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Advisory panel not in favor of new hyponatremia drug approval
The FDA’s Cardiovascular and Renal Drugs Advisory Committee today did not recommend approval of lixivaptan for the treatment of symptomatic hypervolemic and euvolemic hyponatremia associated with HF and syndrome of inappropriate antidiuretic hormone.
The drug at the focus of discussion was lixivaptan (proposed trade name: Lixar, Cardiokine Biopharma/Cornerstone Therapeutics), an orally active, selective vasopressin 2 receptor antagonist. The new drug application for these two patient populations in recommended doses of 25-mg and 50-mg capsules.
Committee members discussed data from three randomized, double blind, placebo-controlled, phase 3 studies and an open-label extension study. The BALANCE study was conducted in patients with hyponatremia and evaluation inpatient initiation of the drug; the LIBRA study was conducted in patients with syndrome of inappropriate antidiuretic hormone (SIADH) and evaluated inpatient initiation; and the HARMONY study was conducted in patients with SIADH and evaluated outpatient initiation. In all three studies, lixivaptain met the primary endpoint of statistically significant improvements in change of serum sodium concentration from baseline to day 7, compared with placebo.
The advisory panel voted unanimously against approval in patients with hypervolemic hyponatremia associated with HF and 5-3 against approval in patients with euvolemic hyponatremia associated with SIADH, citing concerns about inadequate evidence on potential safety issues, a small number of patients in the sponsor studies and moderate clinical effects.
“When we’re thinking about weighing the risk-benefit considering the marginal effects we’ve seen, I believe that further studies to evaluate safety in a larger population need to be there,” temporary voting member Daniel L. Gillen, PhD, said at the meeting. Gillen voted no for both proposed indications.
One topic during the safety discussion more early deaths in patients with CHF taking lixivaptan compared with patients taking placebo.
The committee was divided on whether, if approved, lixivaptin initiation outside of a hospital setting is appropriate. While some members suggested outpatient use may be feasible in specific settings, others said more data on safety are required and guidelines are needed beforehand.
Two vasopressin V2 receptor antagonists are approved for use in the United States: IV conivaptan (Vaprisol, Astellas), which was approved in 2005, and oral tolvaptan (Samsca, Otsuka Pharmaceuticals), which was approved in 2009. Both are approved for hyponatremia in euvolemic and hypervolemic conditions.
Although the FDA is not required to follow the recommendations of the advisory committee, it usually does.