Orexigen Therapeutics Inc. said the Food and Drug Administration is concerned about the heart side effects of its drug Contrave and will require a new study, a costly undertaking that may prove too burdensome for the small drugmaker.

The FDA’s ruling marks the third rejection of a weight loss drug in recent months, raising questions about whether any new drugs in the class can be made safe enough to win approval. The FDA has not approved a new diet pill in more than a decade.

The FDA request for an additional study suggests the agency may yet approve the drug, but makes that path much more difficult. The news led to a sell-off that wiped out nearly three-quarters of the market value of the company.

Orexigen said it is disappointed with the FDA’s decision and will work with the agency to determine its next step.

“We are surprised and extremely disappointed with the agency’s request in light of the extensive discussion and resulting vote on this topic at the Dec. 7 advisory committee meeting,” said President and CEO Michael Narachi, in a conference call with investors.

Narachi acknowledged that studies of the kind requested by the FDA are normally “fairly large,” and would require the company to raise additional money. Clinical trials to study rare events like heart attack can take years to conduct and cost millions of dollars.

Analysts had viewed Contrave as the most promising of three new diet pills recently submitted to the agency. Contrave is a combination pill, mixing an antidepressant with an anti-addiction drug to curb appetite. Four out of 10 patients taking Contrave for a year lost at least 5 percent of their body weight. Those results narrowly met FDA’s guidelines for effectiveness.

Given the drug’s limited benefit, FDA’s rejection was not surprising, according to drug industry analyst Erik Gordon.

“You have life-threatening possible side effects in return for modest weight loss that might not be produced in the real world — no wonder the FDA wants more data,” said Gordon, a professor and analyst at University of Michigan’s Ross School of Business.

La Jolla, Calif.-based Orexigen does not currently have any products on the market, making Contrave a key to the company’s growth and survival. In trading Tuesday, Orexigen shares tumbled $6.59, or 73 percent, to $2.50.

Analysts expect any obesity drug reaching the market to have the potential to become a billion-dollar seller.

With the U.S. obesity rate for adults nearing 35 percent, the FDA has acknowledged the need for new weight loss drugs. But the agency rejected two other drugs last year due to safety risks, a long-standing issue that has plagued weight loss treatments for decades. Those drugs were made by fellow California drug developers Vivus Inc. and Arena Pharmaceuticals Inc. Both companies have said they plan to resubmit their drugs for approval.

Contrave has been pegged as a more promising treatment because of its relative safety. Unlike the other two drugs reviewed last year, it received a positive vote from the FDA’s panel of outside advisers, who voted 13-7 that the drug’s modest weight loss benefits outweighed its risks.

But the FDA meeting assessing the drug was not free of criticism. FDA scientists and safety advocates complained that the company enrolled few elderly patients or patients with a history of heart disease in its trials, making it difficult to determine the drug’s safety in patients who are likely to need it most.

Heart side effects have been an issue with diet drugs, most notably with Wyeth’s diet drug combination fen-phen, which was pulled off the market in 1997. In October, Abbott Laboratories withdrew its drug Meridia after evidence it increased the risk of heart attack and stroke.

Currently there is just one prescription drug on the market for long-term weight loss: Roche’s Xenical, which is not widely used. Several other generic drugs are approved for short-term weight loss, including phentermine.

Technorati Tags: Contrave, new diet drugs, Orexigen, phentermine, short term weight loss, xenical

The 13-7 vote in favor of Contrave came amid agency concerns that the drug might raise blood pressure in some patients and increase the risk of heart attacks and strokes among some users, according to the Associated Press. But panelists voted 11-8 earlier in the day that those potential health risks could be studied after Contrave was approved.

The FDA does not have to follow the advice of its advisory committees, but it typically does. The agency is expected to make a decision on Contrave by Jan. 31, the wire service reported.

Contrave is manufactured by Orexigen Therapeutics Inc. In October, the FDA voted against approving two other weight-loss drugs, Arena Pharmaceuticals’ lorcaserin and Vivus’ Qnexa, because of safety concerns, according to the AP.

Last July, a study funded by Orexigen and published in The Lancet found that Contrave helped users shed pounds when taken along with a healthy diet and exercise.

People who took the drug for more than a year lost an average of 5 percent or more of body weight, depending on the dose used, the team said.

However, the regimen did come with side effects, and about half of study participants dropped out before completing a year of treatment.

Contrave is combination of two well-known drugs, naltrexone (Revia, used to fight addictions) and the antidepressant bupropion (known by a number of names, including Wellbutrin). The drug appears to boost weight loss by changing the workings of the body’s central nervous system, the researchers said.

The study enrolled men (15 percent) and women (85 percent) from around the country, ranging in age from 18 to 65. They were all either obese or overweightm, with high blood fat levels or high blood pressure.

The participants were told to eat less and exercise, and they were randomly assigned to take a twice-daily placebo or a combination of the two drugs at one of two levels.

After 56 weeks, only about half (870) of the more than 1,700 participants initially enrolled remained in the study. Almost half (48 percent) of those who took the highest dose of naltrexone lost 5 percent of their weight or more, while only 16 percent of those who took placebos did.

However, about 30 percent of those taking Contrave experienced nausea, the study authors say, and other side effects included headache, constipation, dizziness, vomiting and dry mouth.

Still, Contrave may give people struggling to lose weight a new option, the researchers contended.

The Lancet findings echo those of studies into other diet drugs such as Meridia, Xenical and Alli, said Lona Sandon, an assistant professor of clinical nutrition at the University of Texas Southwestern Medical Center in Dallas and spokeswoman for the American Dietetic Association.

“When these are combined with a modestly reduced calorie diet, modest amounts of weight loss are achieved,” she said. “One striking thing to note is the study drop-out rate of 50 percent. This may have been due to side effects of medications, the fact that it is hard to stick to dietary changes for 56 weeks, or [the fact that] slow and only modest weight loss did not meet participant expectations.”

Cynthia Sass, a New York City-based nutritionist and author, added that drugs used to treat addiction also appear to help with weight control, supporting “the notion that food can be addictive for many people.”

An accompanying Lancet editorial noted that one concern is that blood pressure did not drop as much as expected in the higher weight-loss group. “More data are needed to get a better overall assessment of cardiovascular risk of this otherwise promising combination therapy for obesity,” wrote Professor Arne Astrup, a nutrition expert at the University of Copenhagen, Denmark.

Technorati Tags: anti-addiction medication, antidepressant, Contrave, Orexigen Therapeutics, weight loss pill, xenical

The U.S. Food and Drug Administration declined to approve the drug, lorcaserin, for treatment of obesity, citing questions about its effectiveness and potential cancer risk.

The agency also requested that Arena provide results from this latest trial involving 604 obese diabetics.

The trial showed that after a year, 37.5 percent of patients taking a 10 mg dose of lorcaserin twice a day lost at least 5 percent of their body weight, compared with 16.1 percent of patients taking a placebo.

Lorcaserin patients had mean weight loss of 4.5 percent, or 4.7 kilograms (10.3 pounds), compared with 1.5 percent, or 1.6 kg, for placebo patients.

“Achieving weight loss in these patients can be difficult … we are excited that the efficacy of lorcaserin was maintained in this diabetic population,” said Jack Lief, Arena’s chief executive.

The San Diego company, which is developing lorcaserin with Japan’s Eisai Co Ltd, said the trial also showed that lorcaserin helped improve glucose levels, cholesterol and triglycerides.

Arena said side effects of the drug included headache, upper respiratory infections and back pain.

Lorcaserin is a serotonin activator like fenfluramine, one of the drugs that was used as part of the recalled fen-phen diet drug cocktail. But the Arena drug is more selective in the receptors it affects and thereby sidesteps heart-related side effects.

In the diabetes trial, 2.9 percent of lorcaserin patients developed valvulopathy (heart valve problems) after six months, compared with 1.9 percent of placebo patients. At one year, 2.9 percent of lorcaserin patients had new valvulopathy, compared with 0.5 percent of placebo patients.

Lief said the number of patients in each group was too small to detect a statistically significant difference.

Arena is one of three small drug developers looking to launch an approved weight loss drug. The FDA, also in October, turned down an application from rival Vivus Inc for its experimental obesity pill Qnexa.

Next up is Orexigen Therapeutics Inc, which will have its drug, Contrave, reviewed by an FDA advisory panel in December.

(Editing by Steve Orlofsky)

Technorati Tags: Arena Pharmaceuticals, Contrave, lorcaserin, obesity pill Qnexa, treatment of obesity

The researchers analyzed 81 weight-loss products that had been taken by 66 patients who had come in to the hospital for treatment for poisoning. One of the patients had died.

While the authors caution their findings should not be interpreted as a full analysis of the weight-loss supplement market, they found two or more pharmaceutical agents in 61 supplements they tested, and two supplements contained six of these drugs.

“A wide variety of illicit, weight-reducing agents has been found in proprietary slimming products that are readily available to the public. Importantly, ingestion of these products may result in significant toxicities and even mortality,” said the study authors, who are researchers at the Princess Margaret Hospital in Hong Kong.

While the study’s research took place in Hong Kong, the problems have reached America’s shores.

“This is exactly the same issue that we’re faced with here,” said Dr. Pieter Cohen, a general internist at Cambridge Health Alliance and an assistant professor of medicine at Harvard Medical School. Cohen said that due to their surveillance procedures for drugs, researchers in Hong Kong are “often on the vanguard of identifying problems.”

In the United States, an estimated $34 billion is spent annually on alternative medicine, including supplements. But the products, sometimes called botanical supplements or herbal remedies, are not well studied and in many cases could be dangerous, according to a study earlier this year in Chemical & Engineering News.

In late 2008 and early 2009, the Food and Drug Administration made three announcements, alerting consumers about a total of 72 weight-loss supplements containing undeclared drugs. Those recalls found drugs in the products that included sibutramine, a controlled substance then-prescribed for weight loss, and fluoxetine, an antidepressant best known as Prozac.

The most common agent found in the supplements in the Hong Kong study was sibutramine, which was detected in 59 of the products tested.

Sibutramine was sold under the trade name Meridia in the United States The anti-obesity drug was voluntarily withdrawn by the manufacturer last week, after a study showed it was associated with an elevated risk of heart attack and stroke.

But a number of supplements tested in the study also contained banned drugs. Thirteen weight loss supplements contained the appetite suppressant fenfluramine.

“Fenfluramine is the bad actor of the Fen-phen diet pill,” said Cohen, referring to the weight-loss drug pulled from the U.S. market in 1997 for its association with heart attacks.

A second banned substance found in the supplements, the laxative phenolphthalein, was outlawed because of an association with cancer.

Cohen said perhaps the most disturbing finding was the presence of analog drugs in the supplements. Analogs are drug molecules that have been further modified in a lab.

“This hasn’t even been studied in mice,” said Cohen. “This is really using the consumer… as guinea pigs.”

The fact that herbal supplements may contain pharmaceuticals, allowing pills to show benefit to consumers while under the guise of being natural, is not a new discovery. But Cohen said findings like these make trouble for consumers, as they cannot simply make a choice to take a supplement based on the research.

“In this case, as soon as you start dealing with adulterants, there’s no ability to make decisions, because you don’t know what is in there or what the side effects are,” he said.

The new study was published today (Oct. 13) in the British Journal of Clinical Pharmacology.

Technorati Tags: anti obesity drug, fenfluramine, herbal remedies, herbal weight loss, sibutramine, weight loss supplements

Those who got the drug said they felt less desire for sweet or starchy foods; felt fuller and had fewer cravings, the researchers said.

Their study, published in the Lancet medical journal, also suggested that feared side-effects from the drug were mild and went away over time.

But one expert said more studies are needed before regulators can assume the drug is safe.

Data from the company-sponsored study has already been presented to the U.S. Food and Drug Administration, which has a panel of advisers scheduled to consider approval in December.

The Lancet submitted it for review by experts before publishing it, said Frank Greenway of the Pennington Biomedical Research Center at Louisiana State University, who led the trial.

Contrave is a combination of the antidepressant bupropion, a generic version of GlaxoSmithKline’s Wellbutrin, and naltrexone, used to treat alcoholism and other addictions.

Greenway and colleagues tested two formulations of Contrave against a placebo in 1,700 overweight or obese volunteers.

Only half the volunteers finished the trial, dropping out for various reasons.

“It is something that seems to be characteristic of obesity studies,” Greenway said in a telephone interview.

“The people in the placebo group seemed to drop out more frequently because they were dissatisfied with the lack of weight loss. People in the drug arm seemed to drop out more because of side-effects. Overall, the groups seemed to be equal.”

But of those who finished the trial and also got the highest dose of the drug, mean weight loss was 13 pounds (6 kg) compared to 3 pounds (1.4 kg) for those who got the placebo.

The drug did raise blood pressure slightly at first, a known side-effect of bupropion and a big worry for a drug being taken by overweight people. But this increase leveled off after a short time, Greenway reported.

“The safety is really nothing different from what we would expect from the components,” Greenway said.

One expert said more study is needed to show if the drug is safe. The drugs have been linked to anxiety, insomnia and to raised blood pressure, as well as to thoughts of suicide.

But the trial showed no increase in any of these, said Arne Astrup of the University of Copenhagen in Denmark.

“These findings suggest that the combination might have fewer adverse psychiatric effects than its components given separately, but a meta-analysis of all continuing or completed phase 3 studies of this combination treatment is needed to assess this effect more accurately,” Astrup wrote in a commentary in the Lancet.

Three U.S. companies are competing to get new weight loss drugs approved by the FDA.

FDA advisers voted against Vivus Inc’s Qnexa earlier this month, expressing concerns that it could cause depression, memory loss and potential birth defects.

Arena Pharmaceuticals Inc has a drug called lorcaserin up for consideration in September.

(Reporting by Maggie Fox; Editing by Tim Dobbyn)

Technorati Tags: bupropion, Contrave, lorcaserin, Orexigen, weight loss drugs

A consultant to Mountain View, California-based Vivus Inc said three separate studies showed patients lost more weight when they took the highest doses of Qnexa, which is up for Food and Drug Administration approval in July.

Shares in Vivus soared 13.6 percent to $11.73 a share in early afternoon trading.

Drops in blood pressure were small but clear and equated with the weight loss, said Dr. Suzanne Oparil of the University of Alabama at Birmingham.

“The weight loss is very impressive, and it is good that there is concomitant reduction in blood pressure,” Oparil said in a telephone interview from a meeting of the American Society of Hypertension in New York.

Oparil, a past president of the American Heart Association, pooled and analyzed the results of three separate studies of Qnexa in nearly 8,000 overweight and obese patients.

“At week 58 there is a nice weight reduction,” she said. The higher the dose, the more weight loss and the more blood pressure went down, she said.

The patients who got the highest dose along with diet and exercise advice lost about 10 percent of their body weight on average, she said.

Vivus is trying to improve on the notorious “fen-phen” combination pulled off the market in 1997 after it was found to damage the heart and cause sometimes fatal cases of pulmonary hypertension.

IMPROVING HEALTH

Fen-phen combined fenfluramine and phentermine. Phentermine, a stimulant now available generically, appears safe and is used at low doses in Qnexa along with the epilepsy drug topiramate, available generically and sold by Johnson & Johnson’s Ortho-McNeil unit as Topamax.

Losing just 10 percent of body weight is enough to lower cholesterol and blood pressure, reduce the risk of diabetes and early death. About 68 percent of U.S. adults are overweight or obese.

In the three studies that Oparil analyzed, about 80 percent of the patients were women, most morbidly obese with weights of 220 to 260 pounds (100 to 118 kg).

Most did not have high blood pressure but among those who did and who took the highest Qnexa dose, the systolic or top number in the blood pressure reading went down an average of 9 points, compared to 4 points for the women who got placebos.

Oparil said the most common side effects were tingling and dry mouth, each seen in 19 percent of the patients who took the highest dosages.

Topiramate acts on the nervous system and tends to act as a sedative, said Oparil. This can reduce appetite. In addition, patients said the drug made carbonated drinks taste metallic and that may have helped patients avoid sugary soft drinks.

Doses of both drugs are far lower than those usually used — when phentermine is used alone to treat obesity, for example, or when topiramate is used for epilepsy, she said.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee is tentatively scheduled to review Vivus’ Qnexa on July 15, the company said.

Thomson Pharma has forecast 2013 sales of $357 million for Qnexa. Vivus reported its first quarter 2010 results on Monday with a net loss of $18.8 million, or $0.23 per share.

Technorati Tags: blood pressure, experimental weight loss drug, lower cholesterol, phentermine, Qnexa, Topiramate, treat obesity, weight loss

The U.S. Food and Drug Administration warned consumers in 2006 of dangers associated with the diet pills, but they remain popular and easy to order online, the researchers say.

“What we have seen and what the FDA has found is that, unfortunately, there are dozens of products that are sold as dietary supplements that are contaminated with pharmaceutical compounds,” said lead researcher Dr. Pieter Cohen, an instructor in medicine at Harvard Medical School.

People already prone to addiction can become dependent on these nonprescription drugs, and stricter oversight by the FDA is needed, Cohen said.

“When you are purchasing these products, you have no idea what you are getting,” he noted. “There is a very lax regulatory framework that surrounds dietary supplements. Basically, all dietary supplements are assumed to be harmless until the FDA demonstrates that they are dangerous.”

In the article, published in the April 5 online edition of the American Journal on Addictions, Cohen and a colleague, Benjamin Smith, tell the story of a 29-year-old who needed psychiatric care to kick her addiction to Brazilian diet pills.

The problem wasn’t with the herbal content; rather, it was a mixture of amphetamines, tranquilizers and antidepressants, the researchers say.

Although sometimes unemployed and homeless, the woman increased her dose over four years, eventually taking four pills a day at a daily cost of $160, Cohen noted.

“Even though she couldn’t afford the pills, she borrowed money so she wouldn’t have to stop,” Cohen said.

When she tried to wean herself off them, she experienced symptoms of withdrawal, including tremor, headache, cravings and anxiety. Only under a psychiatrist’s care was she able to kick her addiction.

Her case is proof that undeclared ingredients in some dietary supplements can cause serious psychiatric problems, Cohen said.

Earlier research found some of these diet pills cause chest pain, racing heart and insomnia, but the resulting psychiatric problems are not well-understood, Cohen said.

The pill makers probably add the pharmaceutical agents because they are the ingredients that promote weight loss, not the herbal concoction, he said.

“If you are taking a dietary supplement and it’s actually working, then I’d be concerned that something else is in that pill,” Cohen said. “Everyone who is consuming dietary supplements, which is half of U.S. adults, are in some ways guinea pigs,” he said.

Given that about 20 million Americans use nonprescription diet pills a year but don’t tell their doctors, the authors said physicians should screen for their use.

Dr. Ihsan Salloum, professor of psychiatry and chief of the division of alcohol and drug abuse at the University of Miami Miller School of Medicine, agreed that the mix of drugs in the diet pills can cause devastating symptoms of addiction.

“When people are withdrawing from a stimulant, they could also have suicidal thoughts and ideation,” he said.

“The frightening thing is they are sold over-the-counter, so people think they’re safe and natural,” Salloum said.

Technorati Tags: Brazilian Diet Pills, dietary supplements, nonprescription diet pills, online diet pills

Weight-loss programs can help people shed the pounds, but many people have trouble keeping it off. The new results could help women figure out how much exercise is sufficient to keep from tipping the scales again.

“The weight creeps back on again, and people put on all the weight they’ve lost, and sometimes more,” study author I-Min Lee of Brigham and Women’s Hospital and Harvard Medical School in Boston, Mass.

In addition, the study lends insight to national recommendations on exercise. For instance, the current U.S. federal guidelines say people should get 150 minutes of moderate-level activity per week to obtain health benefits and reduce the risk of chronic diseases. But the guidelines say nothing about weight-gain prevention. The Institute of Medicine, a non-governmental U.S. organization, recommends that people get an hour of moderate exercise a day, or 420 minutes per week to prevent obesity.

Such drastically different recommendations deserve clarification, Lee said.

Counting pounds

The study involved more than 34,000 women in the United States, and looked at how much weight they gained over a 13-year period, from 1992 to 2007.

The women were divided into three groups: those who engaged in less than 150 minutes of moderate-level physical activity per week; those who performed 150 to 420 minutes of this type of activity per week; and those who did more than 420 minutes per week, which comes out to one hour a day. Moderate-level activities included things like brisk walking, gardening and leisurely bicycling.

On average, the women gained about 6 pounds (2.6 kilograms) during the study period. Those in the two lesser activity groups (less than 150 minutes or between 150 and 420 minutes) gained significantly more weight than those who exercised more than 420 minutes a week.

While more physical activity was associated with less weight gain, this finding only held true for “normal” weight women, those with body mass index (BMI) of 25 or less. (BMI is calculated with a person’s height and weight and is considered an indicator of body fatness. An adult with a BMI between 25 and 29.9 is considered overweight.)

“Among heavier women, there was no relationship between how much activity a women did and what weight she gained,” Lee said.

However, Lee notes that the physical activity levels included in the study were not very high, and higher levels might be more sufficient at preventing weight gain.

The results are published in the March 24 issue of the Journal of the American Medical Association.

How much should I exercise?

Here’s what recommendations from the new study might look like: The results speak to middle aged-women (average age 54) with a normal diet, since that’s who participated in the study.

Only about 13 percent of the women gained less than 5 pounds during the study and did not become overweight or obese. On average, these women got about 420 minutes of exercise per week. So if you’re normal weight and want to avoid weight gain as you age, you should get about an hour of moderate exercise per day, the researcher say.

The same recommendations might not apply to overweight and obese individuals, who in the study did not have the same benefits from physical activity as normal-weight individuals. But that’s not to say heavier individuals should give up exercise, Lee said.

The group differences might come down to how much the individuals move around when they aren’t exercising, Lee said.

“In addition to physical activity, it’s also the things that you do in your regular life that contribute to caloric expenditure,” Lee said. “So it could be that the heavier people are also spontaneously moving less.”

Lee recommends that these individuals still get try to get 150 minutes of exercise per week, since this does have proven health benefits in terms of warding off chronic disease.

“Then if you’re willing to do more, either do more exercise or cut your calories, or a combination of both,” she said.

The study was funded by the National Institutes of Health.

Technorati Tags: medicine, Overweight Women, preventing weight gain, weight loss programs, weight-gain prevention

Japanese researchers fed mice a high-fat diet (45 percent of calories from fat) for six weeks. After the first two weeks, the mice were divided into two groups. One group received isoleucine in their drinking water while the control group received an inert substance. This continued for the remainder of the study.

Even though their dietary, fluid and caloric intake was the same, the mice who received the isoleucine gained less weight than those in the control group from day 17 to the end of the 28-day treatment period. The mice in the isoleucine group also had lower serum insulin concentrations, but there were no differences in levels of glucose, triglycerides or fatty acids.

The researchers also found that isoleucine improved the glucose-lowering effects of insulin, reduced fat deposits and increased fat metabolism.

The findings suggest that isoleucine may prove useful in the treatment of obesity, concluded the researchers, who called for clinical trials to test this hypothesis.

The study is published in the March issue of the Journal of Nutrition.

Technorati Tags: amino acid, insulin, isoleucine, treatment of obesity, weight loss aid

The study, published Jan. 28 in the Journal of the American Geriatrics Society, conflicts with research that suggests that being overweight contributes to a long list of health problems, including heart disease.

“Our study suggests that those people who survive to age 70 in reasonable health have a different set of risks and benefits associated with the amount of body fat to younger people,” lead researcher Leon Flicker, of the University of Western Australia, said in a news release from the journal’s publisher.

Flicker and colleagues looked at a decade’s worth of data regarding the health of more than 9,200 Australians aged 70 to 75 in 1996 when the study began. Australia is ranked as the third most obese country in the world after the United States and the United Kingdom, the study authors noted.

The study defined overweight and obesity levels based on body mass index, a measurement that takes weight and height into account. The four weight categories used in the study included underweight, normal weight, overweight and obese.

Those who were overweight — a step below obese — faced a 13 percent lower risk of death compared with those who were normal weight. But there was no benefit found for those who were obese, the study authors noted.

The researchers also found that being sedentary doubled the risk of death for women and raised it by one-quarter for men.

According to the study authors, it may be time to reevaluate the system that determines who is overweight and obese.

Technorati Tags: obesity, Overweight