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Sodium in Kidney Disease, Heart Failure and Hypertension

Summary

FDA policy and prior actions indicate ZS-9 label will include a warning, potentially a boxed warning, regarding use in patients with heart failure and renal disease.

The target population for ZS-9 is hyperkalemia, which is comprised almost entirely of patients with heart failure and renal disease.

ZS-9 is a high sodium drug; a large part of the intended patient population is sensitive/vulnerable to sodium.

Veltassa (RLYP) is an equally effective recently FDA approved alternative with no significant safety concerns and no sodium.

Given the wealth of research linking sodium to worsening outcome in kidney disease, the FDA should strongly consider restricting use of ZS-9 to patients without kidney disease.

Hyperkalemia is a large and potentially highly profitable market. The recent FDA approval of Veltassa (developed by "Relypsa" or "RLYP") has sent social media channels, investor boards and analysts into a frenzy of comparison between the now broadly approved Veltassa and its nearest competitor, the as of yet unapproved ZS-9 (developed by "ZS Pharma" or "ZSPH").

There are several points of contention in the ongoing Veltassa vs ZS-9 debate which could be discussed at length. This article will focus on the issue of ZS-9's PDUFA date in May 2016 and the probability of (if approved) the FDA including a black boxed warning.

Background

Hyperkalemia is a medical condition of too much potassium in the blood. There are 3 to 4 million patients in the United States alone with hyperkalemia, the vast majority of whom have underlying Heart Failure or Kidney Disease as the approximate cause of their hyperkalemia. (There is an additional "potential" target population of 10-20 million - but that is an entirely different discussion). There are approximately 500,000 hospitalizations involving hyperkalemia each year.

Veltassa was approved by the FDA in October, 2015 with a broad "hyperkalemia" label. It is the first treatment for hyperkalemia to be approved in over 50 years. Veltassa is a "potassium binder" - an oral medication that binds potassium in the GI tract in exchange for calcium. Veltassa is not absorbed by the body, so it and the bound potassium are excreted in the feces. Since only about 5% of ingested calcium is absorbed, most of the calcium that the drug leaves behind is also excreted in the feces.

ZS-9 is not yet approved by the FDA. Its PDUFA date is set for May of 2016. ZS-9 is also a potassium binder - an oral medication that binds potassium in the GI tract.

Because the efficacy of Veltassa and ZS-9 is essentially identical (more on this later), the key difference between ZS-9 and Veltassa is that ZS-9 exchanges sodium for potassium. ZS-9 is not absorbed by the body, so it and the bound potassium are excreted in the feces. Unlike calcium, most ingested sodium is absorbed so the sodium left behind by the drug is simply absorbed by the body.

There is a wealth of information on the topic of sodium in the context of heart failure and renal disease. A small amount of sodium is essential; however the average American consumes several multiples of the maximum daily recommended amount of sodium. Patients with moderate to severe renal disease and heart failure are often unable to tolerate more than just a small amount of daily sodium. Even if tolerated from a symptomatic perspective, increased dietary sodium has been directly associated with long term worsening of cardiorenal disease (heart disease, kidney disease and high blood pressure).

Instead of discussing this in further detail, I have provided links to published resources which will satisfy even the most curious of minds. In summary, sodium is bad for patients with heart failure, kidney disease and hypertension because it worsens their symptoms and leads to more rapid progression of disease.

The FDA is aware of the relationship between increased sodium and worsening of renal disease, heart failure and hypertension. There are innumerable medications that, by some mechanism or another, increase net sodium uptake. These medications have FDA labels which include warnings against their use in renal disease, heart failure and hypertension. Below are some examples of drugs paired with directly quoted FDA warnings from their respective labels. It is very important to recognize that these FDA approved medications were not specifically designed to treat the heart failure and kidney disease population, so it makes sense that the FDA would include warnings to providers in case the drug were to be prescribed to those with renal or heart disease.

Prednisone:

Warning: "Average or large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium...


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