Pharmaprojects R&D Pipeline News Feed
Another one bites the dust
20th November 2008
Solvay has joined the recent trend for the discontinuation of cannabinoid type 1 receptor (CB1R) antagonists, by dropping its Phase II antiobesity compound, ibipinabant. Solvay’s decision to terminate this compound was not based on adverse events or efficacy, but instead on the current regulatory environment, with “new and high regulatory hurdles for approval of a compound of this class”.
In a domino effect throughout pipelines, cannabinoid 1 antagonists are being knocked out in quick succession. At the beginning of October 2008, Merck & Co announced the discontinuation of taranabant (MK-0364), its CB1R inverse agonist antiobesity candidate. Merck cited Phase III trial data, which showed that both efficacy and adverse events were dose-related, with greater efficacy and more adverse events at the higher doses, responsible for the cessation. The drug was within sight of a registration filing when the decision was made.
At the end of October 2008, Sanofi-Aventis followed suit with the discontinuation of surinabant (SR-147778), a CB1R antagonist in Phase II trials, which was to target the obesity, smoking cessation and alcohol dependence markets. The termination of surinabant was, perhaps unsurprisingly, followed shortly after by the discontinuation of rimonabant, the compound to which surinabant was a back-up. Rimonabant is also a CB1R antagonist, developed by Sanofi-Aventis for the same indications as surinabant. It was first launched in the UK in 2006 for the treatment of obesity, and despite showing efficacy for weight loss with the added bonus of improving lipid profiles, according to Sanofi-Aventis the demands of health authorities were felt to be more than could be met, and the drug was discontinued.
The underlying issues for rimonabant stemmed from events such as the US FDA declaring in 2007 it would not recommend the drug for use in obese and overweight patients with associated risk factors, based on the finding that patients were more likely to report suicidal thoughts or actions than those on placebo. Despite earlier approval by the EU’s CHMP, sales in Europe were similarly halted based on the same findings. Other countries, such as Argentina, recommended approval but with strict contraindications for patients with major depression and/or patients on antidepressants due to the risk of psychiatric side-effects. Difficulty in achieving agreements for reimbursements for antiobesity drugs in many countries may have also contributed to the poor financial viability of continuing to seek approval and fund marketing of this drug.
The future of the CB1R field looks uncertain. There may be 17 drugs ranging in status from preclinical to Phase II trials currently in development, but above this level there is now only one Phase III trial drug left, AVE-1625, another Sanofi-Aventis drug. It remains to be seen what will become of the young CB1R antagonists following this latest withdrawal from the market.
This sudden attrition from the cannabinoid field also leaves the rapidly growing obesity market with a gaping space. Despite 85 preclinical antiobesity compounds currently in development, there are only 10 products launched and still marketed for this indication, one in pre-registration and five in Phase III trials. A market that has such potential rewards still remains open to newcomers to grab a share, and potentially reach Blockbuster status, if they can overcome the hurdles.
