Three New Drugs to Combat Obesity

Regulators to Review New Drugs to Curb Appetite

A new generation of anti-obesity drugs could hit the market in coming months, the latest attempt in what has proved a difficult medicine to make safe for patients.

Currently, just two anti-obesity drugs are approved for long-term treatment, and medical practitioners say both can cause undesirable side effects in many patients. The three new medications, which have been submitted for approval to the Food and Drug Administration, also can be expected to have side effects for some patients, particularly because treating obesity with drugs involves altering the body's chemistry. But doctors say different weight-loss medications affect people differently, so having more choices should help them match a patient to a therapy that maximizes weight loss while minimizing side effects.

Obesity has many causes, and ferreting out what is going to work in individuals requires more options," said Charles Billington, a professor of medicine at the University of Minnesota and medical director of the obesity program at the Minneapolis VA Medical Center.

The FDA will need to review data on the drugs, and approval isn't assured. The agency is aware of past problems with anti-obesity drugs and plans to evaluate the new drugs under the assumption that patients likely would use them indefinitely, an FDA spokeswoman said.

The three new drugs awaiting regulatory approval are lorcaserin, manufactured by Arena Pharmaceuticals Inc., Vivus Inc.'s Qnexa, and Orexigen Therapeutics Inc.'s Contrave. The companies are small drug developers and each has held talks to partner with a larger pharmaceutical concern to help sell the products, although no agreements have been signed.

The three drugs work by affecting the patient's central nervous system to dampen appetite, Dr. Billington said. "To say that you are going to do that without any side effects is just not understanding how things work in real life," he said.

Typically, medications help moderately obese patients lose about 5% to 10% of their body weight. While not a large percentage, even that much weight loss can mean a big reduction in diabetes and cardiovascular risk, said Jeanine Albu, chief of the Metabolic Clinic at the New York Obesity Research Center at St. Luke's-Roosevelt Hospital. "The problem is keeping the weight off over time. A lot of people just gradually gain it back," said Dr. Albu.

Lifestyle Changes First

For most obesity patients, a physician's first line of treatment is to modify the person's lifestyle, including through dieting, exercise and counseling. When this isn't successful, some patients might move on to one of the few anti-obesity drugs currently available. And in cases of dangerous obesity, doctors might recommend bariatric surgery, which makes the stomach smaller. The Centers for Disease Control and Prevention estimates that about two-thirds of U.S. adults are overweight, while a third are considered obese. Obesity is defined as having a body mass index—a measure of weight in relation to height—of 30 or higher.

Some earlier diet drugs have had a mixed history. The so-called fen-phen drug combination manufactured by Wyeth, now owned by Pfizer Inc., was recalled in the 1990s after one of the medication's components was linked to heart-valve damage.

One drug currently in use also has stirred controversy. Meridia, sold by Abbott Laboratories, was pulled from the market in Europe this year after a study indicated that people with certain health problems who took the prescription drug had more heart attacks, strokes and other cardiovascular problems than people getting a placebo. In the U.S., the FDA required Abbott to put a stronger warning on the Meridia label.

Another drug currently on the market, Orlistat, which is sold over the counter as Alli by GlaxoSmithKline Plc and in prescription form as Xenical by Roche Holding AG, can cause undesirable bowel-related problems in some patients. The drugs haven't been blockbusters. Financial firm Cowen and Co. estimates that Alli had U.S. sales of $150 million last year, while Meridia and Xenical had sales of $40 million and $35 million, respectively. Doctors also regularly prescribe phentermine, which is approved for short-term use of, say, a few weeks, to treat obesity.

Arena Pharmaceuticals said its lorcaserin drug works by stimulating a neurotransmitter receptor in the brain that helps control appetite and metabolism. The mechanism is similar to the one used by a component of the recalled fen-phen drug combination, but with an important difference.

While the older medications worked on multiple versions of the body's receptors, including those in the heart, lorcaserin has a very specific target that is mostly in the brain, Arena said. Clinical trials have shown there is no increase in such heart-related side effects with the new drug, it said.

In clinical trials, patients taking lorcaserin lost about 6% of their weight on average, while patients taking a placebo lost between 2% and 3%. The most common side effects of the pill, which would be taken twice a day, were headache and nausea, although both symptoms disappeared after an initial period of use.

Combination Therapies

The two other drugs under FDA review are both combination treatments of compounds that are already on the market, but will be delivered in new dosages and methods. Using two drugs at once can be more effective in treating obesity because the brain has multiple ways of making sure that appetite is preserved, as a survival mechanism. Blocking multiple pathways, therefore, can help ensure that a therapy will work.

Orexigen said its Contrave drug works by stimulating a group of neurons in the brain, known as POMC, which, when activated, seem to result in reduced food intake and increased metabolism. The first drug in the combination, the antidepressant bupropion, turns on POMC. But that action also causes the release of a hormone that subsequently switches POMC back off in order to prevent perpetual weight loss. So the second drug in the combination, addiction-treating naltrexone, blocks that hormone in order to allow weight loss to continue, the company said.

Giving the two together as Contrave, in a sustained-release formulation taken twice a day, led to average weight loss that ranged from 5% to 9.3% of a patient's body weight in four clinical trials. Trial participants who took a placebo lost between 1.2% and 5.1% of their body weight. The medication's most common side effects were nausea, constipation and headache, all of which tended to go away after an initial period.

The third drug, Qnexa from Vivus, was the most effective in clinical trials at taking off pounds. In two separate trials, patients lost an average of 10.4% and 11%, respectively, of their body weight, while those taking a placebo lost 1.8% and 1.6%.

Vivus said Qnexa is a controlled-release formulation that combines low doses of the stimulant phentermine, which leads to the release of the stress hormone norepinephrine to cut the body's appetite, and topiramate, which works in various ways to increase satiety, or the sense of feeling full. Combining the two underlying drugs also seems to counteract some of their individual effects: Topirimate can cause cognitive slowing, which phentermine negates, and topirimate counters the blood-pressure raising of phentermine, the company said.

In clinical trials, the most common side effects of the once-daily Qnexa were constipation and dry mouth, along with mild tingling in the finger tips, all of which eventually went away.

From The Wall Street Journal, by Thomas Gryta
Reviewed / Posted by: Scott W Yates, MD, MBA, MS, FACP

Comments:

Of these three, Qnexa appears to be the most promising in general.  However, topimirate can also cause confusion also and this may limit the use of this combination.

SWY