Anti-obesity drug slim on safety aspects
become weighted down in safety concerns as the French company
withdraws its New Drug Application (NDA) in the US and awaits a
safety review in the EU.
Acomplia (rimonabant), also branded as Zimulti, has been the hot contestant in the cure for obesity, but a fortnight ago this was shattered when a US Food and Drug Administration (FDA) advisory committee said that the drug should not be approved because of an increased frequency of psychiatric adverse events, including suicidality.
The drug giant has now pulled its NDA in the US, and while the company was determined the drug would have a US presence, analysts have forecast the drug would now not launch there for at least two to three years pending further testing.
Meanwhile, the future of the drug in the EU is in the European Medicines Agency's (EMEA) hands, after the agency recently announced the Committee for Medicinal Products for Human Use (CHMP) was continuing reviewing the drug's safety, with its conclusions expected by July 19.
As stated in the June monthly report: " The CHMP, as part of the continuous monitoring of the safety of Acomplia/Zimulti (rimonabant), is currently reviewing the available data on psychiatric events (in particular suicidal ideation and depression-related events)."
EMEA spokeswoman Monika Benstetter told in-PharmaTechnologist.com the outcome of the review could suggest one of several regulatory options, such as no changes to the marketing, adding additional warnings, suspending the product until more data was available, or completely withdrawing the drug from the market.
Benstetter was unable to comment on what impact the FDA advisory committee's decision would have on the review, though the EMEA would look at the committee's concerns.
As Acomplia was centrally authorised in the EU, any changes to its marketing would mean changes in all EU countries, Benstetter said.
The packaging already carried a warning about psychiatric side effects.
The case comes as a blow to Sanofi-Aventis' influence in the obesity market in Europe, where Acomplia was approved throughout the EU in June last year.
Now approved in 42 countries and marketed in 20, the drug made a total of €31m in net sales in 2006, according to Sanofi- Aventis' annual report.
Speaking in a webcast on Friday, Sanofi-Aventis senior vice president of scientific and medical affairs Marc Cluzel said there was no impact in EU sales following the FDA advisory committee decision and the US NDA withdrawal.
The company now planned to discuss the drug's US future with the FDA.
Acomplia was approved to treat obesity and overweight patients with associated cardiovascular risk factors, and is the first member of a new therapeutic class of drugs that selectively block the cannabinoid type 1 (CB1) receptors.
When working normally, this system of receptors in the brain and throughout the body helps regulate food intake and how the body uses and stores fats and sugars.
In pivotal clinical trials, rimonabant significantly reduced body weight and waist circumference.
Rimonabant also improved blood glucose levels, the "good" cholesterol HDL, triglycerides and insulin sensitivity.
However, according to the studies, as stated in the FDA advisory committee's review, 26 per cent of the rimonabant 20mg treated patients versus 14 per cent of the placebo experienced a psychiatric symptom reported as an adverse event.
Roughly 50 per cent of subjects in the rimonabant and placebo groups withdrew early from the trials due to depression, anxiety, mood alterations with depressive symptoms and the need for antidepressant medication, and two patients committed suicide, the review added.
"The result of the above analyses should be viewed as incomplete at best and at worse, as an underestimate of the rimonabant risk for suicidality," the advisory committee stated.
Following safety concerns in the review of the NDA's preclinical and clinical data, Sanofi-Aventis was requested in February 2006 to send additional data and analyses to more precisely characterise the potential drug-related adverse events.
Early in June, the advisory committee recommended that rimonabant should not be approved.
The move to withdraw the NDA comes about a month before the FDA was due to make a decision on the drug's status, and considering the advisory committee's response, was more likely than not to turn the drug down.
Acomplia would have been the latest drug to hit the obesity market, which would have directly competed with Roche's Xenical (orlistat) and Abbott's Reductil/Meridia (sibutramine), both of which account for a market valued at a little over $1bn (€738m) and set to increase as obesity reaches epidemic levels.
Ertiprotafib was developed by Wyeth several years ago, but was dropped in Phase II development due to insufficient efficacy and concerns about side-effects.
Meanwhile, GlaxoSmithKline (GSK) has recently released Alli (orlistat), which is the only non-prescription weight loss drug approved by the FDA, which is a half-dose version of Roche's Xenical.
