Published Online: January 21, 2014
Marj P. Zimmerman, BSPharm, MS, and Stanton R. Mehr
Obesity continues to be a growing health concern. The number of adults classified by the Centers for Disease Control and Prevention (CDC) as being overweight or obese, with a body mass index (BMI) of 25 kg/m2 or higher, is almost 155 million; those considered obese (BMI ≥30.0 kg/m2) number 79 million. If left unchecked, obesity-related healthcare costs could top $950 billion by 2030.1 Based on the number of people affected and the associated cost, stakeholders are taking steps to reduce this burden. However, challenges remain (see Highlight Box).
Until 2012, the US Food and Drug Administration (FDA) had not approved a drug to treat obesity since orlistat won approval 13 years ago.2 Safety concerns had limited the number of drugs available to treat obesity, and safety continues to remain a concern. Lorcaserin, marketed as Belviq by Arena Pharmaceuticals, and phentermine/topiramate extended release, marketed as Qsymia by Vivus Inc, were both approved in 2012 to treat obesity alongside a reduced-calorie diet and exercise.
Both drugs have FDA-approved labeling stating the drugs should be discontinued if 5% weight loss is not achieved after 12 weeks of therapy.3,4 The nonincretin medications that are currently in phase III development have mechanisms of action similar to antiobesity drugs that are currently available. Only 1 drug in phase II development has a mechanism of action that does not involve the central nervous system (CNS).
Drugs in Phase III Development
Bupropion/naltrexone. Currently, the only nonincretin product in phase III development in the United States is a combination of bupropion and naltrexone being developed by Orexigen. If approved, it will be marketed as Contrave. Both components of this centrally acting agent affect the pro-opiomelanocortin (POMC) neurons (Figure). So far, this agent has had a bumpy road to approval.
The FDA initially rejected Orexigen’s new drug application (NDA) in January 2011, indicating a concern about the product’s cardiovascular safety. The pivotal study cited in the initial filing was a phase III trial of 1496 patients who were enrolled for 56 weeks of treatment with bupropion/naltrexone or placebo. Fifty-four percent of patients in each treatment arm completed the study. Weight loss was significantly greater at 28 weeks in the bupropion/naltrexone group compared with the placebo group, and the same result was seen at 56 weeks (6.5% vs 1.9%, P <.001; 6.4% vs 1.2%, P <.001; respectively).5 More patients dropped out of the study due to adverse events in the treatment group than in the placebo group (241 vs 68 patients). Nausea, headache, and constipation were the most frequently reported adverse events. Serious adverse events were reported in 2.1% of the treatment group and 1.4% in the placebo group. A myocardial infarction was reported by a patient in the treatment group with active coronary artery disease, and 1 patient in the treatment group who did not have a history of seizures suffered one during the study.5
In its complete response letter, the FDA mandated in 2011 that Orexigen conduct a randomized, double-blind, placebo-controlled trial to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects does not adversely affect the drug’s benefit risk profile.6 To address these concerns, the Light Study was designed and approved by the FDA.
The study began in June 2012 and is expected to be completed in the second quarter of 2017. The FDA proposed that findings from the interim analysis report compiled by the Light Study’s independent data monitoring committee be the basis for the NDA resubmission filing. The primary outcome measure of the Light Study is the length of time to the first confirmed occurrence of a major cardiovascular event in a 4-year period.7 The secondary outcomes measures are also related to safety issues. On November 25, 2013, Orexigen announced that the interim results of the Light Study had been successful, and on December 11, 2013, it resubmitted its NDA filing with approval aimed for June 2014.8
In February 2013, Orexigen initiated another study, the Ignite Study, to assess the percent change in body weight during a 26-week time period. The secondary outcomes measures include both efficacy and safety measures.9 The company anticipates that the study will be completed in December 2014.
Cetilistat. A lipase inhibitor dubbed cetilistat, to be marketed as Cametor by Takeda, is in phase III trials in Japan. A 12-week study compared cetilistat with orlistat, both given 3 times daily, demonstrated similar weight reduction results compared with a placebo. With cetilistat treatment, weight reduction was 3.85 kg (P = .01) in those receiving an 80-mg dose and 4.32 kg (P = .0002 in the placebo comparison) in those receiving a 120-mg dose. The weight reduction was 3.78 kg (P = .008) in the 120-mg orlistat group. There were fewer discontinuations in the cetilistat group than in the orlistat group; the discontinuations due to adverse events in the cetilistat were similar to those patients receiving placebo.10 Norgine, a European company, is developing the product for approval by regulatory agencies outside of Japan and is currently seeking partnerships for such programs.11
Drugs in Phase II Development
Beloranib. A drug with a new mechanism of action for treating obesity is beloranib. The drug is a methionine aminopeptidase 2 (MetAP2) inhibitor that targets imbalances in fat metabolism that are present in patients with obesity.12 Specifically, it reduces the production of new fatty acid molecules by the liver and also helps to convert stored fats into useful energy. Results announced by Zafgen Inc on November 15, 2013, showed significant weight loss and improvements in cardiometabolic risk markers in 147 obese patients over a 12-week period. Study participants taking 0.6 mg, 1.2 mg, or 2.4 mg of the drug lost, on average, 5.5 kg, 6.9 kg, and 10.9 kg, respectively, compared with 0.4 kg for those on a placebo. No serious adverse events deemed related to the drug were reported.13
Bupropion SR/Zonisamide SR. Both components of a new combination drug that will be marketed as Empatic (bupropion SR 360 mg/zonisamide SR 360 mg) affect the CNS. It has shown favorable weight-loss effects. Bupropion increases dopamine levels, while zonisamide increases dopamine and serotonin neurotransmission.12 After 24 weeks of treatment, patients in the treatment group had a mean weight loss of 7.5% vs 1.4% in the placebo group (no P value given). The combination drug was also compared with its components. Greater mean weight loss was seen with the combination drug (7.5% for combination, 2.3% for bupropion, and 5.3% for zonisamide; P <.001). The most commonly reported adverse events were headache, insomnia, and nausea as would be expected with drugs affecting the CNS.14
RM-493. A melanocortin-4 receptor (MC4R) agonist, RM-493 modulates leptin-receptor signaling, resulting in decreased appetite; it has also been implicated as a common genetic variant in obesity is in early phase II trials.15,16 Results for weight loss in humans have been mixed.17,18 Adverse events observed have included nausea, diarrhea, and loose stools, and skin rash, but it was considered well tolerated overall.19 Potential unwanted adverse effects may be increased blood pressure and heart rate as well as penile erection, as MC4 agonists stimulate the sympathetic nervous system.15,16
Tesofensine. Tesofensine inhibits dopamine, norepinephrine, and serotonin uptake. Initial development of the drug was for Parkinson disease and Alzheimer disease; however, researchers discovered weight loss was associated with its use without changing blood pressure.20 In a trial of 203 patients, participantswere assigned to either restrict their diets or take tesofensine in doses of 0.25 mg, 0.5 mg, or 1 mg for 24 weeks. Those in the diet-restricted group lost 2% of their body weight, whereas those in the tesofensine groups lost a mean of 4.5%, 9.2%, and 10.6%, respectively, more body weight greater than did the control group (all P = .0001). Significant increases in diastolic or systolic blood pressure were not observed in the 0.25-mg and 0.5-mg groups, but an increased heart rate (7.4 beats/min) was seen in the 0.5-mg group (P = .0001). The most frequently observed adverse events were dry mouth, nausea, constipation, diarrhea, and insomnia.21
On the Horizon
There are only a few nonincretin drugs in the pipeline for the treatment of obesity. This is disappointing because of the enormous health and financial consequences of obesity. However, it appears that there is beginning to be a convergence of thinking about the importance of addressing obesity in the United States. The government and the AMA appear ready to accept the challenge of reducing obesity. As demand for drugs increases, pharmaceutical and biotechnology companies will undoubtedly respond with new therapeutic entities to treat overweight and obese patients.
It will be up to patients, employers, insurers, and health plans as to whether we proceed on a course to address the challenge.
HIGHLGHT BOX. Stakeholder Activity on Obesity Coverage
Federal Government. The federal Health Care and Education Reconciliation Act of 2010 included provisions relative to the treatment and insurance coverage of conditions related to obesity.
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