SILVER SPRING, MD. — The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 8 – 3 that tolvaptan, an oral selective arginine vasopressin (AVP) V2-receptor antagonist administered once a day, be approved for use in the chronic treatment of hypervolemic or euvolemic hyponatremia.
Recommendations of those voting in favor of approval included limiting treatment to patients with very low serum sodium levels, hospitalizing patients at the start of treatment, and conducting postmarketing follow-up of patients on chronic treatment.
The panel also agreed in an 8 – 3 vote that there was adequate evidence that the drug could be expected to produce clinical benefits in the treatment of this group of patients. But several panelists said they were more convinced about the benefits in people whose serum levels were below 130 mEq/L, and that they would not be comfortable using tolvaptan to treat people with higher sodium levels until there was more evidence about whether treatment made a difference for this group.
Most of the panel agreed that there were no safety issues that would affect approvability, although several panelists were concerned about bleeding in cirrhosis patients, thirst, and the need for more long-term data, because it would be used chronically in many patients.
Tolvaptan, a product of Otsuka Pharmaceutical Development and Commercialization Inc., belongs to the “vaptan” class of compounds that blocks the action of AVP in the collecting ducts and induces free water clearance in the body (aquaresis), according to the company.
Because the company is pursuing approval of efficacy claims based on tolvaptan's ability to increase serum sodium levels in patients with hyponatremia, the agency said it held the meeting to obtain guidance from the panel on “how best to define efficacy for products such as tolvaptan, where there may be a clear demonstration of activity,” which in this case is increasing serum sodium concentration, “without a clearly tangible clinical benefit.”
In addition to the hyponatremia indication, the FDA is also reviewing tolvaptan as a treatment for worsening HF, regardless of baseline serum sodium. The panel was not asked to review or vote on the HF indication, which was studied in patients hospitalized for HF in the phase III study, Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST).
Most of the data presented by Otsuka were from two phase III studies of patients with hyponatremia due to all causes, with heart failure, antidiuretic hormone (SIADH), or cirrhosis; their mean age was 61–62 years, the mean serum sodium was 129 mEq/L, and about half had levels below 130 mEq/L.
The studies, SALT-1 and 2, compared daily treatment with 15 mg of tolvaptan a day to placebo and found that treatment improved hyponatremia, prevented worsening of hyponatremia, and maintained superior mean serum sodium concentrations from day 4 and at 30 days, when compared with those on placebo. More than 70% of patients completed the 30-day evaluation. The largest effects were seen in the SIADH patients.
The primary end point was the average daily area under the curve changes in serum sodium concentration from baseline to day 4 (short-term) and from baseline to day 30 (sustained), which were significant in both studies, and in a pooled analysis of the studies. In the pooled analysis, the average daily AUC of mean change from baseline in serum sodium levels was 4.0 mEq/L for those on tolvaptan, compared with 0. 4 mEq/L for those on placebo (from baseline to day 4), and 6.2 mEq/L for those on tolvaptan compared with 1.8 mEq/L for those on placebo (the sustained effect).
The most common adverse effects included excessive thirst and dry mouth. Serious adverse events included more cases of GI bleeding in cirrhotic patients on tolvaptan than those on placebo. Overly rapid correction of serum sodium was seen in some patients, but without neurologic sequelae, said Otsuka.
The company also used two patient-reported outcome scales to measure the clinical impact of changes in sodium level changes on treatment on quality of life measure. The mental component scores of one of the scales, the SF-12, improved and were positively correlated with changes in serum sodium in one of the two studies, but not the other.
Otsuka also presented supportive data on a subgroup of 475 patients with hyponatremia, who were in the EVEREST study of patients hospitalized for HF, who received 30 mg of tolvaptan daily or placebo. Their mean LVEF was 26%, most were male. Those on tolvaptan had a significantly greater rates of normalization of serum sodium on day 1 and at discharge, and significantly fewer treated patients went from mild to severe hyponatremia, said Otsuka. Patients with treated with tolvaptan also reported greater improvements in dyspnea than those on placebo.