Qnexa (phentermine/topiramate): Past, Present, and Future

New Column! Medical Methods in Obesity Treatment

This month: QNEXA: Past, Present, and Future

by Craig Primack, MD, FAAP, and Wendy Scinta, MD, MS, FAAFP, FASBP

Column Editors: Craig Primack, MD, FAAP, and Wendy Scinta, MD, MS, FAAFP, FASBP

Craig Primack, MD, FAAP is a Medical Bariatrician/Certified Medical Obesity Specialist/
Co-Medical Director, Scottsdale Weight Loss Center PLLC, Scottsdale, Arizona
Wendy Scinta, MD, MS, FAAFP, FASBP, is Medical Director, Medical Weight Loss of NY, BOUNCE Program for Childhood Obesity, Manilus, New York; Clinical Assistant Professor of Family Medicine, Upstate Medical University, Syracuse, New York

Bariatric Times. 2011;9(4):10–11

ABSTRACT
Qnexa, a combination of phentermine and extended release topiramate, if and when approved by the United States Food and Drug Administration will be the first medical management to treat obesity since 1999. This article provides a brief overview of the drug, from development to United States Federal Drug Administration approval status for market use.

Introduction
For the first time in 13 years, we hope to soon have a new weight loss drug, Qnexa (Vivus Inc., Mountain View, California). Qnexa is a combination pill of phentermine and extended-release topiramate. Both drugs have been shown to help weight loss when used as part of a comprehensive weight loss program and together seem to be synergistic, not just additive. There will be three doses of the drug if and when it finally makes the market.

Past
Phentermine has been on the market since 1959 and topiramate since 1996. The combination of phentermine and topiramate is used frequently by bariatricians at varying doses, and has been found to be very effective at treating both hunger and food addictions. Since its approval in 1959, phentermine has be studied numerous times for induction and augmentation of weight loss (in combination with dietary and behavioral modification), as well as maintenance of weight loss. It has repeatedly been proven to be a safe and effective appetite suppressant working in the hypothalamus to control hunger specifically. Topiramate (Topamax®, Janssen Pharmaceuticals, Inc., Titusville, New Jersey) has been well studied in binge eating disorder[1,2] and second-generation antipsycotic weight gain.[3–5] The mechanism of action of topiramate is not entirely known.

The road to achieving approval of this combination drug has not been easy. Vivus Inc., the maker of Qnexa, first submitted their application to the United States Food and Drug Administration (FDA) in 2009. This application was based on the results of two studies on weight loss, EQUIP[6] and CONQUER.[7] In January 2011, the FDA asked Vivus to examine the possibility of birth defects in the drug and to examine it further before possible approval. The FDA also expressed concern about possible adverse side effects, including suicidal thoughts, heart palpitations, and memory lapses. The risk for cleft lip on the drug has been estimated at 1.6 percent where baseline risk is 0.6 percent, an effective one-percent increase.

EQUIP[6] was a 56-week study of 1,267 patients with obesity (body mass index [BMI] ≥35kg/m2). Weight loss with the highest dose Qnexa was 14.7 percent and 6.7 percent in the lowest dose. This is compared to 2.1 percent in the placebo group. The most common side effect was tingling (paresthesias) in 18.8 percent of the high-dose group, likely secondary to the higher topiramate dosing. Additional side effects included dry mouth, constipation, altered taste, and insomnia. Most side effects were seen early in the study, and there was a low dropout rate of 16 percent in the high dose group, 11.3 percent in the low-dose group, and 8.4 percent for placebo group.

CONQUER,[7] also a 56-week study, examined 2,487 patients with overweight or obesity and comorbidities. Weight loss as well as secondary endpoints of cardiovascular, metabolic, and inflammatory risk factors were included. Mean percent weight loss was 9.8 percent on an intention-to-treat last observation carried forward basis (ITT-LOCF) for the high-dose group and 7.8 percent for the mid-dose group. Again, side effects were mostly seen early and dropout was 19 percent in the high-dose group, 12 percent in mid-dose group, and nine percent in the placebo group.
A third study, SEQUEL,8 a one-year extension of the CONQUER study, tested Qnexa on 676 patients with overweight or obesity for a total of 108 weeks. The average weight loss was 10.5 percent for the high-dose group and 9.3 percent for the mid-dose group. Average weight loss for the placebo group was only 1.8 percent (all on an ITT-LOCF basis). Side effects were similar to the initial two studies.

Present
On February 22, 2012, a sub-committee of the FDA voted 22 to 2 to approve the drug. On April 17, 2012, the full FDA is expected to follow the sub-committee recommendation and approve Qnexa.* It will likely be 3 to 6 months after approval before it is available for use.

Future
Qnexa, the first new weight loss drug since 1999, is long overdue. If approved, it will be a good tool for the treatment of obesity. Although both phentermine and topiramate will remain available on their own in generic forms, Qnexa will be the strongest combination drug available to treat overweight and obesity. Finally, it is important to remember that Qnexa is just one of many tools for treatment and that its best effects will be seen as part of a comprehensive program for weight loss that includes diet, exercise, behavior change, and adequate sleep.

*Editor’s note: At the time this article was written, the FDA was scheduled to announce its decision on the approval of Qnexa April 17, 2012. The FDA has since announced its decision to extend this date to July 17, 2012. To read the full press release on this issue, visit http://ir.vivus.com/releasedetail.cfm?ReleaseID=662825

References
1.    McElroy SL, Arnold LM, Shapira NA, et al. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry. 2003;160(2):255–261.
2.    McElroy SL, Hudson JI, Capece JA, et al. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61:1039–1048.
3.    Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacology. 2009;23(2):157–162.
4.    Nickel MK, Nickel C, Muehlbacher M, et al. Influence of topiramate on olanzapine-related adiposity in women: a random, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2005;25(3):211–217.
5.    Ko YH, Joe SH, Jung IK, Kim SH. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol. 2005;28(4):169–175.
6.    Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20(2):330–342.
7.    Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341–1352. Epub 2011 Apr 8.

8.    Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95(2):297–308. Epub 2011 Dec 7.

Funding: No funding was provided in the preparation of this manuscript.

Financial disclosures: The author reports no conflicts of interest relevant to the content of this article.

Category: Medical Methods in Obesity Treatment, Past Articles