Cornerstone's Lixivaptan Faces Mixed FDA Reviews at CRDAC
By Mari Serebrov
Cornerstone Therapeutics Inc. will put its acquisition of Cardiokine Inc. to the test Thursday as it debuts Cardiokine's lone compound, lixivaptan, for the FDA's Cardiovascular and Renal Drugs Advisory Committee (CRDAC).
In a briefing document for the meeting, the FDA presented mixed reviews on lixivaptan, a vasopressin V2 receptor antagonist. Staff has recommended approval of the drug as a treatment for hyponatremia associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH), provided it's initiated in an inpatient setting where volume status, fluid balance and serum sodium concentration can be closely monitored.
Such a restriction would be in keeping with the labeling for two approved vaptans, Vaprisol (conivaptan, Astellas Pharma US Inc.) and Samsca (tolvaptan, Otsuka Pharmaceutical Co. Ltd.). One of the two SIADH Phase III trials had studied the drug in an outpatient setting.
The review wasn't so positive for a second indication, hyponatremia associated with congestive heart failure (CHF). Citing safety concerns in that patient population, staff advised the agency to issue a complete response for the CHF indication.
No show-stopping safety findings were seen in the SIADH trials, but an early imbalance in death nine patients in the lixivaptan arm vs. one on placebo within the first five days of therapy was noted in the Phase III BALANCE trial, which evaluated the drug in CHF patients. Overall, the numeric imbalance wasn't statistically significant, according to the briefing document, but "post hoc analyses in subjects who died soon after randomization or first dose found p values that were nominally significant."
While it's not clear that lixivaptan played a causal role in the deaths, the FDA said it couldn't "exclude the possibility that some subjects with hyponatremia associated with acute worsening congestive failure were exquisitely sensitive to intravascular free water shifts and may not tolerate even a small change in intravascular volume status or osmolality, induced by lixivaptan."
Given what it described as a modest benefit with lixivaptan, the FDA said it had a low tolerance for the uncertainty in risk for the CHF indication.
As for the drug's benefit, the agency acknowledged that lixivaptan reached its primary efficacy endpoint, a change in serum sodium from baseline to day seven, in the Phase III program, but it pointed out that none of the anticipated clinical benefits were detected. The BALANCE trial, for instance, didn't demonstrate a change in days alive or out of hospital, which were secondary endpoints. And none of the three trials detected a favorable treatment effect on cognitive function.
The agency theorized that since the treatment effect on serum sodium was modest, the treatment effect on hyponatremia symptoms would be modest as well. The two SIADH trials weren't powered "to detect such modest effects on cognitive function as might result from such modest changes in serum sodium," it said.
The FDA did note that a larger treatment effect was seen in Phase II, which assessed a twice-daily regimen against a backdrop of fluid restriction. Those results have the agency asking whether a different dosing regimen or instructions on the use of fluid restriction would have produced a larger treatment effect in the Phase III trials.
The inability to demonstrate clinical benefit in the trials doesn't seem to trouble the agency. It accepted changes in serum sodium as a surrogate endpoint when it approved the intravenous conivaptan and the oral tolvaptan for hyponatremia, a metabolic condition that occurs when there isn't enough sodium in the blood.
Cornerstone, of Cary, N.C., obtained worldwide rights to lixivaptan when it acquired Cardiokine late last year. The acquisition became effective Dec. 30, the day after Cardiokine filed the new drug application for lixivaptan. The PDUFA date for the drug is Oct. 29. (See BioWorld Today, May 16, 2012.)
Cardiokine, in turn, had licensed the compound from Wyeth (now part of Pfizer Inc.) in 2004 and partnered its development with Biogen Idec Inc. in 2007. It regained all rights to lixivaptan when Biogen later restructured and exited the cardiovascular space. (See BioWorld Today, April 14, 2004, July 3, 2007, and Nov. 5, 2010.)
FDA Questions West-Ward's Evidence
In addition to lixivaptan, CRDAC will review West-Ward Pharmaceutical Corp.'s new drug application for phenylephrine hydrochloride injection to increase blood pressure in acute hypotensive states, such as shock and peri-operative hypotension. Since intravenous phenylephrine has been marketed for several decades, the Eatontown, N.J.-based generic drugmaker submitted a publication-based application. Of the 50 clinical trials cited, 42 were based on treatment or maintenance of blood pressure in peri-operative situations, and eight involved patients with sepsis or septic shock, the FDA said.
Noting the limitations of the published studies and its inability to document their methodology and results, the agency questioned the extent it can rely on the studies. It is asking CRDAC to discuss the type of evidence needed to establish the clinical benefit of phenylephrine in acute hypotension.
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