We are working on what we believe to be the first non-systemic therapeutic application to treat disordered eating and obesity
Obesity is a complex disease with genetic and psychiatric components, and is associated with increased morbidity from related diseases and conditions such as cardiovascular disease, diabetes, and malignancy.
Binge Eating Disorder (BED) is considered distinct from obesity as a disease, however issues with overweight and obese body habitus, as well as obesity comorbid complications are common within the BED population.
The evolution of hedonic eating
Historically humans have sought food to survive, and sophisticated physiological mechanisms have evolved in order to regulate eating behavior and energy homeostasis. Our early ancestors were often faced with the dilemma of needing to seek out diverse foods to satisfy nutritional demands, while simultaneously fearing that unknown or new foods may be poisonous our toxic. The human sense of taste aided in this decision making: palate-fatigue signals when it’s time to move to a different food, while toxic or poisonous foods often taste bitter.
Over the course of human evolution our ancestors evolved larger brains. One hypothesis proposes that gastrointestinal tracts became smaller to compensate for metabolically demanding brains, which fits with the observation that herbivores typically have larger guts to more efficiently extract nutrients from lower quality plant-based diets. Muscle mass also decreased over the course of human evolution, while the ability to store energy (fat) increased, and increased cognitive abilities allowed for an increase in diet quality.
The demand for nutritionally dense foods led to the domestication of plants and animals, while the invention of fire allowed for cooking, creating a class of foods that are pre-digested. The diversity of meal choices decreased substantially with the move away from hunting and gathering, as did the need for determining which foods are edible, and which foods may be poisonous.
As food became more palatable, humans developed a desire to eat to obtain pleasure in the absence of an energy deficit.
This desire is known as hedonic eating
Reducing Palatability and Liking/Wanting in the Modern Environment
From an evolutionary standpoint, the eat more command in humans is dominant over the stop eating command. Historically during times of food scarcity, we have been able to endure long periods without food by burning fat stores and reducing energy expenditures. However, when energy-rich foods were present, our brains and bodies told us to consume large portions, which in turn led us to seek out more nutrient-rich foods and continue to consume large portions.
We detect the availability of nutrients through a number of internal and external sensors and controls. When nutrients are not readily available, we become highly sensitized to cognitive and hedonic mechanisms that enable us to find and eat food and create reward and pleasure. In the modern environment, highly palatable, energy-dense foods are readily available, we are less physically active, and we are continuously surrounded by food cues, which has led to substantial increases in food intake. Unfortunately, the factors impacting food intake and energy balance do not seem to have an upper limit, which has led to widespread obesity.
Can we change this?
Yes: through reduction in food palatability and corresponding decreases in liking/wanting.
Targeting hedonic eating
Accumulation of excess body fat results when energy intake exceeds that expended. Energy balance is controlled by hypothalamic responses, but these can be overridden by hedonic hunger/reward brain systems.
Published data from a retrospective, 12 week non-controlled study suggests a correlation between greater weight losses and reductions in hedonic hunger.
Palatability of food and hedonic attraction have also been shown to play important roles in the Loss of Control (LOC), which leads to uncontrollable eating in Binge Eating Disorder.
BED patients with high sweet preference have twice as many binge episodes compared to patients with lower preference for sweet taste.
Our aim is to impact the palatability of food, thereby creating direct negative feedback to reduce hedonic eating.
There are no one size fits all interventions for managing eating patterns and obesity
We are developing a highly differentiated, novel therapeutic to treat eating disorders and obesity through the modification of taste, as an alternative to current approved drug and surgical options.
Current treatment options for obesity
A selective serotonin 5-HT2C receptor agonist, lorcaserin may cause an anorectic effect via activation of proopiomelanocortin neurons in the hypothalamus, and was first approved to treat obesity in 2012. Typical side effects include nausea, headaches, fatigue, and dizziness. Since Lorcaserin agonizes the 5-HTC receptor, patients should be monitored for serotonin syndrome serious adverse effects.
Bupropion was first approved in 1989 for the treatment of depression and is a norepinephrine-dopamine reuptake inhibitor. Naltrexone is a mu-opioid antagonist, first approved in 2010 for the treatment of opioid addiction. Although the mechanism for each individual medication is known, their combined mechanism for treating obesity is not understood. Bupropion is contraindicated in patients with a history of seizure disorder or anorexia, while the naltrexone component precludes use in patients receiving opiate medication. Common side effects include nausea, headaches, and constipation, while seizures have been reported with no prior history.
Phentermine was first introduced in 1959 as a weight loss drug, and is a sympathomimetic amine anorectic. Topiramate has been used since 1996 as an antiepileptic drug. The appetite suppression mechanism of phentermine is theorized to be achieved through increased hypothalamic norepinephrine release and raising serum levels of leptin, while topiramate may decrease calorie intake through promoting early satiety, or decreases in gluconeogenesis. There are reported neurological side effects of cognitive slowing and paresthesias with topiramate, while more seriously, oligohydrosis, glaucoma, and acidosis may occur. Phentermine adverse effects include tachycardia, palpitations, insomnia, anxiety, and elevated blood pressure.
A long-acting glucagon-like peptide-1 receptor agonist, liraglutide was first approved in 2010 as a once daily 1.8 mg subcutaneous injection for the treatment of type 2 diabetes mellitus, while the once daily 3.0 mg subcutaneous injection was approved in 2014 for the treatment of obesity. 40% of participants in the pivotal studies for obesity experienced nausea, while 15% experienced vomiting, and 21% experienced diarrhea. Cases of pancreatitis have also been reported in patients receiving liraglutide.
A lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats, Orlistat is sold over the counter at a dose of 120 mg three times a day. In clinical studies, 91% of study subjects experienced at least one GI-related side effect during the first year of treatment, including steatorrhea, (oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine), fecal incontinence and frequent or urgent bowel movements.
Although the mortality rates are low, probably due to the standardization of bariatric surgical care, the complications after bariatric surgery can be deadly and must be treated promptly by surgeons familiar with these problems. Long-term complications may be baffling to those unfamiliar with bariatric surgery: neuropathies due to nutritional deficiencies, internal hernias, anastomotic stenoses, and emotional disorders. Another sometimes baffling complication is hypoglycemia, a condition that may appear as long as 14 yr after the surgery.
Current treatment options for eating disorders
Binge eating disorder drugs
A CNS stimulant and dextroamphetamine prodrug, lisdexamfetamine dimesylate was first approved in 2007 for pediatric and adult attention-deficit/hyperactivity disorder, and is a Schedule II controlled substance in the US. Contraindicated for MOA inhibitors and other amphetamine products, side effects include serious CV reactions, BP and HR increase, psychiatric adverse reactions, suppression of growth and peripheral vasculopathy.
Bulimia nervosa drugs
A selective serotonin reuptake inhibitor approved for acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa.
Other eating disorders
There are currently no drugs approved to treat anorexia nervosa, avoidant/restrictive food intake disorder, pica, rumination disorder, or OSFED*.
*The Diagnostic and Statistical Manual of Mental Disorders (DSM–5) defined other specified feeding or eating disorder, or OSFED, as feeding disorders and eating disorders of clinical severity that do not meet diagnostic criteria for anorexia nervosa, bulimia nervosa, binge eating disorder, avoidant/restrictive food intake disorder, pica, or rumination disorder. OSFED includes five examples: atypical anorexia nervosa, bulimia nervosa (of low frequency and/or limited duration), binge eating disorder of low frequency and/or limited duration, purging disorder, and night eating syndrome.