Gerald Hurowitz, M.D.·Published 29 February 2012·10 min read
Key points
U.S. drug regulators may have a hard time stopping millions of overweight Americans from taking a new obesity drug that many are likely to view as a miracle pill for slimming waistlines, despite its safety risks.
In the mid-1990s, a high number of overweight Americans were taking fen phen with the promise of quick and effective weight loss.
Qnexa® (phentermine and topiramate) Extended-release Capsules is an investigational, once-per-day, weight-loss therapy that combines low doses of two agents approved by the Food and Drug Administration (FDA), phentermine and topiramate, in a controlled-release formulation.
There has been a clamor from patient groups, doctors and lawmakers for the FDA to provide more weight-loss options.
U.S. drug regulators may have a hard time stopping millions of overweight Americans from taking a new obesity drug that many are likely to view as a miracle pill for slimming waistlines, despite its safety risks.
Regulators and doctors are hoping they can limit the pill, called Qnexa, to only those patients that need it most, helping fight the nation's obesity epidemic while avoiding exposing people to unnecessary risks of birth defects and heart problems.
The Food and Drug Administration has been under considerable pressure from lawmakers and patient groups to approve a new obesity drug for the first time in 13 years.
There is also plenty of history with diet drugs that makes the FDA cautious.
The infamous diet drug "fen-phen" was pulled from the market in 1997 after reports of sometimes fatal heart-valve problems. Another diet pill, Meridia, was removed in 2010 after it was linked to heart problems.
"How will these medications be limited in their distribution... so we don't have a repeat of the fen-phen days when people were opening up clinics on every corner, selling these pills for cosmetic purposes?" asked Joseph Nadglowski, chief executive officer of the Obesity Action Coalition, a patient and advocacy group.
As a condition for approval of Qnexa, the FDA and the drugmaker Vivus proposed a restrictive program to stop pregnant women from taking the drug, to provide training to doctors and to limit distribution to certified mail-order pharmacies.
Also, the drug will likely only be recommended for obese patients who have a body mass index over 30, or are overweight but have weight-related health issues. A normal BMI is below 25.
What is Fen Phen?
In the mid-1990s, a high number of overweight Americans were taking fen phen with the promise of quick and effective weight loss. Fen phen contained the combination of two drugs called fenfluramine and phentermine. While one drug suppressed the appetite, the other drug prevented drowsiness. Patients quickly experienced dramatic weight loss and the drug was dubbed a "miracle pill".
Although health experts warned from the start that fen phen should only be used by the seriously obese, everyone wanted to get their hands on the weight loss drug. Seemingly overnight, new weight loss clinics began popping up prescribing fen phen to eager consumers.
The popularity of fen phen was short lived, and scientific evidence surfaced showing a link between serious heart valve damage and a fatal lung condition called primary pulmonary hypertension (PPH). By then, millions of Americans had used fen phen.
On September 15, 1997, the FDA said it asked Wyeth-Ayerst Laboratories to remove fen phen from the market due to the potentially deadly effects. Soon after, fen phen users began filing lawsuits. A 1999 class action lawsuit ensued.
Written and revised by
Gerald Hurowitz, M.D.
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Since then, total charges for fen phen has cost Wyeth $21 billion. In October 2004, Wyeth warned it might need to set aside additional reserves to cover more fen phen liability, including tens of thousands of former patients who have filed lawsuits alleging they were harmed by the products and were not adequately warned of the risks.
The drugmaker lost $1.76 billion in the fourth quarter of 2004. Wyeth has proposed settlement involving about 60,000 people who opted not to participate or were not eligible to participate in a 1999 class action settlement that covered most people who took Redux and Pondimin, half of the diet drug combination fen phen. A settlement would resolve the opt-out fen phen cases from going to trial, but internal FDA documents regarding the questionability of fen phen's safety have been clearly outlined.
It was these restrictions that ultimately convinced 20 out of 22 outside advisers to the FDA to recommend approval of the drug last week, after an expert panel rejected the drug in 2010.
The FDA is set to make its final decision by mid-April.
However, regulators have little power to force doctors to stick to this restrictive program because physicians have latitude to prescribe FDA-approved drugs for other uses, known as "off label."
The prevalence of obesity continues to be a health concern that affects a large and growing proportion of the population, including more than one third (more than 78 million) of American adults. Worldwide more than 500 million people are obese. Obesity directly contributes to numerous life-threatening conditions: diabetes, cardiovascular disease, hypertension and stroke and is the second leading cause of preventable death in the U.S.
Beyond its impact on health, it is estimated that obesity economically accounts for 9.1% of U.S. annual health care spending - nearly $150 billion dollars. By 2030, if trends in the escalating rates of obesity continue, health care costs attributable to obesity may reach $956 billion, accounting for up to 18% of total health care costs, or $1 in every $6 spent on health care.
The Product
Qnexa® (phentermine and topiramate) Extended-release Capsules is an investigational, once-per-day, weight-loss therapy that combines low doses of two agents approved by the Food and Drug Administration (FDA), phentermine and topiramate, in a controlled-release formulation.
In addition, the two drugs in Qnexa are already approved for other conditions, raising the possibility some doctors may already be prescribing them for weight loss.
The FDA acknowledged that it is difficult to craft a restrictive program that sticks. "We struggled with this internally, but we did not find a perfect solution to this problem," Joyce Weaver, senior analyst in the FDA's division of risk management, told the advisers last week.
RISK VS. BENEFIT
There has been a clamor from patient groups, doctors and lawmakers for the FDA to provide more weight-loss options.
Obesity drugs are seen as the middle ground for patients who struggle with strict diet and exercise regimens, but do not want the risks of bariatric surgery.
A Senate appropriations committee has directed the FDA to provide a report by the end of March on how it plans to support the development of new obesity treatments.
Obesity, a leading cause of diabetes, heart disease and other serious health problems, has reached epidemic proportions in the United States, with nearly 68 percent of the U.S. population considered overweight, and a third obese.
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Analysts predict that Qnexa, if approved, will be prescribed widely, with annual sales of $1 billion to $3 billion.
It combines the appetite suppressant phentermine with the anti-seizure drug topiramate, and helped patients lose 10 percent of their weight after a year during trials. However, the pounds started to creep back on after the first 12 months.
In terms of weight loss, Qnexa will likely produce smiles. Clinical data (not yet published) showed participants lost an average of 10 percent of their body weight, according to Vivus' claims. But as Robert Carlisle's Mr. Gold loves to say on the TV hit Once Upon a Time, "All magic comes at a price." What's the price to your overall health of taking Qnexa?
Let's start with what's in the drug. Qnexa is actually a "cocktail," meaning it's a combination of two previously FDA-approved drugs, phentermine - an appetite suppressant - and topiramate, an anti-convulsant.
FDA staff reviewers said patients taking the drug had more safety problems, including memory loss and higher heart rates, than those on a placebo. They also said exposure to topiramate has been linked to a higher rate of oral clefts in infants of women taking the drug during pregnancy.
Experts worry subtle messages of risk versus benefit may slip past people desperate to shed pounds, and there is little the FDA can do to stop them.
"Perhaps the only thing that would be better than a pill to help you lose weight would be a pill that makes you more beautiful," said Dr. David Gortler, a former FDA medical officer on the obesity team and current professor of pharmacology at Georgetown Medical School. "In fact, many fashion advertisers promote and equate beauty with the loss of weight.
"There is going to be a huge demand for Qnexa... (and) if the FDA doesn't regulate Qnexa appropriately there are going to be a deluge of lawsuits," said Gortler.
SLIPPING THROUGH THE CRACKS
The FDA often proposes risk mitigation programs to deal with drugs that may cause birth defects. One of the most restrictive is for the acne drug Accutane from Roche, which is known to cause severe birth defects.
Women who want the drug must take tests every month to prove they are not pregnant. But there is a lack of good information about how effective these programs are.
The FDA rejected the diet pill Qnexa in October 2010, citing numerous side effects including raised heart rate, psychiatric problems and birth defects. Vivus has resubmitted the drug with additional follow-up information on safety, hoping for a more favorable ruling.
Vivus President Peter Tam said the overwhelming panel vote Wednesday underscores the need for effective weight loss drugs.
"I think they see the medical need," Tam said. "Right now there aren't any good treatments out there besides dieting and bariatric surgery, clearly there's a huge gap."
Dr. John Jenkins, head of the FDA's office of new drugs, said such programs are pretty good at avoiding women who are pregnant at the time of first receiving the drug.
"They are not as good at preventing women from receiving it who are pregnant while they are already on the drug," Jenkins told the panel last week. "While we think the number of pregnancies is less, we don't have definitive data."
Qnexa has some uncertain effects on the heart: it lowers blood pressure, but raises heartbeat. Doctors on the FDA panel were divided about what signal that sends, and asked Vivus to conduct more studies on heart safety, most likely after Qnexa is approved.
"This drug, if approved, would likely be prescribed to millions or tens of millions of people," said Dr. Michael Lauer, director of the division of cardiovascular sciences at the National Institutes of Health.
Lauer was one of two people who voted against Qnexa's approval at the FDA panel last week. "Based on the data that we've seen, we think this drug may do enormous good," he said during the panel meeting. "But we may not know that for a long time, or we may find out we've been fooled."
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MORE CONTROL WITH APPROVAL
The FDA has set a high approval bar for obesity drugs in the past, primarily because of worries that a large portion of the population is likely to take them.
Qnexa has had the most impressive weight loss out of a trio of pills vying for approval, from Vivus, Arena Pharmaceuticals and Orexigen.
The drug from Orexigen has also been flagged for heart risks, while FDA reviewers have cautioned about cancer risks associated with the pill from Arena.
In its July 8th Advisory, the FDA also asked - and continues to request - all health care professionals to report any such cases and other toxicities associated with the use of the three drugs to FDA's MedWatch program (1-800-FDA-1088/fax 1-800-FDA-0178) or to the respective pharmaceutical manufacturers. Such reporting allows FDA to better determine the scope of this problem, to better work with the academic community and the manufacturers in determining the reason(s) for this problem, and to better determine the most appropriate regulatory response to this concern.
Thanks to the reporting of health care professionals, as of August 22, FDA has received reports of 82 cases (including Mayo's 24 cases) of cardiac valvular disease in patients - two of whom were men - on combination fenfluramine and phentermine. These reports have been from 23 different states. Severity of the cardiac valvular disease was graded as moderate or severe in over three-fourths of the cases, and two of the reports described deterioration from no detectable heart murmur to need for a valve replacement within one-and-a-half years. Sixteen of these 82 patients required surgery to repair their heart valves. At least one of these patients died following surgery to repair the valves. (The agency's findings, as of July 31, are described in more detail in the current issue of The New England Journal of Medicine, which also carries the Mayo study.)
Five additional reported cases of cardiac valvular disease were associated with exposure to fenfluramine followed by dexfenfluramine, both in combination with phentermine; and 1 additional case was associated with exposure to the combination of all 3 drugs given at the same time.
In addition, there have been reports of cardiac valvular problems associated with the use of fenfluramine alone (n=2) and dexfenfluramine alone (n=7). However, no reports have yet been received of these heart problems developing when fenfluramine or phentermine are used as single agents for the duration presently approved.
In addition, FDA is working with the Centers for Disease Control and Prevention, the National Institutes of Health, and the Mayo Clinic researchers to develop methods to investigate the scope and cause(s) of this problem. Some epidemiologic studies using on-going trials and various data bases are already underway. Other prospective studies are presently being designed.
Qnexa is unique among the three because its ingredients are already on the market.
"These are two medications that are already on the market, and there are hundreds of thousands if not millions of patient care experience with both of these medications. Doctors can combine them, and many of them are," said Dr. Robert Kushner, clinical director of the Northwestern Comprehensive Center on Obesity.
"I think you can better monitor the usage and protect patients if it's approved than if it's not approved."
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(Reuters)
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