Merck’s food intake model aids high-throughput screening of anti-obesity drugs.
According to recent epidemiological surveys conducted in the United States, 17% of children aged 2 to 19 years and 32% of adults over the age of 20 are obese (Ogden et al. JAMA. 2006 Apr 5; 295(13):1549-55). Over the next few decades, life expectancy for the average American could decline by as much as five years unless aggressive efforts are made to slow escalating obesity rates. Cardiovascular disease, diabetes, musculoskeletal disorders, and cancer are just some of the many serious health consequences that can arise as body mass index increases (Li et al. Surg Clin North Am. 2005 Aug; 85(4):681-701, v; Pender JR and Pories WJ. Gastroenterol Clin North Am. 2005 Mar; 34(1):1-7). Accordingly, there is an urgent need to develop safe and effective anti-obesity therapies.
 click to enlarge In each treatment period, subjects were sequestered the evening prior to dosing to standardize the evening meal (consumed completely) as well as the length of the fast. Thirty minutes following administration of the study drug, subjects completely consumed a modest calorie (~200 kcal) fixed breakfast, followed by ad lib test meals at lunch (4 hours), dinner (10 hours, evening snack (14 hours) and breakfast (24 hours). |
The efficacy of commercial weight loss programs is modest, and pharmacologic treatment options remain limited despite great unmet medical need. There are several impediments to the discovery and development of innovative treatments for obesity. The first is the complex, multifactorial nature of the disease. The second is the increasing cost and duration of the drug development process.
To address the second barrier, standardized methodologies are needed to test the effectiveness of possible anti-obesity compounds quickly, robustly, and safely, in the early stages of drug development. The Experimental Medicine department at Merck Research Labs (Minneapolis, Minn.), has been using an ad-libitum food intake model to assess the pharmacologic activity of novel anti-obesity compounds before large-scale clinical trials are initiated. By measuring food intake under highly-controlled conditions, researchers can screen anti-obesity compounds for efficacy in obese subjects after single doses.
Merck scientists have found that the acute reduction of food intake in this experimental medicine model generally predicts weight loss in a 12-week weight loss trial, allowing earlier go/no-go decisions for anti-obesity compounds, without compromising the ability to detect and respond to potential safety signals. This article discusses the role of experimental medicine in drug development and the application of the ad-libitum food intake model for assessing drug-related acute anorexic effects and evaluating dose-response differences in obese subjects.
Role of experimental medicine
As in other complex diseases, developing new treatments for obesity is a long, painstaking process. Although the vast majority of novel agents entering Phase 1 clinical trials have a low probability of success, most drug development decisions are not made until Phase 2 or later, after a great deal of time and resources have been invested. This makes the development of drugs with new mechanisms commercially risky and inefficient.
Merck’s Experimental Medicine department—one of three integrated biomarker departments recently established to increase probability of success—designs innovative, short-term clinical trials in small groups of human subjects to gain a preliminary assessment of pharmacological activity, efficacy, and safety of compounds. These trials involve a collaborative effort among researchers working in various disciplines, including clinical pharmacology, molecular profiling, and imaging, to assess a drug’s effectiveness in engaging its biological target, the extent of the intended biological effect, and various other measures. By providing early evidence of potential benefit or lack of benefit, experimental medicine helps to identify the most promising candidates and eliminate failures more quickly and cost-efficiently. This enables better decision-making earlier in the drug development pathway and allows resources to be invested in more novel compounds.
At Merck, the use of experimental medicine to guide early decision-making played an important role in the development of Januvia, a first-in-class dipeptidyl peptidase (DPP)-IV inhibitor for type 2 diabetes, approved by the US Food and Drug Administration in 2006. Merck measured DPP-IV activity, augmentation of incretin hormones, and reduction of glucose excursion with single doses of Januvia after an oral glucose tolerance test. Early results verified the mechanism of action of Januvia, established the optimum dosing and facilitated a development approach that reduced total development time while maintaining high standards of scientific excellence and attention to patient safety.
 click to enlarge Figure 1. Meals are carefully weighed before and after consumption. |
The discipline of Experimental Medicine at Merck also has helped to eliminate compounds with a low probability of success more efficiently. For example, studies revealed that a particular Merck diabetes compound inadequately engaged its target at the highest tolerated dose, facilitating an early no-go decision for the compound.
Anti-obesity agents
Obesity research at Merck has also benefited from this experimental medicine approach. In particular, Merck used a strategy that rapidly measures the effectiveness of anorexic agents to allow for earlier decisions in moving toward the clinic. Starting with compounds that show robust and acute food intake effects in animal studies, researchers quickly screened promising agents through a modified ad-libitum or “free choice” food intake model (originally developed by Hill and Blundell) before initiating large-scale clinical trials.
The ad-libitum paradigm assesses food consumption, drug-related acute anorexic effects, and dose-response differences in obese subjects. Individuals taking an anti-obesity drug or a placebo are offered a selection of foods in substantial caloric excess to what they could normally consume in a sequestered setting, free from social and time cues, and they are instructed to eat as much or as little as they like (Figure 1). Meals are carefully weighed before and after consumption and weight is converted to total and macronutrient calories (Figure 2).
We have determined that a sample size of approximately 32 to 36 subjects can give such an ad-libitum food intake study an 80% power to detect a 10% reduction in food intake. In addition, it has been estimated that a mean 10% reduction in food intake is required to see a weight loss of roughly three kilograms after 12 weeks.
This study design was used to confirm the mechanism of action of an investigational inverse agonist of the cannabinoid 1 receptor (CB1R), which has been implicated in promoting appetite and food intake. Based on an ad-libitum food intake study, researchers determined that the CB1R inverse agonist may intercept pathways that effect the moderation of food intake.
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Figure 2. Weight is converted to total and macronutrient calories. |
The ad-libitum food intake model was also used to test a selective agonist of melanocortin 4 receptor (MC4R). Previous research has shown that MC4R agonists may influence weight loss by reducing food consumption and increasing energy expenditure. The receptor is believed to play an integral role in the regulation of food intake and body weight through a pathway involving the hormone leptin. Furthermore, studies in humans have revealed that individuals with mutations in MC4R are obese, exhibit binge-eating, and have hyperinsulinemia (excessive insulin levels in the blood).
The investigational selective MC4R agonist had been shown to reduce food intake and body weight in animal studies. To assess its effects in human subjects, Merck compared the compound to the established appetite suppressant sibutramine using the ad-libitum food intake model. In experiments, decreases in food intake with sibutramine 30mg, the positive control, were significant. However, only small, non-significant changes in 24-hour food intake were observed with the investigational MC4R agonist compared with placebo. Therefore, researchers concluded that at the doses tested, the investigational compound promotes only marginal anorexic activity. Development of this agent was discontinued when the lack of efficacy observed in this model was supported by later-stage studies.
The results of this and other studies indicate that an ad-libitum food intake model may be useful for assessing the anorexic activity of novel anti-obesity compounds after acute administration. The model can be used to identify promising anti-obesity agents and to quickly rule out agents that may appear promising in preclinical studies but are unlikely to be effective in humans.
Moving forward
There is a great need for novel approaches to anti-obesity research and drug development. The systematic application of experimental medicine early in drug development could provide the power to interrogate as many new drug mechanisms as possible while keeping costs constant, since the savings associated with early decision-making can be invested in more novel compounds. This will ultimately increase the probability of delivering innovative and effective products to patients, including novel anti-obesity agents.
About the Author
Gary Herman joined Merck’s Department of Clinical Pharmacology in 2001 and was named head of Experimental Medicine in 2006. He has been primarily involved in the early development of diabetes and obesity compounds. Herman received his MD from Harvard Medical School.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 11, November, 2007, pp. 24-28.
Gary Herman joined Merck’s Department of Clinical Pharmacology in 2001 and was named head of Experimental Medicine in 2006. He has been primarily involved in the early development of diabetes and obesity compounds. Herman received his MD from Harvard Medical School.
Filed Under: Drug Discovery
