Because of potential liver toxicity risks, DOV Pharmaceutical Inc. shut down a Phase III trial of its investigational anti-anxiety agent ocinaplon, a setback that could cause the company to drop the drug altogether.
"The immediate trigger for the decision was recent occurrence of an enzyme elevation in a series of liver function tests for one subject in this trial," DOV President and CEO Leslie Hudson explained in a conference call. "The enzyme elevations were sufficient to have DOV, in consultation with its independent data monitoring committee, decide to suspend the trial."
As a result, the Hackensack, N.J.-based company's stock (NASDAQ:DOVP) on Friday dropped $2.98, or 16.6 percent, to close at $14.99.
Still, there is a chance that ocinaplon is not the culprit, as DOV remains blinded to data. But Hudson acknowledged previous occurrences of enzyme elevations in other study participants, though smaller in nature and "not to a degree sufficient to stop dosing in the clinical trial overall." The study had intensive liver function monitoring throughout.
The recent alarming data could be an outlier or could represent a consistent adverse effect of the study drug. The patient for whom the heightened concern was raised has not been hospitalized, as she "has no clinical symptoms at this time," said Warren Stern, the company's senior vice president of drug development, during the call.
The company, which already notified the FDA of its actions, soon will see all study results to fully evaluate the safety findings from the 200 subjects enrolled to date. The trial was to have included 373 patients with generalized anxiety disorder with 60 mg of ocinaplon daily or placebo for four weeks, though it was amended two months ago to also allow subjects without the condition to speed toward conclusion and better focus on safety aspects.
DOV will continue to monitor those enrolled and, upon full analysis and completion of its review, make a decision whether to continue with ocinaplon, a non-benzodiazepine, or select a backup compound from its GABA modulator program. That portfolio includes several late-stage preclinical candidates that could be substituted for ocinaplon if required, Stern said, adding that the process is likely to take several months.
"We will present the results of the interim safety analyses to the FDA prior to any re-initiation of testing," he added, "and will give them ample time to review the findings."
Stern later mentioned two other GABA modulator products with long records of safety, Sonata (zaleplon, from King Pharmaceuticals Inc.) and indiplon (from Neurocrine Biosciences Inc. and Pfizer Inc.), suggesting that the liver enzyme elevation issue is not necessarily common to the whole class but rather potentially due to ocinaplon in particular.
"There are other substances that a patient may take that can cause elevated liver enzymes, or viral infections can," he said. "Until we sort out exactly what proportion of the patients who had elevated liver enzymes were on [ocinaplon] and who was on placebo, and whether they had any other predisposed or causative factors, it would be too speculative to make any further statements."
DOV has rights to the compound through a 1998 licensing arrangement with Wyeth, of Madison, N.J. Its Phase III trial began at the end of last year, about a year after the FDA placed a hold on the study to request additional safety information. Ocinaplon had been in 11 prior clinical studies involving 477 people. After that material was supplied, the Phase III got under way to evaluate the drug's effect in improving Hamilton Anxiety Rating Scale scores as compared to placebo as the primary endpoint.
"We're not certain today that ocinaplon is really the problem," Stern said, "or whether there are potentially other explanations as to what's transpired."
DOV said about 15 million people in the U.S. suffer from an anxiety disorder.
Outside of the ocinaplon setback, the company continues to march forward with a number of other clinical-stage compounds.
It is conducting four Phase III trials of bicifadine for pain. That compound also was in-licensed from Wyeth. Should it reach the market, DOV would owe a 5 percent royalty on net sales. A compound labeled DOV 216,303 is in Phase I/II for indications other than depression, anxiety and addiction, for which the compound has been out-licensed to Merck & Co. Inc., of Whitehouse Station, N.J. Another product, DOV 102,677, is in Phase I for depression and other neuropsychiatric disorders.