DOV Ocinaplon Phase III Anxiety Trial On Hold Again Over Liver Function Tests
This article was originally published in Pharmaceutical Approvals Monthly
Executive Summary
DOV's internal review of Phase III safety data on its anxiolytic ocinaplon will take "several months" and could result in a reduced dosing regimen
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DOV's internal review of Phase III safety data on its anxiolytic ocinaplon will take "several months" and could result in a reduced dosing regimen. Alternatively, the firm could be forced to abandon ocinaplon in favor of other gamma-amino butyric acid (GABA) modulators for anxiety currently in late-stage preclinical development, the company said. The suspension of further dosing with ocinaplon, announced Aug. 25, represents the second time that Phase III trials for the GABA receptor agonist have been put on hold due to liver enzyme elevations. FDA placed the Phase III program on hold in October 2003 and requested additional safety information after one Phase II patient suffered liver enzyme elevations leading to jaundice and hospitalization. The agency lifted the hold in June 2004; the program resumed last November with protocol revisions including more frequent enzyme testing. The trigger for the current trial suspension was liver enzyme elevation in a single patient, observed during the week of Aug. 22. The patient currently has no clinical symptoms and does not require hospitalization, according to the company. Since the program resumed last November, "several other subjects [have] shown small but persistent enzyme elevations but not to a degree sufficient to stop dosing in the clinical trial overall" until now, President and CEO Leslie Hudson, PhD, acknowledged during an Aug. 26 conference call. "The data from the one subject could be an outlier or could represent a consistent adverse effect," DOV said. The firm noted that the 2003 case of liver enzyme elevation that led to trial cessation involved a much higher dose of ocinaplon - 270 mg per day as opposed to the current dose of 60 mg per day. The Phase III ocinaplon study already has enrolled 200 patients out of a planned total of 373. The protocol calls for patients to receive 60 mg/day of ocinaplon or placebo for four weeks. DOV "has notified [FDA] of its actions" and will provide the results of its interim analysis to the agency prior to re-initiation of the study, the firm said. DOV decided to suspend the trial after consulting with its independent data monitoring committee. "In the context of a prior case of jaundice…we need to be perhaps a bit more conservative than would otherwise be the case," Senior VP-Drug Development Warren Stern, PhD, said. While DOV declined to describe the nature of the liver function test elevations seen in its trial, the firm noted that they involved more than one enzyme. "The general FDA standard [for liver function test abnormality] of potential clinical significance is three times the upper limit of normal or higher…. That is the general rule that DOV is following as well," Stern said. Commenting on the potential for elevated liver function tests with approved therapeutics, Stern noted that a recent DOV review of package inserts for various marketed drugs showed rates of elevated liver function test values ranging "from 1% or less to up to 5% - and that's over an entire program as opposed to a single study." In addition to ocinaplon, DOV's pipeline includes indiplon, which licensee Neurocrine has submitted to FDA for approval to treat insomnia (1 Pharmaceutical Approvals Monthly June 2005, In Brief). Meanwhile, the firm's non-opioid analgesic bicifadine is in Phase III for treatment of pain, and a diltiazem formulation for angina and hypertension has completed Phase I (2 Pharmaceutical Approvals Monthly October 2004, p. 6). DOV triple reuptake inhibitors for depression (216,303 and 21,947) also are being developed with partner Merck (3 Pharmaceutical Approvals Monthly August 2005, p. 25). The ocinaplon trial hold represents DOV's second setback since Hudson took over as CEO earlier this summer. DOV announced Aug. 9 a revised Merck licensing deal that returns initial clinical trial responsibility for DOV's 21,947 compound to DOV. Hudson, who has over 15 years of pharma experience including stints in senior leadership positions at Pharmacia and Glaxo, also has served as vice provost, office of strategic initiatives, at the University of Pennsylvania. DOV Chairman Arnold Lippa, PhD, also served as the firm's CEO and president prior to Hudson's appointment. |