In the pipeline: Obesity drug nears approval

March 20, 2006

More than 60 million adults are obese in America, putting them at risk for multiple chronic conditions like heart disease, Type 2 diabetes, respiratory problems, and possibly breast and colorectal cancer. To date, weight-loss medications have been marginally successful, due to lack of insurance coverage for an "obesity indication" and to side effects that cause patients to discontinue the drug. Enter rimonabant (Acomplia) from Sanofi-Aventis, a novel investigational agent that could be FDA-approved within months.

Rimonabant is the first in a new class of drugs whose unique mechanism of action cuts appetite by blocking the central cannabinoid-1 receptors (CB1s) in the brain that normally stimulate hunger. Researchers developed the drug on the premise that cannabinoid receptors, which cause "the munchies" in marijuana smokers, could be blocked in order to reduce appetite and possibly stave off the desire to smoke cigarettes.

The discontinuation rate for rimonabant-treated patients after one year was 12.8%. The most common adverse events leading to discontinuation were depressed-mood disorder, anxiety, and nausea.

Last month, Sanofi-Aventis received an approvable letter for rimonabant for weight management and a nonapprovable letter for smoking cessation.

Quicker recovery of GI function following surgery

For patients undergoing bowel resection, eating is restricted for a few days following surgery; most patients are required to stay in the hospital five to seven days. Adolor and GlaxoSmithKline are hoping that alvimopan (Entereg), an investigational peripherally acting muopioid receptor antagonist, will lessen the time to GI recovery.

New data from a phase III study involving 654 patients showed that 12 mg of alvimopan twice daily, with the first dose given 30 to 90 minutes before surgery, led to recovery of GI function 16 to 20 hours sooner than with placebo. The mean time to discharge order written was about 18 hours sooner with alvimopan compared with placebo.

The companies received an approvable letter for alvimopan in July 2005, with a request from the FDA for additional data. The final results of the recent phase III trial will be submitted to the agency in June 2006 as part of their complete response to the FDA's letter.

New clot buster on the horizon

Nuvelo Inc., San Carlos, Calif., has received fast-track designation for its lead product candidate, alfimeprase, a direct-acting thrombolytic for the treatment of acute peripheral arterial occlusion (PAO). The condition occurs when arterial blood flow to a lower limb is blocked by a clot. According to the company, alfimeprase is also being studied in phase III trials for treatment of catheter occlusion and may eventually prove useful in other situations involving thrombosis, such as stroke, deep vein thrombosis, and myocardial infarction.

Alfimeprase is a recombinant enzyme that breaks up blood clots by directly degrading fibrin. In clinical trials, the drug has been shown to resolve peripheral arterial clots within four hours of initiation of dosing and to clear occluded catheters in 15 minutes or less. The thrombolytic activity of alfimeprase is localized to the site of delivery due to its rapid inactivation by alpha-2 macroglobulin, a protein found in the circulation of the blood. This mechanism of rapid clearance helps to minimize bleeding, said the manufacturer.

The company added that alfimeprase may have another advantage over existing thrombolytic therapies. Plasminogen activators, for example, often require prolonged infusion, averaging 24 to 36 hours in patients with acute PAO, and infusion typically requires admission to the intensive care unit.