ACC: Rimonabant Therapy Fails to Demonstrate Atherosclerosis Benefit
By Peggy Peck
CHICAGO, April 2 -- Reducing abdominal obesity with the investigational diet drug rimonabant had a beneficial effect on metabolic profile, but did not demonstrate a significant reduction in percent atheroma volume on intravascular ultrasound, researchers reported here. But there was a significant improvement in a prespecified secondary endpont, total atheroma volume, which led Steven Nissen, M.D., of the Cleveland Clinic, to conclude that a weight reduction strategy that targets abdominal obesity is promising. Dr. Nissen, who presented the results of the STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant) trial at the American College of Cardiology meeting, said that it is also possible that larger trials of rimonabant or a similar agent might provide evidence of a direct effect on atherosclerosis.
After 18 months of treatment the percent atheroma volume, a measure of plaque in the artery wall, increased in 0.25% in the rimonabant group versus an increase of 0.51% in the placebo arm (P=0.22).
But the total atheroma volume decreased by 2.2 mm2 in the rimonabant arm versus an increase of 0.88 mm2 in the placebo arm (P=0.03).
Moreover, rimonabant therapy was associated with an increase of 5.8 mg/do in HDL, a decrease of 24.8 mg in triglycerides, and a decrease of 1.3 mg/do in C-reactive protein, all of which were significant compared with controls (P<0.001).
Glycated hemoglobin increased in both arms, but the rate of increase was significantly slowed in the rimonabant group (0.11% versus 0.40% P<0.001).
That finding, while not raising to the level of solid evidence, was hypothesis-generating and enough, Dr. Nissen said, to suggest that there was a possibility that CRESCENDO, a large, ongoing outcomes trial of the drug, might provide evidence of real cardiovascular benefit.
The finding was also one more disappointment for what was once widely regarded as a promising drug.
Rimonabant has repeatedly demonstrated its efficacy for weight loss and has also demonstrated efficacy in smoking cessation trials. That evidence paved the way for quick approval in Europe, but the FDA said it won't approve the drug without more safety data.
STRADIVARIUS randomized 839 patients at 112 centers in North America, Europe, and Australia to 20 mg rimonabant or placebo, plus dietary counseling. All patients had baseline intravascular ultrasound and 676 had repeat IVUS on completion of the trial.
The mean baseline body mass index of patients was 35 and the mean waist circumference for men, who made up 65% of the study participants, was 46 inches.
Patients in the rimonabant arm shed about 9.5 pounds (4.3 kg) versus 1.1 pounds (0.5 kg) in the controls. They also reduced their waist circumference by 1.77 inches (4.5 cm) versus a decrease of 0.39 inches (1.0 cm), P<0.001 for both.
Although there was not a clear indication of cardiovascular benefit, there was a significant safety signal in the trial -- 43.3% of the rimonabant patients reported anxiety, depression, and other mood disorders versus 28.4% of the placebo patients (P<0.001).
Moreover, one patient in the placebo group attempted suicide and one patient in the rimonabant arm completed suicide.
It was concern about psychiatric side effects that derailed rimonabant's bid for FDA approval.
As noted in a editorial that accompanied the JAMA publication, an FDA analysis of rimonabant clinical trials found that the 20 mg dose "was associated with a 2-fold higher suicide risk," and an FDA advisory committee unanimously recommended against rimonabant approval.
Asked about the likelihood that rimonabant would ever be available in the United States, Dr. Nissen declined to speculate, but he said that similar compounds are in development, which increased the likelihood that a cannabinoid receptor blocker will eventually win FDA approval.
In the JAMA editorial, John S. Rumsfeld, M.D., Ph.D., of the University of Colorado at Denver, and Brahmajee K. Nallamothu, M.D., M.P.H., of the University of Michigan in Ann Arbor, concluded that until the results of the CRESENDO study are available, "the potential benefits of rimonabant therapy are offset by very real risks of depression and anxiety."
Attacking abdominal obesity as a way to lower lipids is not a novel concept. In November 2005, the RIO-LIPIDS (Rimonabant in Obesity Lipids) investigators wrote that 12 months of treatment with rimonabant, plus a diet that cut daily energy intake by 600 calories was associated with significant improvement in lipids (N Engl J Med 2005; 353: 2121-2134).
And a year earlier, results from the 30,000-patient INTER-HEART study, reported at the European Society of Cardiology and simultaneously published in The Lancet, showed that one of the most potent predictors of cardiovascular risk was waist circumference irrespective of waist or gender (The Lancet, 2004 364: 953-62)
The study was funded by sanofi-aventis.
Dr. Nissen reported receiving research support from AstraZeneca, Atherogenics, Eli Lilly, Novartis, Pfizer, Takeda, Daiichi-Sankyo, and sanofi-aventis and consulting for a number of pharmaceutical companies without financial compensation (all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity, so that neither income nor any tax deduction is received).
Drs. Rumsfeld and Nallamothu reported no financial conflicts.
Additional source: Journal of the American Medical AssociationSource reference: Nissen, SE et al "Effect of Rimonabant on Progression of Atherosclerosis in Patients with Abdominal Obesity and Coronary Artery Disease The STRADIVARIUS Randomized Controlled Trial" JAMA 2008; 299: 1547-1560. Additional source: Journal of the American Medical AssociationSource reference: Rumsfeld JS, Nallamothu BK "The hope and fear of rimonabant" JAMA 2008; 299: 1601-1602.
Showing posts with label rimonabant. Show all posts
Showing posts with label rimonabant. Show all posts
Thursday, April 03, 2008
Wednesday, November 28, 2007
Weight-Loss Drug Rimonabant Increases Risk for Adverse Psychiatric Effects
November 27, 2007 — A meta-analysis of 4 randomized controlled trials of the weight-loss drug rimonabant concurs with Food and Drug Administration (FDA) findings of an increased risk for serious adverse psychiatric effects — depressed mood disorders and anxiety — although depressed mood was an exclusion criteria.
These findings, based on data from the 4 clinical trials in the Rimonabant in Obesity (RIO) program — RIO-Europe, RIO-Lipids, RIO-North America, and RIO-Diabetes — are published in a November 17 article in The Lancet by Robin Christensen, MSc, and colleagues at the University of Copenhagen in Denmark.
Rimonabant (Acomplia; Sanofi Aventis) was approved by the European Agency for the Evaluation of Medicinal Products in June 2006 and is available in Argentina, Austria, Denmark, Finland, Germany, Ireland, Norway, Sweden, Greece, and the United Kingdom. In June 2007, coinciding with the submission of this Lancet article, the Advisory Committee of the US FDA unanimously concluded that more detailed safety information about rimonabant was needed before the drug could be approved for use in the United States, and subsequent to that decision, Sanofi Aventis withdrew its new drug application in the United States.
First Do No Harm
"There's no doubt that this is a serious matter because one should remember that the treatment must never be more harmful than the disease, for weight-loss compounds," study author Arne Astrup, MD, said in a podcast available on the Lancet Web site.
Rimonabant, a selective antagonist for the cannabinoid type 1 (CB1) receptor, is the first drug being marketed in this class of drugs that are involved in inhibiting the effect of food, cannabis, and tobacco on the central nervous system rewarding system.
The 4 RIO trails showed that rimonabant results in a weight loss that is 4 to 6 kg (8.8 - 13.2 pounds) greater than that with placebo, in 6 to 12 months, which is about the same as for the 2 other weight-loss drugs on the market, orlistat (Xenical; Roche) and sibutramine (Meridia; Abbott), the study authors write. Although rimonabant was generally well tolerated, individual trials showed trends to increases in depressed mood disorders, depression, and severe adverse effects.
The group aimed to perform a meta-analysis to obtain more robust data to determine the drug's efficacy and safety, especially adverse psychiatric events. Only double-blind, randomized controlled trials using rimonabant for weight loss in patients with a body mass index (BMI) of 30 kg/m2 or greater or 27 kg/m2 or greater with 1 or more obesity-related comorbidities were eligible.
The 4 large, multicenter, double-blind RIO trials met the study requirements. These trials included 4105 participants who received 20 mg/day of rimonabant or placebo.
High Study Dropout Because of Depression, Anxiety
Compared with patients in the placebo group, patients taking rimonabant had a 4.7-kg greater weight reduction at 1 year, and they were 5 times more likely to achieve at least 10% weight loss.
Compared with patients receiving placebo, those in the rimonabant study groups had a higher risk of developing a serious adverse event (5.9% vs 4.2%) and a greater risk of discontinuing the study because of developing a depressive mood disorder (3% vs 1.4%) or anxiety (1% vs 0.3%).
Higher Risk in Clinical Practice
In countries where rimonabant is being prescribed, clinicians need to be really aware that patients have an increased risk of developing depression or anxiety, said Dr. Astrup. It is also important to note that the clinical trials excluded patients who had existing or past depression or were taking therapies for depression. "We think the risk will be higher in clinical practice," he cautioned. Another reason these findings are important is that 4 or 5 major pharmaceutical companies are developing similar CB1 compounds that they are moving from phase 2 to phase 3, he added. "It is quite important for them to be aware of this problem with depression and anxiety so they will have a chance to do a better job of monitoring all these psychiatric symptoms. . . so we will have a much better idea of the severity of the problem."
Editorialists Agree
"Up to this point in time, there has been controversy over the rates and severity of psychiatric adverse effects with rimonabant," Phillip B. Mitchell, MD, who with Margaret J. Morris, PhD, both at the University of New South Wales, Australia, coauthored an accompanying editorial, told Medscape Psychiatry. "This is the first meta-analysis to examine rates of. . . symptoms severe enough to lead to patients discontinuing treatment."
The findings are significant because they "raise major questions about the safety of rimonabant in obese people, who are already at increased risk of depression. . . and suggest that phase III studies of CB1 antagonists should monitor psychiatric complications very carefully," they write, echoing the words of the study authors. In addition, they note that the link between depression and this CB1 blocker raises theoretical questions about a potential central role for the endocannabinoid system in normal and clinical mood states.
Robin Christensen was the statistical expert/consultant in the Lantus medical expert panel for Sanofi-Aventis (Denmark), the maker of rimonabant, in 2006. Dr. Arne Astrup has participated in several advisory boards for biotechnology and pharmaceutical companies, some of which are developing CB1 antagonists for the treatment of obesity. He is president of the International Society of the Study of Obesity (IASO), which had received funding from Sanofi Aventis when he was president-elect. He also participated in the Danish rimonabant advisory board for Sanofi-Aventis, until the board closed in June 2006. The remaining study authors have disclosed no relevant financial relationships.
Dr. Mitchell has received payments for lectures or advisory board membership from AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, and Lundbeck in the past 3 years. Dr. Morris has disclosed no relevant financial relationships.
Lancet. 2007;370:1671-1672, 1706-1713.
November 27, 2007 — A meta-analysis of 4 randomized controlled trials of the weight-loss drug rimonabant concurs with Food and Drug Administration (FDA) findings of an increased risk for serious adverse psychiatric effects — depressed mood disorders and anxiety — although depressed mood was an exclusion criteria.
These findings, based on data from the 4 clinical trials in the Rimonabant in Obesity (RIO) program — RIO-Europe, RIO-Lipids, RIO-North America, and RIO-Diabetes — are published in a November 17 article in The Lancet by Robin Christensen, MSc, and colleagues at the University of Copenhagen in Denmark.
Rimonabant (Acomplia; Sanofi Aventis) was approved by the European Agency for the Evaluation of Medicinal Products in June 2006 and is available in Argentina, Austria, Denmark, Finland, Germany, Ireland, Norway, Sweden, Greece, and the United Kingdom. In June 2007, coinciding with the submission of this Lancet article, the Advisory Committee of the US FDA unanimously concluded that more detailed safety information about rimonabant was needed before the drug could be approved for use in the United States, and subsequent to that decision, Sanofi Aventis withdrew its new drug application in the United States.
First Do No Harm
"There's no doubt that this is a serious matter because one should remember that the treatment must never be more harmful than the disease, for weight-loss compounds," study author Arne Astrup, MD, said in a podcast available on the Lancet Web site.
Rimonabant, a selective antagonist for the cannabinoid type 1 (CB1) receptor, is the first drug being marketed in this class of drugs that are involved in inhibiting the effect of food, cannabis, and tobacco on the central nervous system rewarding system.
The 4 RIO trails showed that rimonabant results in a weight loss that is 4 to 6 kg (8.8 - 13.2 pounds) greater than that with placebo, in 6 to 12 months, which is about the same as for the 2 other weight-loss drugs on the market, orlistat (Xenical; Roche) and sibutramine (Meridia; Abbott), the study authors write. Although rimonabant was generally well tolerated, individual trials showed trends to increases in depressed mood disorders, depression, and severe adverse effects.
The group aimed to perform a meta-analysis to obtain more robust data to determine the drug's efficacy and safety, especially adverse psychiatric events. Only double-blind, randomized controlled trials using rimonabant for weight loss in patients with a body mass index (BMI) of 30 kg/m2 or greater or 27 kg/m2 or greater with 1 or more obesity-related comorbidities were eligible.
The 4 large, multicenter, double-blind RIO trials met the study requirements. These trials included 4105 participants who received 20 mg/day of rimonabant or placebo.
High Study Dropout Because of Depression, Anxiety
Compared with patients in the placebo group, patients taking rimonabant had a 4.7-kg greater weight reduction at 1 year, and they were 5 times more likely to achieve at least 10% weight loss.
Compared with patients receiving placebo, those in the rimonabant study groups had a higher risk of developing a serious adverse event (5.9% vs 4.2%) and a greater risk of discontinuing the study because of developing a depressive mood disorder (3% vs 1.4%) or anxiety (1% vs 0.3%).
Higher Risk in Clinical Practice
In countries where rimonabant is being prescribed, clinicians need to be really aware that patients have an increased risk of developing depression or anxiety, said Dr. Astrup. It is also important to note that the clinical trials excluded patients who had existing or past depression or were taking therapies for depression. "We think the risk will be higher in clinical practice," he cautioned. Another reason these findings are important is that 4 or 5 major pharmaceutical companies are developing similar CB1 compounds that they are moving from phase 2 to phase 3, he added. "It is quite important for them to be aware of this problem with depression and anxiety so they will have a chance to do a better job of monitoring all these psychiatric symptoms. . . so we will have a much better idea of the severity of the problem."
Editorialists Agree
"Up to this point in time, there has been controversy over the rates and severity of psychiatric adverse effects with rimonabant," Phillip B. Mitchell, MD, who with Margaret J. Morris, PhD, both at the University of New South Wales, Australia, coauthored an accompanying editorial, told Medscape Psychiatry. "This is the first meta-analysis to examine rates of. . . symptoms severe enough to lead to patients discontinuing treatment."
The findings are significant because they "raise major questions about the safety of rimonabant in obese people, who are already at increased risk of depression. . . and suggest that phase III studies of CB1 antagonists should monitor psychiatric complications very carefully," they write, echoing the words of the study authors. In addition, they note that the link between depression and this CB1 blocker raises theoretical questions about a potential central role for the endocannabinoid system in normal and clinical mood states.
Robin Christensen was the statistical expert/consultant in the Lantus medical expert panel for Sanofi-Aventis (Denmark), the maker of rimonabant, in 2006. Dr. Arne Astrup has participated in several advisory boards for biotechnology and pharmaceutical companies, some of which are developing CB1 antagonists for the treatment of obesity. He is president of the International Society of the Study of Obesity (IASO), which had received funding from Sanofi Aventis when he was president-elect. He also participated in the Danish rimonabant advisory board for Sanofi-Aventis, until the board closed in June 2006. The remaining study authors have disclosed no relevant financial relationships.
Dr. Mitchell has received payments for lectures or advisory board membership from AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, and Lundbeck in the past 3 years. Dr. Morris has disclosed no relevant financial relationships.
Lancet. 2007;370:1671-1672, 1706-1713.
Friday, November 16, 2007
Lancet, BMJ studies sound concern over anti-obesity drug rimonabant
Thu Nov 15, 7:15 PM ET
Two overviews of trials of weight-loss drugs have added to concerns that the obesity treatment rimonabant may boost the risk of depression and anxiety.
The papers, published in Saturday's issue of The Lancet and online Friday by the British Medical Journal (BMJ), follow a decision in June by an advisory panel to the US Food and Drug Administration (FDA) that voted against marketing rimonabant in the United States on safety grounds.
Doctors led by Arne Astrup, a professor at the Faculty of Life Sciences at the University of Copenhagen, analysed four trials in which 4,105 patents were either given a 20mg daily dose of rimonabant or a dummy lookalike pill called a placebo.
Over one year, patients on rimonabant realised a weight loss that was 4.7 kilos (10.3 pounds) higher than counterparts in the placebo group.
But they were also 40 percent likelier to experience "adverse" or "serious adverse" events, according to Astrup's study, which appears in The Lancet.
Patients on rimonabant were two and a half times likelier to stop taking the drug because of depression than those on placebo, and three times likelier to discontinue the treatment because of anxiety.
The findings are significant because individuals with a history of depression -- a phenomenon common among the severely obese -- were specifically excluded from the trial, say the authors.
"We recommend increased alertness by physicians to these potentially severe psychiatric reactions," the Lancet paper says.
Meanwhile, a study published online Friday by the British Medical Journal (BMJ) said that rimonabant and two other anti-obesity drugs, orlistat and sibutramine, were of only limited effect in terms of weight loss over the long term.
Canadian researchers reviewed data from 30 trials in which obese volunteers -- average weight 100 kilos (220 pounds) -- took either anti-obesity drugs or a placebo for a year or more.
The three drugs reduced weight by less than five kilos (11 pounds), equivalent to a loss of less than five percent of total body weight.
The three drugs had various beneficial side effects but all had adverse effects, including, in rimonabant's case, an increase in depression and anxiety, they said.
The authors noted that no trials examined rates of death and disease as a result of taking anti-obesity pills and called for trials to looking into this aspect.
In June, all 14 experts on the FDA's Advisory Committee said rimonabant, which French maker Sanofi-Aventis had hoped would become a blockbuster drug under the brand name of Zimulti, voted against authorising the drug after they heard evidence that it was linked with an increased risk of suicide.
The European Union has approved rimonabant, locally marketed as Acomplia, as a support for diet and exercise for obese patients who have Type 2 diabetes and cardiovascular problems associated with obesity.
However, labelling of the drug has been stepped up to warn against prescribing it to European patients with depression or those taking anti-depressants.
A trial among 1,047 volunteers, published in The Lancet in October 2006, found ribonant improved control over blood glucose and blood fats among people with Type 2 diabetes.
The drug was "generally well tolerated," the study said. Among those volunteers who dropped out of the trial, depression, nausea and dizziness were the most cited reasons among the rimonabant group.
Rimonabant blocks endocannabinoid receptors in the brain that cause hunger.
Global sales of anti-obesity drugs reached 1.2 billion dollars in 2005, the BMJ said.
Thu Nov 15, 7:15 PM ET
Two overviews of trials of weight-loss drugs have added to concerns that the obesity treatment rimonabant may boost the risk of depression and anxiety.
The papers, published in Saturday's issue of The Lancet and online Friday by the British Medical Journal (BMJ), follow a decision in June by an advisory panel to the US Food and Drug Administration (FDA) that voted against marketing rimonabant in the United States on safety grounds.
Doctors led by Arne Astrup, a professor at the Faculty of Life Sciences at the University of Copenhagen, analysed four trials in which 4,105 patents were either given a 20mg daily dose of rimonabant or a dummy lookalike pill called a placebo.
Over one year, patients on rimonabant realised a weight loss that was 4.7 kilos (10.3 pounds) higher than counterparts in the placebo group.
But they were also 40 percent likelier to experience "adverse" or "serious adverse" events, according to Astrup's study, which appears in The Lancet.
Patients on rimonabant were two and a half times likelier to stop taking the drug because of depression than those on placebo, and three times likelier to discontinue the treatment because of anxiety.
The findings are significant because individuals with a history of depression -- a phenomenon common among the severely obese -- were specifically excluded from the trial, say the authors.
"We recommend increased alertness by physicians to these potentially severe psychiatric reactions," the Lancet paper says.
Meanwhile, a study published online Friday by the British Medical Journal (BMJ) said that rimonabant and two other anti-obesity drugs, orlistat and sibutramine, were of only limited effect in terms of weight loss over the long term.
Canadian researchers reviewed data from 30 trials in which obese volunteers -- average weight 100 kilos (220 pounds) -- took either anti-obesity drugs or a placebo for a year or more.
The three drugs reduced weight by less than five kilos (11 pounds), equivalent to a loss of less than five percent of total body weight.
The three drugs had various beneficial side effects but all had adverse effects, including, in rimonabant's case, an increase in depression and anxiety, they said.
The authors noted that no trials examined rates of death and disease as a result of taking anti-obesity pills and called for trials to looking into this aspect.
In June, all 14 experts on the FDA's Advisory Committee said rimonabant, which French maker Sanofi-Aventis had hoped would become a blockbuster drug under the brand name of Zimulti, voted against authorising the drug after they heard evidence that it was linked with an increased risk of suicide.
The European Union has approved rimonabant, locally marketed as Acomplia, as a support for diet and exercise for obese patients who have Type 2 diabetes and cardiovascular problems associated with obesity.
However, labelling of the drug has been stepped up to warn against prescribing it to European patients with depression or those taking anti-depressants.
A trial among 1,047 volunteers, published in The Lancet in October 2006, found ribonant improved control over blood glucose and blood fats among people with Type 2 diabetes.
The drug was "generally well tolerated," the study said. Among those volunteers who dropped out of the trial, depression, nausea and dizziness were the most cited reasons among the rimonabant group.
Rimonabant blocks endocannabinoid receptors in the brain that cause hunger.
Global sales of anti-obesity drugs reached 1.2 billion dollars in 2005, the BMJ said.
Saturday, June 30, 2007
Sanofi pulls obesity drug application in U.S.
By Ben Hirschler, European Pharmaceuticals CorrespondentFri Jun 29, 1:07 PM ET
Sanofi-Aventis SA is withdrawing its application to sell obesity drug rimonabant -- its biggest new drug hope -- in the United States, the French drugmaker said on Friday.
The move comes two weeks after a U.S. advisory panel said the medicine should not be approved in the world's largest drugs market because it may increase suicidal thinking and depression.
Sanofi said it would work towards resubmitting the medicine, known by the brand names Acomplia and Zimulti, at a future date and would undertake necessary discussions with the Food and Drug Administration (FDA) on required modifications to its file.
Industry analysts said the decision was a fresh setback for the hoped-for blockbuster, which is also facing an extended safety review in Europe, where it has been on the market since last year.
Paul Diggle of Nomura Code Securities said the drug might yet have a future in the United States as a niche treatment for diabetes but as a weight-loss treatment it appeared "fatally wounded."
Others said the world's third-biggest drugmaker was acting proactively to save face and avoid outright rejection from the
FDA.
Shaojing Tong, an analyst with Mehta Partners in New York, said the medicine could still be approved if it fares well in a large trial underway that may provide a better picture of its risks and benefits -- but this would delay approval until 2011.
"This trial is longer than earlier studies and metabolic benefits from raising HDL (good) cholesterol and lowering triglycerides could be reflected" in terms of patient health benefits, Tong said.
The drug is the first in a new class of drugs that switch off the same brain circuits that make people hungry when they smoke cannabis.
EU DECISION IN JULY
European regulators said they were still reviewing the latest safety data on the medicine and would only come to a final decision on the product next month.
"The review is expected to be finalized at the July CHMP (Committee for Medicinal Products for Human Use) meeting," a spokeswoman for the European Medicines Agency said.
The EU watchdog had initially said it was likely to give a view this month. Sanofi said it was submitting an update of safety data on the medicine to the CHMP.
Shares in Sanofi, which plunged on the U.S. panel decision earlier in June, gave up earlier gains to end 0.6 percent down on the day at 60.10 euros in Paris.
Acomplia is currently not recommended for European patients with major depression, due to its potential psychiatric side effects, and industry analysts believe further restrictions on its use are now very possible.
"I don't think it will be withdrawn in Europe but I think the label is going to get tougher," Nomura's Diggle said. "There is no way that people's forecasts are not going to come down even further."
Paris-based Sanofi has in the past trumpeted Acomplia as potential mega blockbuster, with sales of $3 billion a year or more. But actual take-up of the medicine in those markets where it is available has been slow, partly because of lack of reimbursement.
Worldwide sales of Acomplia in the first quarter of 2007 totaled just 15 million euros ($20.17 million), down from 20 million in the fourth quarter of 2006.
It is currently approved in 42 countries and marketed in 20 to treat obesity and overweight patients with associated cardiovascular risk factors.
(Additional reporting by Ransdell Pierson in New York)
Sanofi-Aventis SA is withdrawing its application to sell obesity drug rimonabant -- its biggest new drug hope -- in the United States, the French drugmaker said on Friday.
The move comes two weeks after a U.S. advisory panel said the medicine should not be approved in the world's largest drugs market because it may increase suicidal thinking and depression.
Sanofi said it would work towards resubmitting the medicine, known by the brand names Acomplia and Zimulti, at a future date and would undertake necessary discussions with the Food and Drug Administration (FDA) on required modifications to its file.
Industry analysts said the decision was a fresh setback for the hoped-for blockbuster, which is also facing an extended safety review in Europe, where it has been on the market since last year.
Paul Diggle of Nomura Code Securities said the drug might yet have a future in the United States as a niche treatment for diabetes but as a weight-loss treatment it appeared "fatally wounded."
Others said the world's third-biggest drugmaker was acting proactively to save face and avoid outright rejection from the
FDA.
Shaojing Tong, an analyst with Mehta Partners in New York, said the medicine could still be approved if it fares well in a large trial underway that may provide a better picture of its risks and benefits -- but this would delay approval until 2011.
"This trial is longer than earlier studies and metabolic benefits from raising HDL (good) cholesterol and lowering triglycerides could be reflected" in terms of patient health benefits, Tong said.
The drug is the first in a new class of drugs that switch off the same brain circuits that make people hungry when they smoke cannabis.
EU DECISION IN JULY
European regulators said they were still reviewing the latest safety data on the medicine and would only come to a final decision on the product next month.
"The review is expected to be finalized at the July CHMP (Committee for Medicinal Products for Human Use) meeting," a spokeswoman for the European Medicines Agency said.
The EU watchdog had initially said it was likely to give a view this month. Sanofi said it was submitting an update of safety data on the medicine to the CHMP.
Shares in Sanofi, which plunged on the U.S. panel decision earlier in June, gave up earlier gains to end 0.6 percent down on the day at 60.10 euros in Paris.
Acomplia is currently not recommended for European patients with major depression, due to its potential psychiatric side effects, and industry analysts believe further restrictions on its use are now very possible.
"I don't think it will be withdrawn in Europe but I think the label is going to get tougher," Nomura's Diggle said. "There is no way that people's forecasts are not going to come down even further."
Paris-based Sanofi has in the past trumpeted Acomplia as potential mega blockbuster, with sales of $3 billion a year or more. But actual take-up of the medicine in those markets where it is available has been slow, partly because of lack of reimbursement.
Worldwide sales of Acomplia in the first quarter of 2007 totaled just 15 million euros ($20.17 million), down from 20 million in the fourth quarter of 2006.
It is currently approved in 42 countries and marketed in 20 to treat obesity and overweight patients with associated cardiovascular risk factors.
(Additional reporting by Ransdell Pierson in New York)
Thursday, June 14, 2007
Unanimous "No" to Rimonabant: Safety Not Demonstrated, FDA Advisory Panel Says
June 13, 2007 (Silver Spring, MD) - In a blow to the drug maker, as well as millions of overweight and obese Americans hoping for a new weight-loss medication, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously to send Sanofi-Aventis back to gather more detailed safety information about rimonabant over the long term, in larger patient numbers.
After a day of discussion and presentations, all 14 members of the advisory committee agreed that rimonabant did not demonstrate a risk/benefit profile to enable it to be approved for the indication the sponsor was seeking: weight management in individuals with a body-mass index of >30 kg/m2 or in individuals with a BMI of >27 kg/m2 when accompanied by at least one comorbid condition.
The committee's concerns centered on what many concluded was a "clear" signal of increased risk of neurological side effects—seizures, depression, anxiety, aggressiveness, and suicidal thoughts among patients randomized to rimonabant. Many were also concerned about the low number of patients—441 in total—who had actually been taking the 20-mg dose for out to two years. Several panel members stated that even current, ongoing studies of rimonabant, including the CRESCENDO study, are not appropriately designed to clarify the types of adverse events occurring in people taking the drug.
After a day of discussion and presentations, all 14 members of the advisory committee agreed that rimonabant did not demonstrate a risk/benefit profile to enable it to be approved for the indication the sponsor was seeking: weight management in individuals with a body-mass index of >30 kg/m2 or in individuals with a BMI of >27 kg/m2 when accompanied by at least one comorbid condition.
The committee's concerns centered on what many concluded was a "clear" signal of increased risk of neurological side effects—seizures, depression, anxiety, aggressiveness, and suicidal thoughts among patients randomized to rimonabant. Many were also concerned about the low number of patients—441 in total—who had actually been taking the 20-mg dose for out to two years. Several panel members stated that even current, ongoing studies of rimonabant, including the CRESCENDO study, are not appropriately designed to clarify the types of adverse events occurring in people taking the drug.
F.D.A. Panel Votes Against Weight-Loss Drug
By STEPHANIE SAUL
A drug once viewed as a possible magic bullet against obesity was rejected today by a federal advisory panel, which cited concerns that it increases the risk of neurological and psychiatric problems, including suicide.
Although the drug is already marketed in 37 countries under the name Acomplia, it is now unlikely that the Food and Drug Administration will approve its sale in the United States. The advisory panel voted unanimously, 14 to 0, against recommending the drug, saying there was inadequate safety data to support its use.
The F.D.A. is not required to follow the advice of such advisory panels, though it typically does.
The panel’s vote was a blow to Sanofi-Aventis, the French company that makes the drug.
As the advisory committee finished its voting, shares of Sanofi-Aventis, which trades in this country as American depositary receipts, closed at $43.07, down $1.31, or 2.95 percent. Sanofi had hoped the drug would be a $3 billion seller, with much of that market in the United States, which has a worsening obesity problem.
Dr. Jules Hirsch, an advisory committee member who is a research physician at Rockefeller University, summed up the sentiments of the other panelists. “I couldn’t in any way suggest that it be approved at the present time for use,” he said.
The drug, which the company had planned to call Zimulti in the United States, works on the brain’s endocannabinoid system. The system was discovered through research into marijuana, which works on brain receptors to give users the “munchies.”
By suppressing those receptors, Zimulti suppresses hunger. Clinical studies revealed that patients taking it lost about 5 percent of their weight.
But the same brain system also modulates depression, phobias, anxiety and post-traumatic stress disorder. Studies cited in testimony today suggest that tampering with the endocannabinoid system also increases such psychiatric problems, including suicidal thoughts.
“The potential market for this drug and the continued uncertainty about its risks, both known and unknown, lead to our concern about the use of this drug in the general population,” an F.D.A. staff medical reviewer, Dr. Amy G. Egan, told the panel.
The committee’s vote that there the safety data was inadequate came after Dr. Egan’s presentation, which indicated that the drug doubled a patient’s risk of psychological problems, including anxiety, depression, aggression and psychosis.
The committee also heard about data showing an increase in suicidal thinking among users of the drug, including four patients who did commit suicide while on it.
A drug once viewed as a possible magic bullet against obesity was rejected today by a federal advisory panel, which cited concerns that it increases the risk of neurological and psychiatric problems, including suicide.
Although the drug is already marketed in 37 countries under the name Acomplia, it is now unlikely that the Food and Drug Administration will approve its sale in the United States. The advisory panel voted unanimously, 14 to 0, against recommending the drug, saying there was inadequate safety data to support its use.
The F.D.A. is not required to follow the advice of such advisory panels, though it typically does.
The panel’s vote was a blow to Sanofi-Aventis, the French company that makes the drug.
As the advisory committee finished its voting, shares of Sanofi-Aventis, which trades in this country as American depositary receipts, closed at $43.07, down $1.31, or 2.95 percent. Sanofi had hoped the drug would be a $3 billion seller, with much of that market in the United States, which has a worsening obesity problem.
Dr. Jules Hirsch, an advisory committee member who is a research physician at Rockefeller University, summed up the sentiments of the other panelists. “I couldn’t in any way suggest that it be approved at the present time for use,” he said.
The drug, which the company had planned to call Zimulti in the United States, works on the brain’s endocannabinoid system. The system was discovered through research into marijuana, which works on brain receptors to give users the “munchies.”
By suppressing those receptors, Zimulti suppresses hunger. Clinical studies revealed that patients taking it lost about 5 percent of their weight.
But the same brain system also modulates depression, phobias, anxiety and post-traumatic stress disorder. Studies cited in testimony today suggest that tampering with the endocannabinoid system also increases such psychiatric problems, including suicidal thoughts.
“The potential market for this drug and the continued uncertainty about its risks, both known and unknown, lead to our concern about the use of this drug in the general population,” an F.D.A. staff medical reviewer, Dr. Amy G. Egan, told the panel.
The committee’s vote that there the safety data was inadequate came after Dr. Egan’s presentation, which indicated that the drug doubled a patient’s risk of psychological problems, including anxiety, depression, aggression and psychosis.
The committee also heard about data showing an increase in suicidal thinking among users of the drug, including four patients who did commit suicide while on it.
Panel rejects new weight-loss drug
By ANDREW BRIDGES, Associated Press WriterWed Jun 13, 10:41 PM ET
Federal health advisers unanimously rejected a weight-loss drug Wednesday after hearing testimony that it increases the risk of suicidal thoughts, even in patients without a history of depression. The manufacturer, Sanofi-Aventis SA, further failed to show the drug rimonabant is safe, the panel said.
The back-to-back, 14-0 votes by the expert panel made it unlikely the Food and Drug Administration will approve the drug. The agency usually follows its panel's advice, but it isn't required to do so.
"There is a reasonable suspicion we better learn some more and watch this affair more closely before we launch into massive use of this drug," said panelist Dr. Jules Hirsch, a senior physician at New York's Rockefeller University.
In studies, patients given the once-daily tablet reported twice as many psychiatric side effects, including depression, anxiety and sleep problems, than those who received sham treatment, Dr. Amy Egan, an FDA medical officer, told the advisers.
"The numbers of events are small, but in aggregate they are worrisome," Egan said.
Officials from Sanofi-Aventis suggested that patients be screened for depression before they are prescribed the drug. They also advised that patients visit their doctors five times during the first year of treatment to be reassessed to further curtail any potential problems.
"Who is the right patient to receive rimonabant? Not everybody," Sanofi-Aventis' Richard Gural told the panel of advisers earlier Wednesday. The drug is not appropriate for anyone with a history of depression or suicidal thoughts, or who has been diagnosed with depression or is taking antidepressant medication, he added.
The FDA is to make a final decision on the drug by July 27.
The company proposes selling the drug under the brand name Zimulti. Rimonabant already is sold in Europe as Acomplia.
The litany of mental problems associated with the drug clearly gave the panelists pause.
"I think this is a drug that needs further understanding with respect to what it does to people's psyche," said panelist Dr. Sid Gilman, a University of Michigan neurologist.
Even if the FDA does approve the first-in-its-class drug, the findings make it highly likely it would bear stern warnings. Company officials embraced the idea of such warnings, which could exclude FDA-approved use in some patients.
The company, FDA and panelists all agreed that Zimulti, along with diet and exercise, works to help shed weight. In yearlong studies, patients on the drug lost roughly 14 pounds. Those given dummy pills lost only about 4 pounds. However, patients regained weight when treatment was stopped after a year.
But the FDA and its outside advisers shared deep concerns that the drug's effect on the body could lead to an array of psychiatric symptoms, including anxiety, phobias, post-traumatic stress disorders and depression. No panelist felt the company had sufficiently characterized the drug's safety.
"What I am really troubled by is the lack of good safety data," said panel chairman Dr. Clifford Rosen, senior staff scientist at the Maine Center for Osteoporosis.
The company believes those increased cases were associated with depression or other disorders and weren't directly caused by its drug. Egan, however, said they were.
"We strongly believe that it is causal," Egan said. She noted 88 percent of those reporting psychiatric problems while on the drug had no prior history of depression.
Furthermore, patients in the studies were carefully screened and monitored, suggesting the problems would be more common should the drug enter broad use, Egan added.
The screenings proposed by the company won't keep the depressed and obese from Zimulti, warned Lynn McAfee, head of medical advocacy for the Council on Size & Weight Discrimination, a fat acceptance group.
"If this gets out to be a real big deal in the public, you can figure out how to answer those questions to get the drug," McAfee said. "It's not going to stop anyone." The potential market for the drug is huge, as obesity rates have exploded in the past two decades. Today, nearly one in three American adults age 20 or older is obese, according to government data.
Dr. Sidney Wolfe, of the advocacy group Public Citizen, said the obese are more likely to be depressed. Many of them likely would take Zimulti along with the antidepressants they already use — with unknown consequences, Wolfe told panelists.
Rimonabant blocks the same pleasure centers in the body activated when pot smokers get the munchies. Blocking the receptors leads to patients eating less and losing weight. Sanofi-Aventis also believes the drug decreases fat storage.
The FDA previously told the French company it would not approve the drug to help smokers quit.
Sanofi-Aventis has proposed selling 20-milligram Zimulti tablets to the obese and to those who are overweight and have type 2 diabetes, high blood pressure or other conditions that put them at risk of cardiovascular disease.
There currently are two FDA-approved prescription drugs for the long-term treatment of obesity: Meridia, an appetite suppressant, and Xenical, which limits the amount of fat the body can absorb. Sales of Alli, a lower-dose version of Xenical that won't require a prescription, start this week.
Heart problems led to the withdrawal of the diet drug fenfluramine in 1997. It had made up with phentermine the popular yet unapproved fen-phen combination treatment.
Federal health advisers unanimously rejected a weight-loss drug Wednesday after hearing testimony that it increases the risk of suicidal thoughts, even in patients without a history of depression. The manufacturer, Sanofi-Aventis SA, further failed to show the drug rimonabant is safe, the panel said.
The back-to-back, 14-0 votes by the expert panel made it unlikely the Food and Drug Administration will approve the drug. The agency usually follows its panel's advice, but it isn't required to do so.
"There is a reasonable suspicion we better learn some more and watch this affair more closely before we launch into massive use of this drug," said panelist Dr. Jules Hirsch, a senior physician at New York's Rockefeller University.
In studies, patients given the once-daily tablet reported twice as many psychiatric side effects, including depression, anxiety and sleep problems, than those who received sham treatment, Dr. Amy Egan, an FDA medical officer, told the advisers.
"The numbers of events are small, but in aggregate they are worrisome," Egan said.
Officials from Sanofi-Aventis suggested that patients be screened for depression before they are prescribed the drug. They also advised that patients visit their doctors five times during the first year of treatment to be reassessed to further curtail any potential problems.
"Who is the right patient to receive rimonabant? Not everybody," Sanofi-Aventis' Richard Gural told the panel of advisers earlier Wednesday. The drug is not appropriate for anyone with a history of depression or suicidal thoughts, or who has been diagnosed with depression or is taking antidepressant medication, he added.
The FDA is to make a final decision on the drug by July 27.
The company proposes selling the drug under the brand name Zimulti. Rimonabant already is sold in Europe as Acomplia.
The litany of mental problems associated with the drug clearly gave the panelists pause.
"I think this is a drug that needs further understanding with respect to what it does to people's psyche," said panelist Dr. Sid Gilman, a University of Michigan neurologist.
Even if the FDA does approve the first-in-its-class drug, the findings make it highly likely it would bear stern warnings. Company officials embraced the idea of such warnings, which could exclude FDA-approved use in some patients.
The company, FDA and panelists all agreed that Zimulti, along with diet and exercise, works to help shed weight. In yearlong studies, patients on the drug lost roughly 14 pounds. Those given dummy pills lost only about 4 pounds. However, patients regained weight when treatment was stopped after a year.
But the FDA and its outside advisers shared deep concerns that the drug's effect on the body could lead to an array of psychiatric symptoms, including anxiety, phobias, post-traumatic stress disorders and depression. No panelist felt the company had sufficiently characterized the drug's safety.
"What I am really troubled by is the lack of good safety data," said panel chairman Dr. Clifford Rosen, senior staff scientist at the Maine Center for Osteoporosis.
The company believes those increased cases were associated with depression or other disorders and weren't directly caused by its drug. Egan, however, said they were.
"We strongly believe that it is causal," Egan said. She noted 88 percent of those reporting psychiatric problems while on the drug had no prior history of depression.
Furthermore, patients in the studies were carefully screened and monitored, suggesting the problems would be more common should the drug enter broad use, Egan added.
The screenings proposed by the company won't keep the depressed and obese from Zimulti, warned Lynn McAfee, head of medical advocacy for the Council on Size & Weight Discrimination, a fat acceptance group.
"If this gets out to be a real big deal in the public, you can figure out how to answer those questions to get the drug," McAfee said. "It's not going to stop anyone." The potential market for the drug is huge, as obesity rates have exploded in the past two decades. Today, nearly one in three American adults age 20 or older is obese, according to government data.
Dr. Sidney Wolfe, of the advocacy group Public Citizen, said the obese are more likely to be depressed. Many of them likely would take Zimulti along with the antidepressants they already use — with unknown consequences, Wolfe told panelists.
Rimonabant blocks the same pleasure centers in the body activated when pot smokers get the munchies. Blocking the receptors leads to patients eating less and losing weight. Sanofi-Aventis also believes the drug decreases fat storage.
The FDA previously told the French company it would not approve the drug to help smokers quit.
Sanofi-Aventis has proposed selling 20-milligram Zimulti tablets to the obese and to those who are overweight and have type 2 diabetes, high blood pressure or other conditions that put them at risk of cardiovascular disease.
There currently are two FDA-approved prescription drugs for the long-term treatment of obesity: Meridia, an appetite suppressant, and Xenical, which limits the amount of fat the body can absorb. Sales of Alli, a lower-dose version of Xenical that won't require a prescription, start this week.
Heart problems led to the withdrawal of the diet drug fenfluramine in 1997. It had made up with phentermine the popular yet unapproved fen-phen combination treatment.
Wednesday, June 13, 2007
Feds to ponder risks of weight-loss drug
Federal advisers are considering whether a proposed weight-loss drug raises the risk of depression, a finding that could lead to stern warnings on the medication if it is approved.
Sanofi-Aventis AS has told the Food and Drug Administration it wants to sell the drug rimonabant under the brand name Zimulti. Concerns about its psychiatric effects have delayed a final FDA decision on the medication. The agency previously told the French company it would not approve the drug to help smokers quit.
An outside advisory committee was to consider the drug Wednesday.
A final ruling by the FDA is expected by July 27. The agency isn't required to follow the advice of its outside advisers but does so most of the time.
Rimonabant blocks the same pleasure centers in the body activated when pot smokers get the munchies. Blocking the receptors leads to patients eating less and losing weight.
The prescription drug, when used in conjunction with a modest calorie diet and physical exercise, significantly decreases body weight and waist circumference in overweight or obese patients, according to Sanofi-Aventis. In yearlong studies, patients on the drug lost roughly 14 pounds. Those given dummy pills lost only about 4 pounds. Patients regained weight when treatment was stopped after a year, the company said.
What worries FDA reviewers is that the drug's effect on the body's cannabinoid receptors could lead to psychiatric symptoms, including anxiety, phobias, depression and post-traumatic stress disorders.
In studies, 26 percent of patients given Zimulti reported such a symptom, compared with 14 percent of those given sham treatment. Specifically, 9 percent of those treated with the drug reported symptoms of depression, compared with 5 percent given dummy pills.
Sanofi-Aventis seeks to sell 20-milligram Zimulti tablets to the obese and to those who are overweight and have type 2 diabetes, high blood pressure or other conditions that put them at risk of cardiovascular disease.
Obesity rates have exploded in the past two decades. Today, nearly one in three American adults age 20 or older is obese, according to government data.
Generally, anyone with a body mass index, a ratio that takes into account height and weight, greater than 30 is considered obese. The overweight BMI range is 25 to 29.9. Normal is 18.5 to 24.9.
Rimonabant is sold under the brand name Acomplia in Europe.
Sanofi-Aventis AS has told the Food and Drug Administration it wants to sell the drug rimonabant under the brand name Zimulti. Concerns about its psychiatric effects have delayed a final FDA decision on the medication. The agency previously told the French company it would not approve the drug to help smokers quit.
An outside advisory committee was to consider the drug Wednesday.
A final ruling by the FDA is expected by July 27. The agency isn't required to follow the advice of its outside advisers but does so most of the time.
Rimonabant blocks the same pleasure centers in the body activated when pot smokers get the munchies. Blocking the receptors leads to patients eating less and losing weight.
The prescription drug, when used in conjunction with a modest calorie diet and physical exercise, significantly decreases body weight and waist circumference in overweight or obese patients, according to Sanofi-Aventis. In yearlong studies, patients on the drug lost roughly 14 pounds. Those given dummy pills lost only about 4 pounds. Patients regained weight when treatment was stopped after a year, the company said.
What worries FDA reviewers is that the drug's effect on the body's cannabinoid receptors could lead to psychiatric symptoms, including anxiety, phobias, depression and post-traumatic stress disorders.
In studies, 26 percent of patients given Zimulti reported such a symptom, compared with 14 percent of those given sham treatment. Specifically, 9 percent of those treated with the drug reported symptoms of depression, compared with 5 percent given dummy pills.
Sanofi-Aventis seeks to sell 20-milligram Zimulti tablets to the obese and to those who are overweight and have type 2 diabetes, high blood pressure or other conditions that put them at risk of cardiovascular disease.
Obesity rates have exploded in the past two decades. Today, nearly one in three American adults age 20 or older is obese, according to government data.
Generally, anyone with a body mass index, a ratio that takes into account height and weight, greater than 30 is considered obese. The overweight BMI range is 25 to 29.9. Normal is 18.5 to 24.9.
Rimonabant is sold under the brand name Acomplia in Europe.
Tuesday, June 12, 2007
FDA sees suicidal behavior with Sanofi drug
By Lisa RichwineMon Jun 11, 5:24 PM ET
People who took a Sanofi-Aventis SA obesity pill in clinical trials were more likely to report suicidal thoughts or actions, U.S. drug reviewers said in an analysis released on Monday.
Food and Drug Administration staff also said a 20-milligram dose of the drug, Zimulti, plus a low-calorie diet reduced weight about 5 percent more than diet alone over one year.
The agency will ask an advisory panel on Wednesday to weigh the possible benefits and risks and decide whether to recommend approval of U.S. sales. Known generically as rimonabant, the drug is sold in 18 other countries under the name Acomplia.
U.S. regulators have delayed a final decision several times amid safety questions.
"We remain concerned about rimonabant's adverse event profile, specifically adverse psychiatric reactions," an FDA staff summary said.
Psychiatric problems "represent the most common and worrisome rimonabant-induced adverse events," the reviewers said. Twenty-six percent of Zimulti patients reported a psychiatric symptom, compared with 14 percent of placebo patients, they said.
Suicidal thoughts were reported for 0.63 percent of Zimulti patients and 0.38 percent of placebo patients, Sanofi said in a separate summary. One Zimulti patient actually committed suicide.
The company said all of the cases were associated with depression or other psychiatric disorders, and it would recommend that the drug not be used by patients with serious, uncontrolled mental illness.
The drug's benefits "clearly outweigh the defined risks that are manageable in clinical practice," Sanofi said. Aside from weight loss, Zimulti reduced waist size and improved levels of cholesterol, blood sugar and blood fats known as triglycerides.
Zimulti works by blocking food craving signals in the brain. Sanofi developed the drug to target brain receptors that trigger intense hunger after marijuana use.
The French drugmaker has predicted in the past that the drug could generate sales of $3 billion a year or more. Sales for the first quarter of 2007 were about $20 million.
Zimulti is an important drug for Sanofi, which faces potential generic competition to key products.
The FDA will ask the outside advisers if they believe Zimulti increases suicidal behavior, other psychiatric problems, neurological problems and seizures, and if the drug should be approved, the staff review said.
The agency usually follows panel recommendations.
Some industry analysts said it was unclear how the panel would decide.
Vontobel analyst Karl Heinz Koch noted that other weight-loss drugs such as Roche AG's Xenical and Abbott Laboratories Inc.'s Meridia are approved even though higher rates of depression are noted on their labels.
"One can throw the dice" on the panel's outcome, Koch said.
The agency is expected to rule on Sanofi's bid for U.S. approval by July 26.
The FDA staff and Sanofi summaries were posted on the agency Web site at
http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4306b1-fda-backgrounder.pdf.
People who took a Sanofi-Aventis SA obesity pill in clinical trials were more likely to report suicidal thoughts or actions, U.S. drug reviewers said in an analysis released on Monday.
Food and Drug Administration staff also said a 20-milligram dose of the drug, Zimulti, plus a low-calorie diet reduced weight about 5 percent more than diet alone over one year.
The agency will ask an advisory panel on Wednesday to weigh the possible benefits and risks and decide whether to recommend approval of U.S. sales. Known generically as rimonabant, the drug is sold in 18 other countries under the name Acomplia.
U.S. regulators have delayed a final decision several times amid safety questions.
"We remain concerned about rimonabant's adverse event profile, specifically adverse psychiatric reactions," an FDA staff summary said.
Psychiatric problems "represent the most common and worrisome rimonabant-induced adverse events," the reviewers said. Twenty-six percent of Zimulti patients reported a psychiatric symptom, compared with 14 percent of placebo patients, they said.
Suicidal thoughts were reported for 0.63 percent of Zimulti patients and 0.38 percent of placebo patients, Sanofi said in a separate summary. One Zimulti patient actually committed suicide.
The company said all of the cases were associated with depression or other psychiatric disorders, and it would recommend that the drug not be used by patients with serious, uncontrolled mental illness.
The drug's benefits "clearly outweigh the defined risks that are manageable in clinical practice," Sanofi said. Aside from weight loss, Zimulti reduced waist size and improved levels of cholesterol, blood sugar and blood fats known as triglycerides.
Zimulti works by blocking food craving signals in the brain. Sanofi developed the drug to target brain receptors that trigger intense hunger after marijuana use.
The French drugmaker has predicted in the past that the drug could generate sales of $3 billion a year or more. Sales for the first quarter of 2007 were about $20 million.
Zimulti is an important drug for Sanofi, which faces potential generic competition to key products.
The FDA will ask the outside advisers if they believe Zimulti increases suicidal behavior, other psychiatric problems, neurological problems and seizures, and if the drug should be approved, the staff review said.
The agency usually follows panel recommendations.
Some industry analysts said it was unclear how the panel would decide.
Vontobel analyst Karl Heinz Koch noted that other weight-loss drugs such as Roche AG's Xenical and Abbott Laboratories Inc.'s Meridia are approved even though higher rates of depression are noted on their labels.
"One can throw the dice" on the panel's outcome, Koch said.
The agency is expected to rule on Sanofi's bid for U.S. approval by July 26.
The FDA staff and Sanofi summaries were posted on the agency Web site at
http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4306b1-fda-backgrounder.pdf.
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