Cornerstone’s Lixivaptan Falls Prey To Advisory Panel’s Desire For Clinical Benefit

FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against approval of the vasopressin2 receptor antagonist for treating hyponatremia.

Modest treatment effect in an endpoint that panel members believe does not indicate clinical benefit produced two negative votes for Cornerstone Therapeutics Inc.’s lixivaptan during a Sept. 13 Cardiovascular and Renal Drugs Advisory Committee to assess the drug for hyponatremia.

The panel unanimously rejected an indication for treating symptomatic hypervolemic hyponatremia associated with heart failure, voting 8 to 0 against approval in that manifestation of the disease.

The vote was more balanced – five against and three in favor – for lixivaptan to treat euvolemic hyponatremia associated with a syndrome of inappropriate antidiuretic hormone (SIADH).

Hyponatremia is characterized by a subnormal concentration of sodium in the blood and can cause symptoms ranging from mild neurological effects to significant morbidity and mortality.

The primary endpoint for three Phase III lixivaptan trials was the change in serum sodium from baseline to Day 7, with at least a 1.2 mEq/L greater increase found for heart disease patients receiving therapy compared to placebo in one study. The difference in treatment effect was 2.2 and 2.4 mEq/L in patients with SIADH in two other Phase III studies.

Searching For Clinical Benefit

Sponsors of two vaptans currently on the market for hyponutremia – Astellas Pharma US Inc.’s intravenous Vaprisol (conivaptan) and Otsuka America Inc.’s oral Samsca (tolvaptan) – received approval for their products with serum sodium as the endpoint, but members of the Sept. 13 advisory committee questioned the benefit of increasing the electrolyte.

There’s no evidence that a change in the serum sodium levels lead to clinical improvement, Daniel Gillen, University of California-Irvine, contended during the discussion of lixivaptan to treat hyponatremia associated with heart disease.

Vasilios Papademetriou, VA Medical Center, Washington, D.C., maintained that “hyponatremia is a marker of underlying disease and treating the markers, most of the time, does not help with the disease itself. Here we don’t have any evidence that it’s even very effective in correcting the marker of the disease.”

Linda Fried, VA Pittsburgh Healthcare System, agreed that in the case of patients with heart disease, lixivaptan, a vassoprtessin2 receptor antagonist, does not treat the pathophysiology of hyponatremia. The decline in sodium is due to the heart disease and not arginine vasopressin, the target of lixivaptan, she explained, and the effects of treating the heart disease explain why there was the small difference in treatment effect for the therapy compared to placebo.

Also working against lixivaptan for heart patients was the finding of a higher number of deaths in the treatment arm of the study with those patients.

Without a demonstration of improvement in quality of life or another marker that suggests clinical benefit, Mori Krantz, University of Colorado, expressed discomfort with approval based on the surrogate marker given the small safety signal.

Importance of Precedence

The majority in the split vote on lixivaptan to treat hyponatremia with SIADH again largely argued for a demonstration of clinical benefit.

This time, taking a positive view on approval, Fried contended that in SIADH patients, lixivaptan addresses the pathophysiology and other treatments are limited.

In the absence of a safety signal and a larger difference in treatment effect, lixivaptan garnered two votes for approval based on use of the same endpoint for Vaprisol and Samsca.

“I think that in the absence of a reason to refute or reject a thought-out decision of the past that we should, in a sense of fair play, apply the same rules to a company that went forward prospectively thinking that the ground rules had been established,” committee Chairman A. Michael Lincoff, Cleveland Clinic, explained

To Hospitalize, Or Not

The vaptans must be titrated to prevent overly rapid correction of serum sodium and in one of the studies for hyponatremia with SIADH, Cornerstone collected data to show the drug could be titrated safely at a well monitored site, such as a clinic or long-term care/nursing home facility, but outside the hospital setting. Both conivaptan and tolvaptan are initiated in the hospital.

FDA briefing documents had suggested lixivaptan initiation in the hospital would be the preferable course (Also see "FDA Review Panel For Cornerstone’s Lixivaptan To Consider Safety Of Outpatient Initiation" - Pink Sheet, 11 Sep, 2012.).

If FDA were to approve lixivaptan, panel members generally preferred initiation in a hospital where a patient can be closely monitored and there is the capability for rapid analysis of serum sodium levels, which are required at 8, 24 and 48 hours after the first dose. Fried countered that facilities with point-of-care analysis could be suitable.

Lincoff suggested outpatient titration could be possible “with a very specific, a very strict REMS, not the sort of hand-waving to educate, but the very specific procedures on how it should be done” in a facility where the lab values can be seen quickly.