FDA panel gives thumbs down to rimonabant

Unanimous decision by Endocrinologic and Metabolic Drugs Advisory Committee based on risk for psychiatric events.

In a June meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously voted against approval of the proposed weight-loss drug rimonabant due to unclear safety information and data pointing to an increased risk for psychiatric and neurological adverse events.

Clinical trial data on rimonabant, known in the U.S. as Zimulti and manufactured by Sanofi Aventis, demonstrated that patients who were assigned the once-daily pill had a higher incidence of suicidal thoughts, symptoms of depression, seizures, anxiety, insomnia and aggressiveness.

Sanofi Aventis is seeking approval of rimonabant 20 mg with an indication for patients who are obese or overweight or who have type 2 diabetes, high BP and/or other risks for CVD. The FDA will decide by July 27 whether to allow the drug to be sold in the U.S., and although the FDA is not required to follow the advice of the advisory panel, it usually does.

The drug was approved last year in Europe and is marketed there as Accomplia. More than 100,000 European patients have been prescribed the drug. As a result of this rejection by the FDA advisory panel, the European Medicines Agency will receive safety data for rimonabant in Europe next week.

“In this particular case, the adverse events tell the story,” said Clifford Rosen, MD, acting chair of the advisory panel. “They are a big deal … and until we really know that information and the true prevalence of these adverse events, we cannot make a decision.”

Rimonabant, a cannabinoid receptor 1 antagonist/inverse agonist, helps regulate food intake and the body’s storage of fat and sugar.

Sense of unease

As of March 2007, more than 15,000 patients had taken at least one dose of rimonabant 20 mg (3,478 patient-years). The most common adverse event was nausea (13%). Neurological symptoms were vague, according to Sanofi Aventis officials. However, these adverse events occurred more often in patients who were assigned to rimonabant 20 mg compared with placebo (27.4% vs. 24.4%).

“A vast array of evidence gave us a considerable sense of uneasiness,” said Amy Egan, MD, MPH, medical officer, FDA/CDER division of metabolic and endocrine drug products. Egan presented clinical efficacy and safety data of rimonabant. “These data are worrisome because there is reason to believe overweight and obese patients may have a disposition toward depression.”

“Who is the right patient to receive rimonabant? Not everybody,” Richard Gural, PhD, vice president, drug regulatory affairs, Sanofi Aventis, said to the panel. The drug is not appropriate for any individual with a history of depression or suicidal thoughts, patients who are currently depressed or receive antidepressants and/or those with treated epilepsy, according to Gural.

Of concern to the panel was the 5.9% incidence of psychiatric disorders, especially suicidal thinking or behavior, in patients assigned to rimonabant compared with 2.1% in those who were assigned to placebo.

Patients assigned to rimonabant experienced a twofold increase in suicide or thoughts of suicide. According to Egan, an FDA meta-analysis indicated an increased risk for suicide ideation in patients assigned to rimonabant 20 mg compared with placebo, which correlated with one additional case of suicidal thoughts or behavior per year for every 300 patients treated.

There were two suicides recorded in the entire rimonabant clinical trial database. One was a patient in the RIO-North America trial who was assigned rimonabant 5 mg, and the other was in the ongoing STRADIVARIUS trial in a patient assigned to rimonabant 20 mg.

“The incidence of suicidality – specifically suicidal ideation – was higher for 20 mg rimonabant compared with placebo. Similarly, the incidence of psychiatric adverse events, neurological adverse events and seizures were consistently higher for 20 mg rimonabant compared with placebo,” according to an FDA briefing document.

Depressive events, or any symptom that triggered a psychiatric consultation, were monitored during the clinical trials. Officials from Sanofi Aventis recommended patients be screened for depression before being prescribed the drug. The company said most of the events occurred in patients with a history of depression; however, 88% of patients who reported psychiatric symptoms while taking rimonabant had no prior history of depression.

“This is a drug that needs further understanding of what it does to people’s psyches,” said Sid Gilman, MD, FRCP, professor of neurology, University of Michigan.

High attrition rate, lack of long-term data

Many panelists expressed concern regarding the high number of patients who dropped out of the RIO trials. Attrition rates ranged from 32% to 49% within the first year.

The lack of long-term safety data presents a serious issue since rimonabant is proposed as a life-long weight-loss medication. There are data for 441 patients who were assigned to rimonabant 20 mg for two years in the clinical trials database.

“The real implication here is that you have lost data on adverse events, and you have lost serious data on depression and anxiety,” said Domenic A. Ciraulo, MD, chairman and physiatrist-in-chief, Boston Medical Center/Boston University.

The estimates of adverse events may be low given the high attrition rate due to adverse events, according to Katherine M. Flegal, PhD, senior research scientist, National Center for Health Statistics, CDC.

No sufficient safety data

“It is our job here to tell what is good and what is bad about what [Sanofi Aventis] has presented us. The greatest good is people are trying to do something pharmacologically about obesity,” said Jules Hirsch, MD, Sherman Fairchild professor/senior physician, Laboratory of Human Behavior and Metabolism, Rockefeller University.

The main problem is “that the number of people who are going to lose weight is fairly small. There is a reasonable suspicion we better watch this whole affair carefully before we launch into massive use of the drug,” Hirsch said.

Data from the RIO trials demonstrated that one-quarter of obese patients who were assigned to rimonabant lost 10% of their body weight after one year, and half lost about 5% of their original weight. These weight reductions were significantly greater than those among the placebo groups.

“I am glad the drug is available. I hope a lot more good work will be done, but I wouldn’t in any way suggest it be approved at the present time for any use,” Hirsch said.

Rimonabant has about the same efficacy as sibutramine and orlistat, the two other approved weight-loss drugs, according to Paul D. Woolf, MD, chairman, department of medicine, Crozer-Chester Medical Center, Upland, Pa.

“I am concerned about what we do not know and the dangers we can fall into,” Woolf said. He said that there are not enough patient data for a long enough period of time to know what is going to happen down the road. “We need to err on the side of caution in this case.” – by Katie Kalvaitis