Hello, and thank you for joining us for this presentation on novel approaches to understanding risks and treatment of hyperkalemia.

Hello, and thank you for joining us for this presentation on novel approaches to understanding risks and treatment of hyperkalemia. PP-US-DSE-00032. 2015 Relypsa, Inc. All rights reserved. Relypsa and the Relypsa logo are trademarks of Relypsa, Inc. 1

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There are 4 main objectives that I d like to cover with you today: First, to review the definition, prevalence, and risk of hyperkalemia Second, to review why RAASi are recommended in guidelines Third, to understand how hyperkalemia can be a barrier to implementing guidelinerecommended therapies And finally, to describe current approaches for managing hyperkalemia 3

Let s begin with reviewing the definition, prevalence, and risks associated with hyperkalemia 4

The definition of hyperkalemia, or elevated serum potassium, can vary across clinical studies and from physician to physician. The normal serum potassium range is typically considered between 3.8 and 5.0 meq/l; however, this can vary. The upper limit of normal in published studies is typically 5.0, 5.5, or 6.0 meq/l. 5

While in clinical studies with strict exclusion criteria related to impaired kidney function, baseline serum potassium levels can be relatively low, real-world studies examining hyperkalemia rates (hyperkalemia defined as >5.5 meq/l) have shown very high rates of hyperkalemia. As you can see, the risk of hyperkalemia increases in patients as kidney function declines, as defined by CKD stage. 6

This is an analysis from the Humedica database that included 1.63 million persons aged 5 years who had potassium values assessed on 2 dates between 2008 and 2012. Hyperkalemia was defined as highest reported potassium value 5.1 meq/l in 2008 to 2012. The study included patients with values between 2.5 and 10 meq/l during 2008 to 2012 to exclude any values at either extreme of the spectrum. The control population was composed of patients 65 years without CKD stages 2 to 5, heart failure, diabetes, or ESRD. These data highlight that hyperkalemia is frequent as kidney function declines in patients with CKD. 7

HCUPnet is a free, online query system based on data from the Healthcare Cost and Utilization Project (HCUP). It provides access to health statistics and information on hospital inpatient and emergency department utilization. In 2011, nearly 70,000 emergency department visits were related to hyperkalemia; of these, approximately 45,000 were for Medicare members. Nearly 40,000 hospitalizations were also reported for patients with hyperkalemia; of these, nearly 30,000 were for Medicare members. These hospitalizations for Medicare admissions equaled nearly $700 million in costs and the average length of stay was 3.2 days. Clearly, hyperkalemia represents a burden to our health care system. 8

There has been debate about whether patients with chronic kidney disease can become tolerant to elevated levels of serum potassium. Dr. Collins and Dr. Pitt conducted an elegant study that was presented at the 2014 American Society of Nephrology. In this analysis, they looked at de-identified medical records of individuals with at least 2 serum K + readings collected from a Humedica database in Cambridge, Massachusetts, between 2007 and 2012. Comorbidities were identified using ICD-9 diagnosis codes. Mortality was then evaluated through hospital discharge records or the Social Security registry. This data set of more than 400,000 patients included a diverse patient population with >50% RAASi utilization in the last 12 months, >20% heart failure, and >40% diabetes. 9

These data highlight that in an elderly population (mean age of 74 years), there is a significant increase in mortality risk at serum potassium levels below 4.1 meq/l and above 5.0 meq/l in patients with stages 3 to 5 CKD. Confidence around these curves were extremely tight as represented by the shaded area around the blue and orange lines. This increase remained after adjustment for patient comorbidities. 10

In 2009, Lisa Einhorn published data from Veterans Affairs including nearly 250,000 veterans with at least one serum potassium measurement during 2005. Here you see the increased risk of death within 24 hours of a hyperkalemic event based on serum potassium level. As you can see, as potassium levels increase, so does the risk of mortality. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD. 11

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Two pivotal studies support the use of the angiotensin II receptor blocker in patients with diabetic nephropathy. The landmark RENAAL study randomized over 1500 patients to losartan or placebo with an average follow-up of over 3 years. 13

IDNT was the second landmark study of diabetic nephropathy to establish the benefit of ARBs in this condition. This study included over 1700 patients, and randomized patients to irbesartan, the calcium channel blocker amlodipine, or placebo and had a follow-up of approximately 2.5 years. 14

As these graphs illustrate, the use of ARBs delays the progression of chronic kidney disease defined as death, progression to dialysis, or a doubling of the serum creatinine. These data are why ARBs are the cornerstone therapy recommended by the guidelines for patients with diabetic nephropathy. 15

It is important to note that these 2 pivotal trials built in design features within their protocols to minimize the risk of hyperkalemia. RENAAL excluded patients with serum potassium levels >5.5 meq/l, patients using NSAIDs, and patients with a serum creatinine >3.0 mg/dl. Similarly, IDNT excluded patients with elevated serum potassium and patients with serum creatinine >3.0 mg/dl. In addition, close monitoring of these patients was conducted in 3-month intervals. IDNT also incorporated measures to treat hyperkalemia over 6.0 meq/l to try to keep patients in the study. 16

Despite this careful patient selection and monitoring, rates of hyperkalemia were 18.6% with irbesartan using a >6.0 meq/l cut-off and 10.8% with losartan using >5.5 meq/l as a cut-off. These rates of hyperkalemia were 2 to 3 times higher than seen with placebo. 17

In a more recent study called NEPHRON-D, nearly 1500 patients with diabetic nephropathy were randomized to receive either losartan alone or the combination of losartan with the ACEi lisinopril. This study was prematurely stopped in 2012 due to safety concerns (serious adverse events, hyperkalemia, and acute kidney injury) related to the dual RAASi arm. The risk of hyperkalemia using a cut-off of >6.0 meq/l was 4.5% in the losartan alone arm and 9.9% in the combination arm. 18

I think we all know from clinical practice that hyperkalemia is a major reason for either not starting or discontinuing RAASi therapy in patients with CKD. Surprisingly, there is little published information on how frequently patients are not receiving RAASi therapy because of hyperkalemia. In this study of 279 CKD patients with a baseline egfr of 33 ml/min/1.73 m 2 and a baseline serum potassium of 4.7 meq/l, hyperkalemia was a common reason for not starting RAASi therapy and the number 1 reason for discontinuing RAASi therapy. 19

We previously reviewed the RENAAL and IDNT studies, which contain some of the key evidence that drives the recommendations seen in guidelines such as the K/DOQI guidelines from the National Kidney Foundation. These guidelines recommend that patients with CKD receive either an ACEi or an ARB; importantly, moderate to high doses should be targeted. The guidelines recommend continuing therapy if patients do not have a GFR decline of 30% over 4 months or a serum potassium level >5.5 meq/l. If hyperkalemia develops, the guidelines recommend cutting the dose in half and reassessing serum potassium approximately a week later. If the hyperkalemia does not resolve, the recommendation is to switch the patient to an alternative antihypertensive medication that may not offer the renoprotection of a RAASi. 20

It s also important to remember that a large portion of patients with CKD have heart failure and/or diabetes. This large, epidemiologic study published by Dr Go in the New England Journal of Medicine looked at over 1,000,000 patients who had an egfr assessed between 1996 and 2000. As these data clearly show, as kidney function declines, the chances of the patient having comorbid heart failure or diabetes rises. While I won t go into details, the patients with heart failure were receiving standard of care, which may have included an aldosterone receptor antagonist, because they demonstrated benefits related to mortality and hospitalizations related to heart failure. Of course, we know that these potassium-sparing diuretics can further increase serum potassium. 21

Finally, at the European Society of Cardiology meeting last year, one of the most discussed late-breaking trials was related to the PARADIGM-HF trial. In this trial, a novel agent called LCZ-696, which is an angiotensin receptor neprilysin inhibitor, reduced mortality compared to the ACEi enalapril in patients with heart failure. Importantly, the benefits were consistent in patients with and without CKD. However, the risk of hyperkalemia was still present with this novel agent despite extensive efforts to avoid elevated serum potassium levels. The study excluded patients with an egfr <30 ml/min/1.73 m 2 or a serum potassium level above 5.2 meq/l. In addition, there was a run-in phase of about 2 weeks that excluded patients who developed hyperkalemia early after initiation of either LCZ-696 or the ACEi. Despite these efforts, the investigators saw hyperkalemia rates over 15%, highlighting that this issue remains a key limitation of agents that inhibit the RAAS system. 22

And, when looking at contemporary trials of RAAS blockade in high-risk patients for cardiovascular events, the rates of hyperkalemia were high in the large outcomes trials of ONTARGET, ALTITUDE, and AVOID, especially when patients received dual RAASi therapy. 23

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This study is a schematic of various treatment options for hyperkalemia. On the far left are the key agents used in the emergency department for hyperkalemia: insulin and beta-adrenoreceptor antagonists. These agents work by pushing potassium from serum into the cells. Calcium gluconate salt is commonly given, especially in the presence of ECG changes to stabilize cell membranes. Dialysis, loop diuretics, and sodium bicarbonate are also therapies to eliminate potassium from the body, although I will tell you in a moment why sodium bicarbonate may not be a good option for certain patients. Finally, for longer-term options to manage persistent hyperkalemia, we are left with few options. Kayexalate, or sodium polystyrene sulfonate, has a warning related to intestinal necrosis and a precaution related to sodium load; and long-term, ongoing use of SPS has not been systematically studied. Therefore, putting patients on a difficult-to-adhere-to low potassium diet or stopping renoprotective RAASi therapy is often the only option. 25

Here is a description highlighting that sodium bicarbonate may not be the effective agent for hyperkalemia that we once thought. Most of the studies looking at bicarbonate were uncontrolled observational studies and a study by Dr. Fraley going back to 1977 highlighted that 4 to 6 hours of bicarbonate only reduced serum potassium from 0.5 to 2.8 meq/l. 26

As discussed earlier, Kayexalate had a warning issued in 2009 related to colonic necrosis, which was further refined in 2011 by the FDA. These warnings indicate that Kayexalate should not be used in patients who do not have normal bowel function or who develop constipation; considering the age of many patients with CKD, this is a significant limitation. In addition, the warning cautions against using with the cathartic sorbitol. These cases of necrosis, while rare, can be associated with death. 27

In addition, many patients who develop hyperkalemia also have heart failure. These patients are on sodium- and fluid-restricted diets. Administering Kayexalate (sodium polystyrene sulfonate) 1 to 4 times/day would be a significant proportion of their daily sodium and fluid intake. Caution is advised when Kayexalate is administered to patients who cannot tolerate even a small increase in sodium loads (ie, severe congestive heart failure, severe hypertension, or marked edema). In such instances compensatory restriction of sodium intake from other sources may be indicated. 28

Since Kayexalate (sodium polystyrene sulfonate) uses sodium to exchange for potassium in the gastrointestinal tract, there is a precaution in the label related to sodium load. 29

A low potassium diet is extremely difficult to adhere to, since many foods are rich in potassium. Trying to adhere to a low potassium diet can be challenging for patients and caregivers. 30

Foods rich in potassium content are pervasive and all encompassing. 31

Build Slide part 1 of 2 Potassium is common in many foods. In addition, because these foods are rich in magnesium, restricting them can also result in low levels of magnesium. 32

In addition, the DASH Diet, which can reduce blood pressure and delay kidney progression, is rich in high-potassium food. Hence, hyperkalemia often forces us to tell our patients to avoid many healthy foods, which also has a significant impact on the patient s quality of life. 33

The guidelines are consistent when providing recommendations related to prescribing RAASi to patients at risk for hyperkalemia. The K/DOQI, NICE, the Heart Failure Society of America, and the American College of Cardiology/American Heart Association all recommend avoiding RAASi therapy in patients with serum potassium >5.0 meq/l. In addition, the European Society of Cardiology and K/DOQI guidelines both recommend discontinuing or lowering the dose of RAASi if serum potassium levels rise above 5.5 meq/l. And finally, the NICE guidelines from the United Kingdom recommend stopping RAASi if hyperkalemia >6.0 meq/l develops. 34

In summary, long-term management of hyperkalemia has numerous limitations. A low potassium diet is difficult to implement and contrary to a healthy diet of fruits and vegetables. Reducing RAASi is stopping the very medications that can delay dialysis. Kayexalate (sodium polystyrene sulfonate) has serious GI warnings and sodium load precautions that limit its use. 35

Hyperkalemia is highly prevalent in patients with CKD and/or diabetes. As the kidney is the primary route for potassium elimination, CKD is associated with chronic risk of hyperkalemia. The use of RAASi to preserve kidney function in CKD further increases this risk. Hyperkalemia contributes to ED visits, hospitalizations, and health care costs. Hyperkalemia is associated with increased mortality. 36

Current treatment options including low-potassium diets and sodium polystyrene sulfonate have significant limitations. Because of the unmet need for hyperkalemia treatments, down-titration or discontinuation of RAASi is a common consequence of hyperkalemia. 37

PP-US-DSE-00032. 2015 Relypsa, Inc. All rights reserved. Relypsa and the Relypsa logo are trademarks of Relypsa, Inc. 38