was conducted under special protocol assessment (SPA) with the FDA. Part A, in which all participants received patiromer, was a single-blind trial in 243 patients with hyperkalemia (102 HF, 141 non-HF) who were also being treated with RAAS inhibitor medications. The primary endpoint of Part A was the change in serum potassium from Part A baseline to Part A week 4. Part B, the placebo controlled randomized withdrawal phase of the trial, was designed to provide additional evidence of the efficacy of patiromer in treating hyperkalemia and to assess the need for chronic dosing. Patients from Part A whose baseline serum potassium level was greater than or equal to 5.5 mEq/L at enrollment and whose serum potassium level was controlled at week 4 were eligible for Part B. These patients were then randomized into two groups: one to continue on patiromer (27 HF, 28 non-HF), and a second to receive placebo (22 HF, 30 non-HF) instead of patiromer for an additional eight weeks. The primary endpoint for Part B was the difference between the patiromer and placebo groups in the change in serum potassium from Part B baseline to Part B week 4 or to an earlier time point when the patient first had serum potassium less than 3.8 mEq/L or greater than or equal to 5.5 mEq/L.

Latest news:

• • On June 27, 2016, Relypsa announced that results of a pre-specified exploratory analysis of the Phase 3 OPAL-HK trial of Veltassa® (patiromer) for oral suspension were published online by Kidney International, the journal of the International Society of Nephrology. The previously published OPAL-HK study evaluated Veltassa® in patients with hyperkalemia (elevated blood potassium levels) and chronic kidney disease who were taking renin angiotensin aldosterone system (RAAS) inhibitors. Results of this newly published analysis found that patients taking Veltassa® in the study had significant decreases in systolic and diastolic blood pressure and reduced levels of aldosterone in the blood.
• Results of Pre-Specified Analysis of OPAL-HK Trial: The main results of the pivotal Phase 3 OPAL-HK study of Veltassa® were previously published in the New England Journal of Medicine (See below). This pre-specified exploratory analysis examined the effect of Veltassa® on systolic and diastolic blood pressure, as well as various cardiovascular and renal biomarkers including: levels of aldosterone in the blood, plasma renin activity (PRA; a measure of the activity of the plasma enzyme, renin, which regulates angiotensin and aldosterone production), and urinary albumin-to-creatinine ratio (UACR; a test used to diagnose and monitor kidney disease by evaluating how much albumin is excreted in the urine). Results of this analysis are summarized below. During the initial four-week treatment phase, when all patients were taking Veltassa®:
• - Systolic blood pressure significantly decreased by -5.64 mmHg and diastolic blood pressure significantly decreased by -3.84 mmHg (p < 0.0001 for both).
• - Mean levels of aldosterone in the blood significantly decreased by -1.99 ng/dL (p=0.0001).
• - PRA did not change.
• - UACR significantly decreased by -203.7 mg/g (p=0.0003). Following the initial treatment phase, during the eight-week randomized placebo-controlled withdrawal phase:
• - Mean systolic blood pressure and diastolic blood pressure were significantly reduced in patients taking Veltassa® (- 6.70 mmHg; p < 0.0001 and -2.15 mmHg; p?0.05, respectively); in patients taking placebo, mean changes in systolic blood pressure and diastolic blood pressure were not significant (-1.21 mmHg and +1.72 mmHg, respectively).
• - Mean aldosterone levels were maintained at baseline levels in patients taking Veltassa (+0.23 ng/dL); in patients taking placebo, levels significantly increased (+2.78 ng/dL; p?0.03).
• - There were no statistically significant changes in PRA in patients taking Veltassa®; PRA significantly decreased in patients taking placebo (-3.90 µg/L/hr; p=0.0067).
• - By the end of the withdrawal phase, 94 percent of patients in the Veltassa® group were still receiving their RAAS inhibitor medication, compared with 44 percent of patients in the placebo group. Among patients in the placebo group, 52 percent discontinued RAAS inhibitor therapy because their hyperkalemia was insufficiently controlled while taking these medications.
• • On November 21, 2014, Relypsa, a biopharmaceutical company, announced that results from the pivotal Phase 3 program of Patiromer for Oral Suspension (Patiromer FOS), were published in the New England Journal of Medicine. Last month, the company announced that it had submitted a New Drug Application to the FDA for Patiromer FOS for the treatment of hyperkalemia. All endpoints were met in the two-part Phase 3 program consisting of a treatment phase, which was designed to assess the ability of Patiromer FOS to correct hyperkalemia, and a placebo-controlled randomized maintenance phase designed to evaluate the effect of continued treatment with Patiromer FOS on potassium control and ability of patients to continue RAAS inhibitor therapy compared to placebo. In the treatment phase, among 237 evaluable patients receiving Patiromer FOS, the mean change in the serum potassium level was ?1.01 mEq/L (P<0.001). At week 4, 76% (95% confidence interval) of the patients were within the target potassium level (3.8 to < 5.1 mEq/L). Subsequently, 107 patients were randomly assigned to Patiromer FOS (55 patients) or placebo (52 patients) for the maintenance phase. Of note during this phase, the Patiromer FOS group had no change in median potassium from baseline, but in the placebo group, median serum potassium increased (P<0.001). Further, a recurrence of hyperkalemia (serum potassium level >= 5.5 mEq/L) occurred in 60% of the patients in the placebo group as compared with 15% in the Patiromer FOS group through week 8 (P<0.001). In a pre-specified analysis, 44% patients in the placebo group as compared with 94% in the Patiromer FOS group were still receiving RAAS inhibitor therapy at the end of the study. Mild-to-moderate constipation was the most common adverse event (11% of the patients in the treatment phase and 4% in the Patiromer FOS group in the maintenance phase). Importantly, there was no evidence of drug-induced edema or urinary tract infections. The hypokalemia rate over the 4 week treatment period was low (3%) and no patients in the maintenance phase experienced hypokalemia. No serious drug-related adverse events were reported in either the treatment or maintenance phases.
• * On September 15, 2014, Relypsa announced that data in heart failure (HF) patients from its pivotal Phase 3 clinical trial of patiromer were presented as a late-breaking oral presentation at the 18th Annual Scientific Meeting for the Heart Failure Society of America (HFSA) being held in Las Vegas. Consistent with the results from the overall population, patiromer rapidly corrected hyperkalemia and prevented recurrence of this serious condition in heart failure as well as non-heart failure patients. In addition, the data showed that fewer patients treated with patiromer discontinued guideline recommended renin-angiotensin-aldosterone-system inhibitor (RAASi) therapy compared to placebo. The data, which were generated as part of Relypsa\'s Phase 3 program for patiromer, were presented at HFSA by Dr. Pitt. The two-part Phase 3 clinical trial was conducted under special protocol assessment (SPA) with the FDA. Part A, in which all participants received patiromer, was a single-blind trial in 243 patients with hyperkalemia (102 HF, 141 non-HF) who were also being treated with RAAS inhibitor medications. The primary endpoint of Part A was the change in serum potassium from Part A baseline to Part A week 4. Part B, the placebo controlled randomized withdrawal phase of the trial, was designed to provide additional evidence of the efficacy of patiromer in treating hyperkalemia and to assess the need for chronic dosing. Patients from Part A whose baseline serum potassium level was greater than or equal to 5.5 mEq/L at enrollment and whose serum potassium level was controlled at week 4 were eligible for Part B.
• All Part A and Part B efficacy endpoints for patients with and without HF were met. For the Part A primary endpoint, a statistically significant reduction in serum potassium of 1.06 mEq/L (p < 0.001) was demonstrated in patients with HF which was similar to the reduction demonstrated for those without HF. For the Part B primary endpoint, the difference between the placebo and the patiromer groups in the median change from Part B baseline in serum potassium in patients with HF was 0.64 mEq/L(95% CI, 0.29, 0.99), p < 0.001; which was also similar to that demonstrated in patients without HF. In addition, fewer heart failure patients in the patiromer group experienced recurrent hyperkalemia than the placebo group (8 percent compared to 52 percent, p < 0.001) with a similar trend in non-heart failure patients (23 percent compared to 66 percent, p < 0.001). Consequently, more patiromer-treated patients remained on guideline-recommended RAASi therapy compared to placebo. Patiromer was well tolerated in both HF and non-HF patients with a low risk of hypokalemia.

Is general: Yes