FDA Staff Questions Slim Data on Weight-Loss Drug

[Guest guest]

An investigational diet drug called Contrave that combines an antidepressant

and an anti-addiction drug appears at least somewhat efficacious at helping

obese patients lose weight, but comes with an increased risk for high blood

pressure.

The Endocrine and Metabolic Drugs Advisory Committee will meet Tuesday to

vote on whether the benefits for the sustained-release bupropion and

naltrexone combination are greater than the drug's risks.

Both drugs have been used individually for 20 years -- naltrexone for opioid

addiction and alcohol dependence and bupropion for depression and smoking

cessation -- but little is known about combining the drugs for weight

managment.

Orexigen, the company that makes the combination in partnership with Takeda,

is seeking approval for treatment of obesity and weight management in

patients with a body mass index of 30 or above, or 27 or above and with one

or more risk factors (e.g., diabetes, dyslipidemia, or hypertension).

In briefing documents posted online Friday, FDA reviewers analyzed results

from Orexigen's four placebo-controlled, one-year, phase III clinical

trials, which enrolled 3,200 obese patients with at least one comorbid

condition, including diabetes and depression.

In all four trials, patients on the naltrexone/bupropion combination lost

more weight than those in the placebo group (*P*<0.001), and more than 30%

lost at least 5% of their body weight, which is one standard by which the

FDA judges efficacy of weight-loss drugs.

In a pooled analysis, naltrexone/bupropion patients lost an average of 4.2%

more weight than the placebo group (ranging from 3.3% to 4.8%). That falls

short of the other FDA standard that after one year, the difference in mean

weight loss between the active and control group should be at least 5%.

And the weight loss comes with side effects, FDA staff said. Hypertension

was more common in the naltrexone/bupropion group than in the placebo group,

which was particularly pronounced in a trial that tested the drug in

patients with diabetes.

" NB attenuates or eliminates the blood pressure and pulse reductions that

are normally seen with weight loss, " the reviewers wrote. " It is not known

how these vital sign changes in the overweight and obese population would

impact cardiovascular risk over the long term. "

Also, two patients in the clinical trials experienced seizures after going

on naltrexone/bupropion. No participants in the placebo group had seizures.

Patients on naltrexone/bupropion were also more likely to discontinue the

study, often because of nausea.

The FDA reviewers said the number of major adverse cardiac events in the

trials was too small to make any reliable guesses about how

naltrexone/bupropion might effect cardiovascular risk.

Because of that lack of data, the advisory panel will be asked whether a new

study assessing cardiovascular risk should be required and whether it should

happen before or after approval.

Stand-alone bupropion has been associated with suicide ideation, attempts,

and completion, but there were no suicides in the trials, and suicide

ideation was actually higher in the placebo groups, the FDA reviewers noted.

However, " Contrave could have widespread use, and the potential for safety

issues (including seizures, suicidality, and cardiovascular events) cannot

be dismissed, " FDA reviewers said.

Overall, the reviewers felt the company didn't submit enough data for the

agency to accurately determine how safe naltrexone/bupropion is.

Contrave is the third investigational diet drug to go before an FDA advisory

committee this year, and the other two have not fared well. Advisory panels

have shot down new drug applications for the phentermine/topiramate

combination

Qnexa<http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/21190>and

the investigational drug

lorcaserin <http://www.medpagetoday.com/PrimaryCare/Obesity/22266>. The FDA

rejected both.

There is currently just one FDA-approved obesity medication: orlistat

(Xenical).

In the company's briefing documents, Orexigen said naltrexone/bupropion is a

" viable " option for patients who don't tolerate orlistat and who may not

have high enough BMIs to be eligible for bariatric surgery or who don't want

the risks of undergoing surgery.

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--

Ortiz, MS, RD

*The FRUGAL Dietitian* <http://www.thefrugaldietitian.com>

Check out my blog: mixture of deals and nutrition

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