The long delay in FDA action on diet drug rimonabant (Acomplia / Zimulti) is the result of concern over "increased frequencies of psychiatric adverse effects" including suicide and seizures, the agency's staff disclosed on June 11th.

The confirmation of long-rumored FDA worries over the neuropsychiatric side-effects of this novel diet drug -- which works by blocking the CB1 receptors in the brain -- came in a briefing paper prepared for the June 13th airing of issues surrounding rimonabant by an FDA panel of outside medical experts.

The staff report suggests that rimonabant's developer, Sanofi-Aventis, is in for a rough day Wednesday, and that without a favorable recommendation by the advisory panel, the FDA may well decide in July to defer approval of sale of rimonabant in the United States until it has more data -- perhaps until 2010.

"Among the most significant adverse events throughout the Phase 3 (clinical trial) program were those in the primary System Organ Class (SOC) Psychiatric Disorders, specifically depressive events, anxiety, psychomotor agitation, and sleep disorders," the FDA staff said.

While the FDA reported only two completed suicides during the trials by participants on Acomplia, the "possible and/or definite cases of suicidality" during the trials identified by a Columbia University team that advises the FDA totalled 74 with those on rimonabant outnumbering those on a placebo by almost three to one.

The staff also pointed out that an unusually high percentage of participants withdrew early from the clinical trials, the staff reported, "with more rimonabant subjects doing so due to depression, anxiety, mood alteration with depressive symptoms, and the need for antidepressant medication.

"Given the lack of systematic follow-up of these subjects and rimonabant’s long half-life (the time it continues acting after a person stops taking it), the results of the above analyses should be viewed as incomplete at best and at worse as an underestimate of rimonabant’s risk for suicidality," the staff said.

The FDA said that subsequent to Sanofi's submission of a safety update on Acomplia trials that are still continuing in March 2007, it has received 2 additional reports of suicide attempts - one by a 60-year-old female and the other by a 56-year-old male taking rimonabant in the CRESCENDO trial.

The staff said the FDA also has been maintaining a log of all adverse event reports reported by patients taking Acomplia in countries where it has been approved for sale.

The agency said that in addition to 15 reports of thoughts of or planning for suicide, it had received " 4 reports of delusional symptoms, 6 reports of psychotic behavior (including a man who attempted to strangle his daughter),
and 5 reports of aggression (including a man who beat his wife.)"

The FDA said data from countries where Acomplia is being marketed also "reveal that reports of nervous system disorders are frequent (15% of
adverse events reported) and are driven predominantly by dizziness."

The staff also reported that experts had identified 11 likely or possible cases of "seizures" among participants in the clinical trials, as well as four confirmed cases of multiple sclerosis among trial participants taking rimonabant.

During the trials, the staff reported that dizziness and vertigo occurred with greater frequency in the rimonabant 20 mg group...motor impairment occurred with greater frequency (driven predominantly by “tremor” and “balance disorder)... .and cognitive disorders occurred with greater frequency ... driven
predominantly by “mental impairment”, “somnolence”, and “disturbance in
thinking/perception.”

"These neurological adverse events may well have contributed to the disproportionate number of subjects who sustained injuries (contusions, concussions, falls, road traffic accidents, whiplash, and injuries) during the RIO trials in the rimonabant 20 mg group," the staff added.

(Editors note: We will have additional reports drawn from the FDA staff's 88-page briefing paper later in the day)