FDA Panel Votes Against Approval of Hyponatremia Drug


SILVER SPRING, MD. – A Food and Drug Administration advisory panel has recommended against the approval of lixivaptan, an orally administered vasopressin-2 receptor antagonist, for treating hyponatremia in two groups of adult patients at a meeting on Sept. 13.

The manufacturer, Cardiokine Biopharma, has proposed that lixivaptan be approved for the treatment of hypervolemic hyponatremia associated with heart failure, and for the treatment of euvolemic hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH). The company submitted the results of three phase III placebo-controlled trials that evaluated the changes from baseline in serum sodium at day 7 of treatment, the primary efficacy end point. The company proposed that for the SIADH indication, treatment could be initiated in an outpatient setting, which would be a potential benefit over existing treatments, including the only approved orally administered vasopressin-2 receptor antagonist that is approved for hyponatremia, tolvaptan (Samsca). Tolvaptan is approved for inpatients with diagnoses that include SIADH, heart failure, and cirrhosis, and is initiated in the hospital. The other approved "vaptan" – zomivaptan (Vaprisol), approved in 2005 – is administered intravenously.

Lixivaptan acts specifically on the vasopressin-2 receptor in the kidneys, "causing water to be excreted while sparing sodium without affecting other electrolytes," according to Cardiokine. While the changes in serum sodium from baseline to day 7 among treated patients over placebo were statistically significant, the improvements were modest and were not associated with improved cognitive function, the FDA reviewers pointed out.

In the study of patients with hypervolemic hyponatremia hospitalized with New York Heart Association (NYHA) class III or IV heart failure (652 patients), the increase in serum sodium at day 7 was 1.2 mEq/L greater among treated patients, compared with those on placebo. The mortality rate was 17.7% among those who had at least one dose of lixivaptan, compared with 14.3% on placebo; most deaths were related to heart failure, according to Cardiokine, which was recently acquired by Cornerstone Therapeutics.

In the two other studies, comprising a total of 312 patients with SIADH, the increases in serum sodium at day 7 over placebo were 2.2 mEq/L and 2.4 mEq/L.

But at the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel unanimously voted against approval of lixivaptan for the heart failure indication, because its members were not convinced that the modest effect of treatment on hyponatremia observed in the study of heart failure patients provided evidence that it benefited patients. The panel also agreed that more data on how improvements in serum sodium translated to clinical benefits, such as quality of life improvements, were needed. Another concern was that mortality was higher among the patients treated with lixivaptan than in those on placebo, particularly early in treatment.

The panel voted 5 to 3 against approval for treatment of hyponatremia in patients with SIADH, with clinicians voting on both sides of this question.

Dr. Linda Fried, professor of medicine at the VA Health Care System in Pittsburgh, voted in favor of approval because she said she believed that the vaptans directly affect pathophysiology in SIADH, and because she did not see a safety signal.

But Dr. Mori Krantz, associate professor of cardiology at the University of Colorado, Denver, voted against approval, because there were not enough data to show whether the improvements with treatment were clinically meaningful. He said that a larger study evaluating the effects of improvements in serum sodium with treatment on quality of life and other measures was needed, "to at least give clinicians some sense of security that they are helping patients."

Most panelists questioned the feasibility of initiating treatment as an outpatient, in most clinical settings.

The FDA is expected to make a decision on approval by Oct. 29.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

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