Hyperkalemia

Chronic Kidney Disease (CKD)

Congestive Heart Failure (CHF)

Renin-Angiotensin-Aldosterone (RAAS)

Overview
RLY5016 is a novel potassium-binding agent that has substantial clinical and commercial potential in treating hyperkalemia (elevated levels of serum potassium). Hyperkalemia can directly result in life-threatening arrhythmias (abnormal heart rhythms) which can lead to sudden death. Hyperkalemia is a particular problem in patients whose kidneys are not functioning effectively.  In addition, hyperkalemia can result from drugs that inhibit the renin angiotensin aldosterone system (RAAS), which are commonly prescribed for high blood pressure, kidney disease and heart failure. When hyperkalemia occurs in patients taking RAAS inhibitors, physicians typically reduce the dose or discontinue treatment, denying patients the benefits from these drugs.   Relypsa is working to develop RLY5016 for the acute and chronic treatment of hyperkalemia across multiple diseases with large patient populations and significant unmet medical need. The company expects to initiate Phase 3 clinical trials in 2012, with a planned NDA filing in 2013.

RLY5016 is composed of a calcium salt formulated with a proprietary polymer into spherical beads of a uniform size optimized to minimize gastrointestinal (GI) side effects and enhance palatability.  It is provided as a tasteless powder that can be suspended in liquid or mixed with semi-solid food. RLY5016 was discovered and optimized in-house by Relypsa scientists who synthesized and tested thousands of possible compounds. The selection process included screens that replicate the conditions of the gastrointestinal tract, and the polymer and its mechanism of action were optimized in animal models.

RLY5016 has broad patent protection comprising several families of issued patents or pending patent applications. Patent protection for RLY5016 is expected to last into 2029, with claims directed to compositions, methods, combination products, manufacturing methods, dosing regimens and formulations. Patents have already been granted in the United States (#7,556,799), Europe (#1 732 523) and several other jurisdictions.

Market Opportunity
Relypsa is pursuing a clinical development strategy for RLY5016 that will support a broad label comprising treatment of acute and chronic hyperkalemia regardless of etiology or patient population. Approximately 1 million people in the United States alone were diagnosed with hyperkalemia in 2007. Relypsa believes that, with the introduction of a safe and effective drug to treat hyperkalemia, the market may expand due to the current underutilization of RAAS inhibitors for the treatment of chronic kidney disease (CKD).

While maximal doses of RAAS inhibitors have been shown to effectively slow progression of CKD patients to dialysis by an average of 2.6 years (65%), they are frequently withheld or reduced to ineffective doses in patients with or at risk for hyperkalemia. Consequently, less than 30% of CKD patients receive effective RAAS doses. Lower doses of these agents have not been shown to be effective in slowing progression to End Stage Renal Disease (ESRD). It is estimated that 11 million people in the United States alone have Stage 3/4 CKD, of which more than 5 million could benefit from maximal RAAS therapy.

The availability of a safe and effective drug to treat hyperkalemia should enable dosing of RAAS agents at effective levels in more patients, potentially improving outcomes for CKD patients and delaying the onset of dialysis and ESRD. The target market in this indication is large, with approximately 3.75 million Stage 3/4 CKD patients in the US currently being treated with sub-optimal doses of RAAS drugs, despite medical guidelines supporting such treatment. The ability to treat hyperkalemia in patients receiving RAAS therapy may enable more effective treatment of CKD, which should slow disease progression.

RLY5016 has the potential to address a significant unmet medical need in the 1.4 million heart failure patients who also have reduced kidney function.  In one study, 40% of patients with heart failure were also found to have reduced renal function. Physicians reported that hyperkalemia is the key limiting factor for use of aldosterone antagonist (AA) therapy in these patients, and that they would use AAs in at least half of their heart failure patients if hyperkalemia could be avoided. RLY5016 also has the potential to enable more effective AA therapy in the 20% of patients who have hypertension that is resistant to standard drug therapy.

Mechanism of Action
RLY5016 works in the lower GI tract. Rather than binding to dietary potassium, RLY5016 binds to potassium in the colon. This reduces the amount of free potassium in the colon, causing additional potassium to move from the serum into the colon and reducing serum potassium levels. Once in the colon, this potassium is excreted with the feces, leading to a reduction in levels of serum potassium. Due to its proprietary polymer formulation, RLY5016 is not absorbed out of the digestive tract, eliminating systemic exposure and the potential for associated systemic adverse effects.

Preclinical Data
In preclinical studies RLY5016 has been shown to bind up to 1.5mEq of potassium per gram, and administration of RLY5016 to rats and pigs with normal renal function increased the fecal excretion of potassium. When RLY5016 was administered to rats with compromised potassium regulation (NADR-TQ model), serum potassium levels remained in the normal range while potassium excretion in feces increased. These results are consistent with the RLY5016 mechanism of action. Additionally, the preclinical data demonstrate that RLY5016 is safe and non-absorbed with no systemic exposure.

Clinical data
RLY5016 has been evaluated in two Phase 1 studies in healthy volunteers and three Phase 2 studies in patients with heart failure, CKD, or on hemodialysis. A Phase 2b study in patients with CKD and diabetic nephropathy treated with RAAS inhibitors was initiated in 2011 and is ongoing.

In the Phase 1 studies, RLY5016 doses of up to 60g/day were well tolerated by all subjects and there was no apparent dose-response relationship with respect to gastrointestinal adverse events. There were significant increases in fecal potassium excretion and decreases in urinary potassium excretion with increasing doses of RLY5016 compared with placebo. These results were observed when RLY5016 was dosed once, twice, or three times a day.

Phase 2 data demonstrate that RLY5016 significantly decreased serum potassium in heart failure patients on standard therapy who had reduced kidney function or a history of hyperkalemia in response to standard heart failure therapy. A significant reduction in the incidence of hyperkalemia compared with placebo also was observed. Use of RLY5016 allowed more patients to increase their dose of RAAS inhibitor medication compared with placebo. Another Phase 2 study evaluated the effects of individualized dose titration of RLY5016 according to serum potassium levels in patients with chronic kidney disease and heart failure. Results of this study showed that more than 90% of patients were able to maintain serum potassium within the desired target range while maximizing their heart failure therapy. Few titrations were necessary, with half of the patients requiring no more than one titration and 80% requiring no more than two.  All patients were able to increase their dose of RAAS inhibitor medication by Day 14 of the 49–day study period. A 50% reduction in the albumin to creatinine ratio (ACR, a measure of the amount of protein in the urine) was observed in a subset of patients with proteinuria.

Gastrointestinal adverse events (AEs) were the most common AEs observed in the completed Phase 2 trials of RLY5016, occurring in 16-21% of patients. These gastrointestinal AEs were mild to moderate and included abdominal pain/discomfort, flatulence, diarrhea, nausea and vomiting. The number of patients with at least 1 serious adverse event (SAE) and the number that discontinued from study due to AE were similar between the RLY5016 and placebo groups (4% vs. 4% and 7% vs. 6%).

Regulatory Strategy
In May 2011 Relypsa initiated a Phase 2b clinical trial of RLY5016 for the treatment of hyperkalemia in CKD patients with hypertension and diabetic nephropathy.  The trial, also known as AMETHYST-DN, will evaluate the safety and efficacy of RLY5016 in reducing hyperkalemia in patients who have moderate to severe kidney impairment and are being treated with RAAS inhibitors, including angiotensin receptor blockers (ARBs). The trial is an open-label, international, multicenter study enrolling both patients with pre-existing hyperkalemia and those that develop hyperkalemia during a run-in period of up to four weeks, during which they are treated with proven, guideline-recommended doses of an ARB. 

Under the study design, instead of discontinuing or reducing the dose of RAAS inhibitor therapies per treatment guidelines when serum potassium becomes elevated, up to 300 patients with hyperkalemia will be randomized to RLY5016 in order to reduce serum potassium and enable patients to remain on effective doses of RAAS inhibitors. The primary efficacy endpoint of the trial is mean change in serum potassium compared with baseline at four weeks.  Secondary endpoints include mean change in blood pressure and proteinuria.  Additionally, all patients completing eight weeks of treatment continue treatment for an additional 44 weeks, which will provide for a full year of safety monitoring.

Relypsa held an End of Phase 2 meeting with FDA in November 2011 to gain agreement on the clinical development plan, including the design of the Phase 3 pivotal trials. Based on guidance from that meeting, the company is in the process of designing a relatively small Phase 3 clinical program, which is expected to begin in mid 2012 and lead to an NDA filing in 2013.