Ron Zimmerman

October 03, 2012

October 3, 2012 (San Antonio, Texas) — Five studies of phentermine/topiramate were presented here at Obesity 2012: The Obesity Society 30th Annual Scientific Meeting. They were designed to answer physicians' questions about the safety and effectiveness of the combination therapy.

The extended-release formulation of phentermine/topiramate (PHEN/TPM ER) (Qsymia [previously known as Qnexa], Vivus, Inc) became available in pharmacies after the US Food and Drug Administration (FDA) finally approved the combination in July.

Thomas Najarian, MD, from Boston, Massachusetts, patented the combination. He had seen an abstract that mentioned in passing that weight loss was associated with topiramate. "I thought this might be a good drug to try," Dr. Najarian told Medscape Medical News. "There are so many mechanisms involved in eating that blocking just a single receptor doesn't work. For an obesity treatment to be effective, you have to hit a lot of different receptors; hit them hard and often."

Dr. Najarian first tried topiramate on one of his epilepsy patients who weighed 450 pounds. The patient's weight decreased to 240 pounds, "the lowest he'd been in years.... Eventually, I found a ratio of the drugs that would cancel out each other's side effects. That was back in 1999."

Dr. Najarian continued to study the effects of using the combined drugs off-label and in 2001 he patented his compound.

Generalizing the overall results of what he described as nearly 40 clinical trials during the approval period, Dr. Najarian said that "one of the basic conclusions is that if you look at all the data, whether it's for high blood pressure, diabetes, or lipid abnormalities, the patients with the most severe abnormalities at baseline had the biggest improvements percentage-wise. That's what you hope to see."

The dose of phentermine in the PHEN/TPM ER combination is lower than that in the combination of fenfluramine/phentermine (fen-phen), which caused the notorious heart valve controversy and led to that drug being withdrawn from the market. PHEN/TPM ER, which is taken once daily, comes in a low- and high-dose formulation (containing either 7.5 mg or 15 mg of phentermine); fen-phen contained 16 mg of phentermine and was taken 3 times a day.

Topiramate, which is used to treat migraines and epilepsy, has a number of potential adverse effects, including fetal toxicity, increased resting heart rate, suicidal ideation, glaucoma, sleep disorders, cognitive impairment, metabolic acidosis, hypoglycemia, hypotension, and renal complications. In PHEN/TPM ER, the dose of topiramate has been kept low to moderate its adverse effects. The low-dose formulation contains 46 mg of topiramate and the high-dose formulation contains 92 mg. When used to treat epilepsy, the dose can be up to 200 mg twice daily.

In each of the 5 studies presented, patients received the low-dose or high-dose formulation of PHEN/TPM ER or placebo.

Diabetes Study Results

Study 1 (poster 459-P) was a double-blind study of the effect of PHEN/TPM ER in reducing weight and antidiabetic medication use. The primary study period was 56 weeks, which was followed by a 56-week extension. Weight loss in both the low- and high-dose groups was identical (9%); in the placebo group, there was a 2% weight gain (P < .0001).

In the placebo group, 25.5% had a net increase in antidiabetic medication (P = .0005); in the low-dose group, 0.0% had a net change; and in the high-dose group, 3.1% had a net decrease (P = .0005).

Study author Timothy Garvey, MD, an endocrinologist at the University of Alabama-Birmingham VA Medical Center, concluded that PHEN/TPM ER might provide beneficial therapeutic effects beyond weight loss for obese patients. "I view this as a tool in prediabetic patients and those with metabolic syndrome to prevent progression to diabetes," Dr. Garvey told Medscape Medical News.

"Weight loss was robust, it was sustained over 2 years, and it did lead to improvements in glucose control. While the placebo group had increases in doses and number of medications over the study period, the [PHEN/TPM ER] group did not," he said.

Will the availability of PHEN/TPM ER change clinical practice? Dr. Garvey explained that although his medical group has a highly intensive lifestyle intervention approach and does bariatric surgery, "we had a void to help our patients get intermediate weight loss (10% to 15%). The availability of [PHEN/TPM ER] gives us that tool. This really should be considered in any patient who is overweight with type 2 diabetes."

Comorbidities Study Results

In study 2 (poster 460-P), subjects were categorized according to the Edmonton Obesity Staging System (EOSS).

Patients in the 3 study groups — EOSS 1 (mild risk factors in physical symptoms and functional limitations), EOSS 2 (obesity-related chronic diseases and moderate activity limitations), and EOSS 3 (end-organ damage and significant functional limitations) — all showed significant weight loss after 56 weeks of PHEN/TPM ER, regardless of the presence of comorbidities.

Study coauthor Arya Sharma, MD, from the University of Alberta in Edmonton, Canada, underscored the study's main result. "Irrespective of whether the patients have comorbidities...they still show significant weight loss. It doesn't matter the dosage; higher weight loss with higher dosage wasn't statistically significant."

Dr. Sharma added that although EOSS 3 patients are sicker than EOSS 2 patients, " there wasn't any difference in the distribution of side effects between the 2 groups. So, from a tolerability aspect, it appears that people who have organ damage tolerate [PHEN/TPM ER] just as well as those not as sick."

Blood Pressure and Triglyceride Study Results

In study 3 (poster 461-P), PHEN/TPM ER-induced weight loss was associated with statistically significant improvements in blood pressure, triglyceride levels, and lipid levels in nearly 2500 subjects.

Dr. Sharma, who was also involved with this study, pointed out that the 2 drugs seem to have a synergistic effect when used together that produced dramatic weight loss in this study's patients, bringing them into the 10% to 12% range.

"The key development is not only the low dose, but also chronic slow release," Dr. Sharma said. "This gives you a better profile for both adverse effects and tolerability. The extended release means you're getting 24-hour action, because the half-life of these drugs is just a couple of hours; otherwise, you'd have to use multiple doses every day.... You get better compliance with just 1 capsule a day," he explained.

Cardiovascular Risk Study Results

In study 4 (poster 462-P), Timothy Church, MD, MPH, PhD, from the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge, and colleagues conducted a study of cardiovascular risk. For one of the primary end points, weight loss at 56 weeks, least-squares mean percentage weight loss was 1.5% in the placebo group, 8.3% in the low-dose group, and 10.4% in the high-dose group (P < .0001 vs placebo). In this study, PHEN/TPM ER was associated with significant decreases in systolic blood pressure in the low-dose and high-dose groups, compared with placebo (5.2% vs 5.2% vs 2.1%; P < .0001), and in diastolic blood pressure (3.3% vs 2.9% vs 1.9%; P < .05). Mean change in heart rate was slightly higher in the low- and high-dose groups, compared with placebo (+0.6 beats/min vs +1.6 beats/min vs no change).

Rate pressure product (RPP) scores were calculated for the various groups, and the greatest benefit was seen in the low-dose group. The mean decrease in RPP from baseline was 0.13 in the placebo group, 0.23 in the low-dose group, and 0.18 in the high-dose group.

During the study period, 12.6% of the subjects discontinued therapy because of a treatment-emergent adverse event. The dropout rate was 8.4% in the placebo group, 11.6% in the low-dose group, and 17.3% in the high-dose group. The rates of serious adverse events were 3.3%, 2.8%, and 3.6%, respectively.

Reported adverse events were paraesthesia, dry mouth, constipation, dysgeusia, insomnia, dizziness, and nausea. Overall, these events occurred at a rate of more than 5%, and 1.5 times more in the PHEN/TPM ER groups than in the placebo group.

Treatment Algorithm Study Results

Study 5 (poster 34-LB-P), conducted by Vivus staff researcher Roman Dvorak MD, PhD, and colleagues, proposed a treatment algorithm to improve effectiveness. The algorithm titrates the dose starting with a phase-in dose of 3.75 mg PHEN/23 mg TPM once daily for 2 weeks. The dose then steps up to a half dose of 7.5 mg/46 mg once daily for 12 weeks. Patients are evaluated at that point for weight loss, and "responders" (patients with weight loss of 3% or more of body weight) are maintained on that dose. "Nonresponders" (those with weight loss less than 3% of body weight) are either discontinued or receive increased doses.

Those receiving increased doses are stepped up to an intermediate dose of 11.25 mg/69 mg once daily for 2 weeks, then stepped up again to a final full dose of 15 mg/92 mg daily for 12 weeks. At the end of the full-dose period, responders with weight loss of 5% or more are maintained on their doses, and nonresponders with weight loss of less than 5% are discontinued.

After 12 weeks, 83.5% of patients were classified as responders. At the 1-year mark, the placebo group had a weight loss of 1.2% (n = 979) and responders receiving the 7.5 mg/46 mg dose had a weight loss of 11.4% (n = 348).

"What's important," Dr. Dvorak told Medscape Medical News, "is that not only do the nonresponders have the lowest weight loss and the responders have the highest, the application of the algorithm makes the responders even better. Most of the adverse events occur early, within a few months of treatment, so if you eliminate nonresponders, you're left only with the ones who benefit, who have a lower risk. This is a remarkable thing."

Dr. Dvorak emphasized that the decision points for prescribing physicians are at 12 weeks (to determine if patients have achieved 3% weight loss) and then at 6 months (to decide if patients' doses should be stepped up). "We're making sure that only patients who truly benefit remain in therapy," he said. "All physicians will be trained on the algorithm. We think it makes a lot of sense."

Several physicians at the meeting were cautiously enthusiastic about the availability of PHEN/TPM ER. One primary care physician, Zenon Bednarski, MD, from Auburn, Alabama, told Medscape Medical News that he had come to the meeting specifically to find out about pharmacological advances that he could apply in his practice.

"We're not like a bariatric clinic where you can get patients into workout or diet programs," he said. "It's hard for a family physician to get all that going like a bariatric practice does, but there's as huge a demand from the general population to help them with their weight. The fact that the FDA approved 2 new products is great." (The FDA approved lorcaserin [Belviq, Arena Pharmaceuticals] in June for the treatment of obesity.)

Erik Hemmingsson, PhD, from the Karolinska Institutet in Stockholm, Sweden, told Medscape Medical News that there is a sense of desperation among physicians who treat weight loss because the few existing drug therapies are only modestly effective. "It's an absolute necessity," Dr. Hemmingsson said. "We've struggled for many years having very few drug solutions. This drug is looking very effective."

Dr. Hemmingsson did express concern about the possible adverse effects of PHEN/TPM ER. However, he noted that both the components have been used as monotherapies. "That may be a safe way to go, because both those drugs were already approved and checked out in large studies.... I'm excited but a little worried," he said.

European Approval

Dr. Hemmingsson mentioned that the drug has not yet been approved by European regulators. Vivus said last week that it does not expect to gain approval with its first application to regulatory authorities.

Barbara Troupin, MD, MBA, vice president of scientific communication and risk management at Vivus, told Medscape Medical News that the European approval process would likely take the same step-by-step iterations that marked approval in the United States. "In October, we'll get a written response from them and we'll know how to address any objections."

Dr. Troupin pointed out that the company recommends a pregnancy test for all women before starting PHEN/TPM ER, and monthly while receiving treatment. "That's an agreement not at the pharmacy but between the doctor and the patient," she said, adding that there is a voluntary training program for physicians. "We encourage doctors to take the training program, although not taking it doesn't block you from prescribing."

Currently, PHEN/TPM ER is only available at 2 national pharmacy chains in the United States — Walgreens and CVS, she noted.

Dr. Najarian, the drug's patent holder, is looking forward to completion of the studies that he thinks will show the ultimate benefit of PHEN/TPM ER, which he says goes beyond weight loss.

"In 3 or 4 years, we'll see end points and know whether we've reduced death rates from cardiovascular events," he told Medscape Medical News. "I think it will."

Dr. Najarian and Dr. Dvorak are employees of Vivus. Dr. Sharma reports receiving speaker's and consulting fees from Vivus. Dr. Garvey reports being on scientific advisory boards for Alkermes PLC and Daiichi-Sankyo, receiving speaker's fees from Merck & Co, and receiving corporate financial support for his clinical trials. Dr. Church reports being a consultant for Vivus, being on the advisory board for Jenny Craig, and being a board member for Catapult Health. Dr. Hemmingsson reports receiving grant funding from iTrim, a Swedish commercial weight loss program. Dr. Bednarksi has disclosed no relevant financial relationships.

Obesity 2012: The Obesity Society 30th Annual Scientific Meeting. Posters 459-P, 460-P, 461-P, 462-P, 34-LB-P. Presented September 21, 2012.