May 4, 2010 (New York, New York) — New data on an investigational weight-loss therapy, a combination of phentermine and controlled-release topiramate, have unusually been presented at the American Society of Hypertension (ASH) 2010 Scientific Meeting. The highest dose of the drug combination induced a "substantial" weight loss of 10% after one year and resulted in significant drops in systolic blood pressure, reported Dr Suzanne Oparil (University of Alabama at Birmingham).

Drs Suzanne Oparil and Louis Aronne

Obesity expert Dr Louis Aronne (Weill Cornell Medical Center, New York), who worked with Oparil on the studies, told heartwire that the "clever thing is in the combination." Oparil concurred: "They [phentermine and topiramate] work together." However, they stressed the importance of this particular formulation, which uses a controlled-release form of topiramate, an anticonvulsant drug, and "very, very" low doses of phentermine, an appetite suppressant, and strongly advised against anyone trying to use currently available forms of these drugs together. "Don't try this at home," Oparil cautioned.

Asked by heartwire why a pooled analysis of trials on an obesity drug had been presented as a late breaker at a hypertension meeting, ASH president Dr Henry Black said: "We're about more than just blood pressure; we're about cardiovascular risk."

Product to Be Discussed by an FDA Advisory Committee This Summer

The combination product, which if approved will be known as Qnexa (Vivus), is to be discussed by an FDA advisory committee this summer, Aronne told heartwire . It will be appropriate for patients with a body-mass index (BMI) of 27 to 30 and comorbidities or those with a BMI of >30, he said, and therefore will potentially fill "a big gap between diet/physical activity and surgery. This is a breakthrough; drugs that we know are effective but using more appropriate doses.

Don't try this at home.

"The trend now is to use less invasive surgeries and combination therapies, and these things are beginning to meet in the middle, and that's where the greatest need is," Aronne added. "If your BMI is very high, then surgery might be the thing to do; if your BMI is a little bit above normal, then diet and exercise is the best thing, but what do you do for the millions, a third of the population, who fit in the middle and have all the risk and are appearing in the doctor's office with all these complications?"

ASH president-elect Dr George Bakris (University of Chicago Pritzker School of Medicine, IL) agrees. He told heartwire that Qnexa could "definitely" fill the gap left by Sanofi-Aventis's rimonabant, which was never approved in the US and was removed from the market in Europe and elsewhere because of psychiatric side effects. "I like it. It's been packaged with careful thought about the correct doses, of how to use them. There is a very meaningful drop in body weight and, unlike what I predicted knowing the drugs individually, blood pressure went down."

Bakris says the latter is important because the product "is not revving the system very much, the weight loss is overcoming any potential [BP] increase you would see [from phentermine]." He also emphasized the warnings of Oparil and Aronne, stressing how important it is that people do not try to re-create this cocktail of drugs themselves: "You could easily blow out your heart or your brain if you use those high doses; they will rev the catecholamine system and raise your pressure dramatically."

Significant Weight Losses, From 5% to 10%, Depending on Qnexa Dose

What do you do for the millions, a third of the population, who fit in the middle and have all the risk?

Oparil reported the findings of a pooled analysis of three Qnexa studies in a press conference and presented them at the late-breaking clinical-trial session.

She explained that the product harnesses the effects of the two different but complementary mechanisms specific to each component, phentermine and topiramate, "which allows for lower doses of each agent, which should be safer." Phentermine was part of the controversial fen-phen combination used for weight loss, use of which was abandoned when fenfluramine was associated with abnormal valvular regurgitation.

Phentermine, as an appetite suppressant, works immediately, and then the sustained-release form of topiramate is longer lasting, inducing a sense of satiety, Oparil said.

The three trials included in her analysis were EQUATE, which compared full-dose Qnexa (15 mg of phentermine/92 mg of topiramate sustained release [SR]) and mid-dose Qnexa (7.5 mg/46 mg) with placebo and the respective single agent phentermine and topiramate components for 28 weeks in obese adults (BMI >27); EQUIP, which compared full-dose and low-dose (3.75 mg/23 mg) Qnexa with placebo for 56 weeks, again in obese individuals (BMI>35); and CONQUER, which compared full-dose and mid-dose Qnexa with placebo for 56 weeks in "all-comers," including the obese and overweight adults (BMI 27–45) who had to have two or more weight-related comorbidities.

After 28 weeks, the primary end point--least-squares (LS) mean percentage weight loss of the intention-to-treat last-observation-carried-forward (ITT-LOCF) population--was significantly greater for all the doses of Qnexa: reductions were 9.9% with the full dose (n=1581), 8.0% with the mid dose (n=591), 5.1% (n=234) with the low dose, and 1.9% (n=1579) with placebo (p<0.0001 for all doses of Qnexa vs placebo).

The 56-week data, from CONQUER and EQUIP, showed that the weight loss was maintained out past a year: 1479 patients taking the full dose had a mean weight loss of 10.4%; 488 taking the mid dose lost, on average, 8.2% of body weight, and 234 on the lowest dose lost 4.7%, all of which were significant losses compared with the 1.5% mean loss in the 1477 placebo patients (p<0.0001).

Adverse reactions were "characteristic" of those that would be expected from these two agents, said Oparil, including altered taste, constipation, dizziness, dry mouth, and headache.

And discontinuations due to side effects were higher with Qnexa, peaking at 17.5% of patients on the highest dose and around 11.5% of those on the mid and low doses, compared with 8.5% on placebo.

Topiramate Contributes to BP Reduction, as Does Weight Loss

Overall in the three trials, significantly greater reductions in mean blood pressure were seen with the mid and high doses of Qnexa, compared with placebo, averaging a decrease of 6.5/2.8 mm Hg with the higher dose and 6.8/3.1 with the mid-dose, compared with a drop of 3.1/1.3 mm Hg with placebo.

And among a prespecified subgroup of patients with hypertension enrolled in the all-comers CONQUER trial, the only doses of Qnexa tested, mid and high, also led to statistically significant reductions in BP, of 9.1/5.8 mm Hg with the high dose and 6.9/5.2 mm Hg for the mid dose compared with 4.9/3.9 mm Hg with placebo. This illustrates "that the BP reduction in the hypertensive subjects was comparable with the study group as a whole," said Oparil.

In addition, 10.5% and 6.6% of the hypertensive patients in CONQUER taking the high and mid doses of Qnexa, respectively, were able to reduce the number of antihypertensive medications they were on over the year of the study, compared with a net increase of 3.4% in such medications seen in the placebo group.

Oparil explained that topiramate itself has some intrinsic antihypertensive efficacy and that the weight loss incurred among those taking the active drug combination also contributes to the reduction in blood pressure that is seen.

"If you can get people to lose weight you get a lot of benefits--improvement in every cardiometabolic risk factor," Aronne commented.

Oparil agreed, adding that if patients can lose even a little bit of weight, it may motivate them to exercise and diet more aggressively to get to where they should be: "It takes away the hopelessness." Such weight loss might also enable adjustment of doses of antihypertensive medications or even eventually allow doctors "to take away an antihypertensive medication people didn't like," she concluded.

Oparil and Aronne are consultants to Vivus.

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