Combination Approaches to Obesity Treatment
Monotherapies that selectively target one specific system in the CNS have rarely achieved greater than 5% weight loss; hence, the concept of tackling multiple targets in the regulatory pathways of energy balance has become more popular as a potentially safer and more efficient strategy for obesity treatment. Many of these combination treatments target the brain's reward circuitry. The first drug combinations have now reached Phase III clinical trials, including the phentermine–topiramate (Qnexa), the bupropion–zonisamide (Empatic®, Orexigen Therapeutics) and the bupropion–naltrexone (Contrave) combinations.
Qnexa has been presented as an effective combination therapy involving low doses of the amphetamine derivate, phentermine, and the anticonvulsant agent, topiramate. The mechanisms of action for both topiramate and zonisamide have not been fully characterized; however, they have demonstrated biphasic dopaminergic and serotinergic activity.[99–101] At least three Phase III studies have been completed, testing three different dose combinations of phentermine and topiramate. The EQUATE (756 obese subjects comparing mid- and full-dose Qnexa with the individual components and a placebo over 28 weeks), the EQUIP (1267 morbidly obese patients treated with low- or full-dose Qnexa or placebo over 52 weeks) and the CONQUER (2487 overweight and obese patients with high blood pressure, high cholesterol or Type 2 diabetes receiving mid- or full-dose Qnexa or a placebo over 52 weeks) trials assessed the effect of mid- and full-dose combinations, in which treatment caused a major weight loss of approximately 8.3 (8.5%) and 9.0 kg (9.2%) after 28 weeks and of 8.6 kg (8.4%) and 10.7 kg (10.4%) after 56 weeks.[211,212] Psychiatric mood assessments were carried out during the trials and did not show evidence of increased depression or suicidal thoughts.
However, 18% of participants on high-dose treatment were withdrawn from the trials after experiencing mild side effects (such as tingling of the hands and feet, headache and constipation) and approximately 40% of all participants did not complete the study for various reasons. In fact, the rate of withdrawal of patients on the highest dose for depression, anxiety and sleep disorders was sevenfold higher than in the placebo group. The highest dose combination was also associated with an increased heart rate of 1.5 bpm, which was not seen with the mid-dose combination, and slightly more disturbances in attention, amnesia and memory impairment. Owing to these reports, the FDA committee expressed concerns over the risk of psychiatric and cognitive dysfunction and cardiovascular issues, prompting the agency to finally vote against Qnexa in July 2010. However, in November 2010, the FDA issued a letter to Vivus asking them to provide data on any birth defects or cardiovascular adverse events that may be associated with Qnexa, suggesting that approval might be granted at a later time if they are able to provide satisfactory safety data.
Empatic is another combination that has already been evaluated in a few Phase II clinical trials and includes bupropion and the anticonvulsant zonisamide. Bupropion, a dopamine and norepinephrine-reuptake inhibitor approved for the treatment of depression and smoking cessation, was consistently related to significant weight reduction in obese patients with or without depression compared with placebo. As an antidepressant, bupropion has proved to be both clinically effective and well tolerated, without the potential for abuse associated with more efficacious stimulators of dopamine function. The underlying mechanism of zonisamide-induced bodyweight loss has not been fully characterized; however, it has been shown to have dopaminergic and serotoninergic activity and is likely to act through these systems.
In a pilot study of 18 obese women conducted over 12 weeks, subjects were treated with either zonisamide alone or a combination of zonisamide (100 mg rising to 400 mg over 4 weeks) and bupropion (100 mg rising to 200 mg after 2 weeks). Bodyweight loss was 2.9 kg (3.1%) in the zonisamide group compared with 7.2 kg (7.5%) in the combination-therapy group. Zonisamide alone was relatively poorly tolerated, with a 44% drop-out rate due to fatigue, speech difficulties, drowsiness, nausea and diarrhea, while the combination appeared to be better tolerated, with a 22% drop-out rate.
In a subsequent double-blind placebo-controlled Phase IIb trial over 24 weeks, two doses of zonisamide were administered alone (120 and 360 mg) and the same doses were combined with bupropion 360 mg together with additional placebo and buproprion monotherapy controls. Zonisamide 120 mg and 360 mg alone gave a 3.2 and 5.3% weight loss, while bupropion 360 mg gave a 2.3% weight loss and placebo a 1.4% weight loss. Empatic, containing 120 mg zonisamide, resulted in a 6.1% weight loss, while the 360 mg zonisamide administration gave a 7.5% weight loss. Overall, 60.4% of high-dose Empatic and 46.9% of lower-dose Empatic-treated subjects achieved more than 5% weight loss and the corresponding figures for more than 10% weight loss were 32.3 and 24.7%, respectively. The doses of zonisamide and bupropion tested here for weight-loss therapy were comparable to those used in other indications. Discontinuation rates were 34% for high-dose Empatic and 29% for placebo. The main adverse events were headache, drowsiness, insomnia and nausea, which conform to the typical side-effect profile of bupropion and zonisamide.
It should be noted that the bupropion prescribing information notes that severe hypertension has occasionally been observed in patients with and without pre-existing hypertension. High doses of bupropion (400–500 mg) caused a rise in supine blood pressure in cardiac patients but had no effect on pulse rate, while no changes in blood pressure or heart rate occurred at a lower dose of 300 mg/day. Although the cardiovascular side effects of bupropion appear to be mild, it cannot be recommended for patients with heart disease. In previous analyses, zonisamide has been associated with cognitive impairment, mood disorders and teratogenicity. These concerns need to be addressed in more detail in upcoming Phase III studies for Empatic before firm conclusions about its safety profile can be drawn.
Expectations were high for a third combination therapy, which was the first weight-loss drug in over a decade to gain FDA recommendation for approval. Contrave combines bupropion and naltrexone, a centrally active opioid receptor antagonist. Both agents stimulate the firing of anorexigenic POMC neurons. Naltrexone is hypothesized to block the opioid-mediated negative feedback that suppresses POMC firing. Several Phase III trials have been completed in diabetic and nondiabetic patients (Contrave Obesity Research [COR]-I, COR-II, COR-Intensive Behavior Modification [BMOD] and COR-Diabetes trials),[111–113] demonstrating that patients on Contrave had an average placebo-subtracted weight loss of 4.2%. Although these results did not meet the 5% or more weight loss criterion for approval, the total number of patients reaching 5% or more weight loss was promising (44.5% on treatment vs 18.9% on placebo).
A note of caution should also be expressed regarding the cardiovascular profile of Contrave, where the anticipated benefits of weight loss on cardiovascular function have not been observed to date but, indeed, a small increase in blood pressure and heart rate have been demonstrated when compared with placebo.
This uncertainty of the cardiovascular safety profile was also the main reason for the negative FDA expert vote on Contrave in February 2011. Before approval, the panel demanded a randomized double-blind placebo-controlled trial to investigate whether there is a risk of major adverse cardiovascular events in obese patients.
Expert Rev Endocrinol Metab. 2011;6(4):563-577. © 2011 Expert Reviews Ltd.
Cite this: Pharmacotherapy for Obesity - Medscape - Jul 01, 2011.