Generic Name: phentermine and topiramate
Approval Status: NOT Approved
Company: Vivus Inc.
Proposed Indication: Obesity
The New Drug Application (NDA) that was submitted for Qnexa in October 2011 is currently under FDA review with a revised FDA action date of July 17, 2012. Qnexa was recommended for approval by FDA Endocrinologic and Metabolic Drug Advisory Committee on February 22, 2012 by a vote of 20:2 based on a favorable benefit-risk profile. The FDA is not bound by the recommendations of its advisory committees, but often follows them.1,2
Treatment of obesity, including weight loss and maintenance of weight loss, in patients who are obese (BMI > 30 kg/m2) or overweight (BMI > 27 kg/m2 with co-morbidities such as hypertension, type 2 diabetes, dyslipidemia or central adiposity.
Qnexa is also in phase 2 clinical development for the treatment of type 2 diabetes and obstructive sleep apnea.
Strengths and Dosage Forms: Three strengths of Qnexa have been studied in clinical trials: a low (3.75 mg phentermine/23 mg topiramate CR (controlled release), mid (7.5 mg phentermine/46 mg topiramate CR), and high strength (15 mg phentermine/92 mg topiramate CR). Mid-dose phentermine/topiramate CR once daily is the recommended maintenance dose.
The final, marketed strength(s) will not be known until the FDA makes its final determination. Qnexa, if approved, will be available as an extended-release capsule and a controlled substance Schedule IV drug due to the phentermine component.
Phentermine and topiramate are separately licensed for use in the United States. Both agents are available generically.
About Qnexa (phentermine/topiramate)
Mechanism of Action: Phentermine is an appetite suppressant and stimulant. Topiramate is classified as an anticonvulsant, but has been found to have weight loss as a common side effect. Qnexa combines low doses of these two agents for weight loss and control. Qnexa is designed to decrease appetite and increase satiety (the sense of feeling full), the two main mechanisms that impact eating behavior.
Phentermine (Adipex-P), approved in 1959 as an appetite suppressant, is available in strengths ranging from 15 mg to 37.5 mg. Phentermine was a component of the drug combination "fen-phen" (fenfluramine/phentermine) from the late 1990s that resulted in potentially fatal heart valve damage and pulmonary hypertension. However, it was determined that only the fenfluramine (Pondimin) component of "fen-phen" led to the heart side effects. Analysis of available data suggested that fenfluramine and dexfenfluramine (Redux) were the causal agents of cardiac abnormalities, and both drugs were withdrawn from the market in September of 1997.
Topiramate (Topamax) was approved in 1996 for the treatment of seizures at doses up to 400 mg/day in adults and in 2004 for the prevention of migraine headaches at doses up to 100 mg/day.
Qnexa Background: Worldwide there are more than 500 million people who are obese. In the U.S., more than one-third (78 million) adult Americans suffer from obesity. Obesity is a risk factor for the development of diabetes, heart disease, high blood pressure, and stroke, and is the second leading cause of preventable death in the U.S.
In December, 2009, Vivus, Inc., submitted an original New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval of Qnexa (phenterime/topiramate) for the treatment of obesity. In July of 2010, although Qnexa had met FDA benchmarks for effectiveness in weight loss, the FDA Advisory Committee members voted against approval of Qnexa due to safety concerns, primarily over the potential for teratogenicity due to the topiramate component and elevated heart rate due to phentermine.1,2
Qnexa Phase 3 Clinical Trials
Qnexa Efficacy: In phase 2 and 3 clinical trials (n=3,750), patients taking Qnexa demonstrated statistically significant weight loss, blood sugar control, and improvement in cardiovascular risk factors, when used in combination with a diet and lifestyle modification program.
The 28-week EQUATE (OB-301) study, and the 56-week EQUIP (OB-302) and CONQUER (OB-303) phase 3 studies were submitted to the FDA for review. In these studies, the average BMI ranged from 36.3 to 42.1 kg/m2, and the average baseline weight ranged from 223 to 256 lbs. All patients were asked to follow a low calorie diet and advised to implement a simple lifestyle modification program.
Weight loss of up to 14.7% (36 lbs) of baseline weight was recorded in the Equip study. A statistically significant 69% of patients completed treatment compared to placebo group completion rates. FDA efficacy benchmarks for weight loss agents were exceeded at all three doses of Qnexa tested in the clinical program.
In year two of treatment, some patients did regain some of the weight they had lost. The high-dose Qnexa group experienced more weight regain in the second year than the mid-dose Qnexa group. An analysis showed that in the second year, 26.8% of weight lost in the first year was regained in the placebo group, 10.9% of weight lost was regained in the mid-dose Qnexa group, and 18.4% of weight lost was regained in the high-dose Qnexa group.1
Qnexa Safety: Although labeling is not available for Qnexa warnings, precautions and side effects, clinical trials have brought forth important safety issues.1,2
Qnexa side effects
Commonly reported side effects include:
- dry mouth
- altered taste
Potentially serious side effects may include:
- elevated heart rate
- suicidality risk
- cognitive dysfunction
- metabolic acidosis
- low serum bicarbonate
There were 5 main safety concerns that arose when the original Qnexa NDA was submitted to the FDA and reviewed by the subcommittee in 2010. Subsequently, Vivus completed additional safety studies in the areas of cardiovascular risk assessment and teratogenicity.
Suicidality: A 2008 FDA analysis suggested the antiepileptic drug class (of which topiramate is a member) is associated with an increased risk of suicidality. In the Qnexa one year safety clinical trial, there was one report of suicidality in the active treatment group, and one in the placebo. There were no reported suicidality events in a 2-year safety cohort study. In both studies, there were no reported suicide attempts, suicidal behaviors, or instances of serious suicidal ideation.1
Cognitive-related adverse events: Topiramate at doses used for epilepsy and migraine prophylaxis is associated with cognitive related side effects such as confusion, psychomotor slowing, difficulty with concentration and attention, memory impairment, and language difficulties. A similar adverse event profile was demonstrated with Qnexa treatment, ranging in incidence from 2 to 7.8% dependent upon dose. The most common side effect related to cognitive dysfunction was disturbance in attention.1
Metabolic Acidosis: Clinical trials with topiramate monotherapy, as well as Qnexa clinical experience, demonstrated that in roughly 30% of patients topiramate can cause metabolic acidosis through inhibition of carbonic anhydrase resulting in levels <21 mEq/L. Consequences of untreated chronic metabolic acidosis may include hyperventilation, fatigue, anorexia, and increased risk for osteomalacia or osteoporosis, but the clinical importance of long-term low bicarbonate levels is unknown in this patient population.
Cardiovascular Risk: Qnexa has demonstrated statistically significant positive effects on blood pressure-lowering in clinical trials. However, in one (n=3879) and two year (n=675) safety cohorts, mean heart rates in the Qnexa groups increased 0.6 to 1.6 beats per minute (bpm). Additionally, 13.5 to 25.8 percent of the Qnexa group had increases in heart rates greater than 20 bpm, compared to 11.9 to 21.6 percent of placebo patients. FDA Advisory Committee members have expressed concern over the increased heart rate side effect noted with Qnexa, and the possibility that this might increase the risk for heart attack or stroke. Vivus has agreed to complete a large, prospective, post-approval clinical trial to assess these risks in an at-risk, obese population.
Teratogenicity Risk: It is expected that Qnexa will be contraindicated for use in women who are pregnant due to an elevated risk for teratogenicity with topiramate, and will have Pregnancy Risk Category X. In FDA Advisory Committee meetings, the concern with teratogenicity focused on the 2- to 5-fold higher risk for oral clefts. A Risk Evaluation and Mitigation Strategy (REMS) program to address safety issues related to Qnexa use was proposed by the manufacturer. If Qnexa is approved, it may fall under a restricted distribution program to help prevent it’s use in pregnancy. Of note, all weight-loss products are being reclassified by the FDA as Pregnancy Category X (no benefit for use in pregnancy and potential risks) according the the Qnexa FDA docket.