Drug Development for Eating Disorders and Obesity - Weighing Up the Difference
Eating disorders are serious mental illnesses characterized by excessive preoccupation with body weight, leading to abnormal eating habits. In women, lifetime prevalence of anorexia nervosa is estimated to be 1–4%, bulimia nervosa 1–3%, and binge eating disorder 1–4%. Among men, 0.1–0.5% report eating disorders.  By comparison, lifetime prevalence for depression ranges from 1.5%–19% across different countries.  Despite lower prevalence, eating disorders have the highest mortality rate of any psychiatric disorder, with anorexia nervosa having the highest mortality rate of all. Yet as a group of illnesses they are some of the most inadequately understood and difficult to treat due to their complex multifactorial nature. Eating disorders are on the rise, and has been estimated to cost the UK alone £15 billion per year. 
Patients with anorexia nervosa have an intense fear of gaining weight, even if they are dangerously underweight. There is currently no medication specifically approved for the disease and almost half of patients don’t fully recover. The key aim of treatment is weight restoration, however medication is currently only prescribed to tackle underlying psychological problems. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs), or olanzapine, an antipsychotic may be used but they are not effective in weight gain or preventing relapse. 
With no drug currently available, it is especially striking that there is also currently no confirmed development for this specific indication by any pharmaceutical company. (Table 1) Previous candidates included a corticotropin releasing factor 2 receptor antagonist, an antipsychotic, and synthetic human ghrelin, the latter reaching the highest status of Phase III before being discontinued by Daiichi Sankyo. As a “hunger hormone” that is naturally released to stimulate food intake, the ghrelin pathway has also been targeted in the related areas of anorexia (lack of appetite) and cachexia (the wasting of the body associated with illness). Anamorelin hydrochloride is one such ghrelin agonist that works by both stimulating appetite and the release of growth hormone. It is at pre-registration for treatment of anorexia and cachexia in cancer patients, symptoms which are also found in patients with anorexia nervosa. 
Although not specifically indicated for anorexia nervosa, IGC-504 and IGC-506 are preclinical cannabis-based drug candidates being developed by IGC for eating disorders, including cachexia. It is interesting to note that a cannabinoid drug by Cannabics Pharmaceuticals has already reached Phase III trials for cancer-related anorexia and cachexia. As with ghrelin, it appears that drugs that are being used to improve appetite and weight gain in other disease areas, have, or are being considered for eating disorders. The deadliest aspect of anorexia nervosa stems from loss of body mass, so it appears a logical step to look towards a metabolic treatment, taking insights from anorexia and cachexia research rather relying on a purely psychological intervention to encourage weight gain. However, there is a lack of real success stories to give credibility to these approaches, and therefore a direction in the landscape is far from apparent. Even within the scientific community the etiology of anorexia nervosa is still being hotly debated, with various models being posited from the possibility that it is a type of starvation addiction, to differences in gut microbiota.  Without consensus, there remains a significant development challenge faced by pharma companies, and therefore further research is needed to illuminate this complex disease before a healthier looking drug pipeline can be expected.
Bulimia nervosa and binge eating disorder
Bulimia nervosa and binge eating disorder are both characterised by uncontrollable consumption of abnormally large amounts of food (binge eating episodes) at their core. The key differentiator between the two is that bulimia nervosa is followed by deliberate purging to avoid weight gain. Patients may therefore be of normal weight, but over time, the binge-purge cycle can lead to heart problems and gastric intestinal ulcers and inflammation. 
The only drug launched for bulimia nervosa is the antidepressant fluoxetine (Prozac). Like the use of antidepressants with anorexia nervosa, it is prescribed to tackle comorbid mental illness that is associated with the binge-purge cycles. However, efficacy is low: for every 9–10 patients treated with Prozac, remission is seen in only one patient.  Meanwhile, lisdexamfetamine dimesylate (Vyvanse) is the only available drug for binge eating disorder. (Table 2) It is a stimulant that was initially approved for treating ADHD before being harnessed for its ability to suppress appetite. The aim of treatment is to reduce the frequency of the bingeing episodes rather than to lose weight directly, although obesity is often comorbid. 
In the current drug development pipeline, it seems that Sunovion Pharmaceuticals is following in Vyvanse’s footsteps by taking dasotraline, their norepinephrine, dopamine and 5-HT reuptake inhibitor currently filed for ADHD, into Phase III trials for binge eating disorder. [Table 1] Although dasotraline is also not directly intended for weight loss, other triple reuptake inhibitors such as Saniona’s tesofensine have capitalized on this effect for tackling obesity.
Naloxone nasal spray at Phase II by Opiant Pharmaceuticals is an opioid receptor antagonist that aims to treat the compulsive bingeing habit common to both binge eating disorder and bulimia nervosa. (Table 1) Naloxone has already been approved for treating opioid overdose and recent studies have found a common neurobiological basis to addiction, substance use and compulsive bingeing through their release of opioid-like peptides or endorphins in the brain. The drug of choice here being, of course, food.  Dampening down the pleasurable response associated with food in the brain is a mechanism that has already been successfully utilised by anti-obesity opioid receptor antagonists such as Contrave.
On reviewing the preclinical pipeline, there is further evidence that pharmaceutical companies are placing their bets on this addiction theory. There are two orexin 1 receptor antagonists, a target which has also been implicated in compulsive eating and substance use disorders and a selective inhibitor of cyclic nucleotide phosphodiesterase type 7 which is being developed in parallel for cocaine and nicotine addiction. 
Awareness of eating disorders has entered the public consciousness, but historically development in this area has been sparse, with other weight-related conditions such as obesity receiving much more R+D attention. On review of the current pipeline, it appears that not much has changed in this respect. There are only a handful of drugs in later stage development for eating disorders, as it has proved tricky to untangle the psychological and metabolic aspects of these multifactorial conditions.
A cross comparison between drugs in development for the various eating disorders shows that a psychological approach to treatment through the modification of neurotransmitters, is favoured. Anorexia nervosa appears to be a particularly challenging illness to develop for, however recently there has been interest in targeting the metabolic aspect of the condition, looking to mechanisms under investigation for cancer-related anorexia and cachexia. Although too small a data point to extrapolate from, this could be a hint as to the direction that future research will continue to take. There has been a paradigm shift for bulimia nervosa and binge eating disorder, fuelled by conceptualisation of the bingeing behaviour (also found in obesity) as an addiction disorder, leading to a wave of interest in anti-addiction drugs. However there remains a significant lack of drug candidates in the pipeline. With current treatments often ineffective and eating disorders only projected to increase , this review underscores the critical need for additional research in this area.