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FDA Rejects Lixivaptan for Hyponatremia

Agency follows advisory committee’s recommendations (Nov. 1)

The FDA has issued a Complete Response Letter (CRL) rejecting the New Drug Application (NDA) for lixivaptan (formerly CRTX 080, Cornerstone Therapeutics) for the treatment of symptomatic hypervolemic and euvolemic hyponatremia associated with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH), respectively.

The CRL requests additional clinical and nonclinical information in order for the FDA to consider approval of lixivaptan.

Lixivaptan is a non-peptide, oral capsule that works by reducing the action of vasopressin, a hormone that blocks fluid excretion. The drug acts specifically on vasopressin-2 receptors in the kidneys, causing water to be excreted while sparing sodium without affecting other electrolytes. Three large clinical trials — two evaluating lixivaptan for SIADH and one evaluating the drug for heart failure — met the primary endpoint of producing a significant increase in the serum sodium concentration compared with placebo at treatment day 7.

Hyponatremia is estimated to affect up to six million people in the U.S., with direct medical costs ranging between $1.6 and $3.6 billion annually. It is the most common electrolyte disorder among hospitalized patients and is often diagnosed in patients with heart failure. Other causes of hyponatremia include burns, diuretic medications, kidney disease, liver cirrhosis, and SIADH.

On September 13, the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended against agency approval of the NDA for lixivaptan. The panel voted unanimously (8 to 0) against approval of the drug for heart failure patients and voted 3 to 5 against approving it for use in patients with SIADH. The agency said that the heart failure study showed an "imbalance" of deaths between patients treated with lixivaptan and those given placebo.

Sources: Cornerstone Therapeutics, Inc., November 1, 2012; Wall Street Journal, September 13, 2012.

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