Tolvaptan gets FDA advisory-panel nod for hyponatremia indication

June 26, 2008

Silver Spring, MD - By an eight-to-three vote, an FDA advisory panel yesterday recommended approval of tolvaptan (Otsuka America Pharmaceuticals), a selective vasopressin-receptor antagonist that can be taken orally, for the indication of hypervolemic or euvolemic hyponatremia. Most members of the panel, regardless of their vote, had reservations about some of the drug's remaining unknowns and pressed for studies that follow broader populations of patients for longer than the tolvaptan trials performed so far.

Prominent among those trials were the Studies of Ascending Levels of Tolvaptan in Hyponatremia (SALT 1 and SALT 2), which, as previously reported by heart wire , suggested the drug could correct hyponatremia associated with heart failure, cirrhosis, and other disorders [1].

 
I think the evidence has shown that the agent significantly and rapidly improves serum sodium and urine output vs placebo, and I think it's a sustained effect.
 

"I think the evidence has shown that the agent significantly and rapidly improves serum sodium and urine output vs placebo, and I think it's a sustained effect," said panelist Dr Frederick J Kaskel (Albert Einstein College of Medicine, Bronx, NY) during the proceedings. "There was improvement in overall well-being without the improvement in the physical component, but that may need to be addressed later." He said evidence for the agent's efficacy in the outpatient setting is "very strong" but also that its long-term use should be monitored in future studies.

"And, as a pediatric nephrologist," said Kaskel, who voted in favor of approval, "I'd like to see, down the line, the application [of tolvaptan] to another subpopulation that also suffers from acute and chronic hyponatremia, of which one of the major side effects is neurocognitive impairment that is permanent."

Panelist D r Lynne Warner Stevenson (Brigham and Women's Hospital, Boston, MA), who also voted for approval, was also for keeping a close eye on how patients fare when taking the drug, both initially and over the long term. "I would strongly favor hospitalization for initiation of this therapy, because I suspect that other medications will have to be adjusted, and it's very difficult to do that in the outpatient setting," she said. "And I would suggest postmarket surveillance of the chronic therapy."

Speaking with heart wire , panel chair Dr William R Hiatt (University of Colorado, Denver), who voiced one of the panel's three negative votes, observed that initiation of tolvaptan in outpatients hasn't even been tested and also cautioned against allowing it. "We don't know how much of [tolvaptan's] risk was mitigated because it was started in an inpatient setting. We don't know if the safety profile we saw reflected that scenario or [instead] could be extrapolated to the outpatient setting," he said.

As for the serum sodium threshold for indicating therapy with tolvaptan, the panel in general favored 130 mEq/L but was "unconvinced" it was a magic concentration below which treatment would improve clinical outcomes, according to Hiatt.

 
I think that there's not enough information about this particular drug to let the genie out of the bottle to the broad population of patients.
 

"It's a slippery slope if we start approving drugs for these surrogate indications," he said. "We have surrogates that we're comfortable with, like blood pressure and LDL cholesterol, but we didn't feel that the sponsor had crossed that threshold to now say, serum sodium is also a very robust surrogate and, particularly in the mild range, that treating that number was definitely linked to clinical benefit. That wasn't shown."

Dr Robert A Harrington (Duke University, Durham, NC), who also voted against approval, pointed out that drug outcomes in clinical trials often aren't the same as those in clinical practice. "My sense is that the drug was studied in very controlled situations: patients were in the hospital setting for the first 24 hours, they were studied by experts, mostly in renal disease." That won't be the case if the drug is used in general practice, he observed. "So if it's approved, I'd want to see it be in a fairly narrow indication with a lot of the caveats brought up here, which I think are good ones," he said. "I think that there's not enough information about this particular drug to let the genie out of the bottle to the broad population of patients."

If approved, tolvaptan would not be the only available drug in its class. The nonselective vasopressin receptor inhibitor conivaptan (Vaprisol, Astellas) was approved almost three years ago for hyponatremia in some narrow clinical situations, but it's an IV drug and labeled for no more than four days of administration.

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