Overview Document PDF (requires pdf reader)
Obesity is a substantial contributing factor to a range of diseases that represent the major causes of death and disability in the developed world today. Individuals that are clinically obese have elevated rates of cardiovascular disease, stroke, diabetes, and certain types of cancer. The percentage of individuals who are defined as clinically obese has risen dramatically over the past several decades. According to the United States Centers for Disease Control and Prevention, or CDC, the incidence of obesity in the United States has increased at an epidemic rate during the past 20 years. A recent analysis conducted by the CDC (see here) now estimates that 35.7% of adults in the United States are clinically obese, and almost 17% of children. Approximately two-thirds of the population is considered either overweight or obese, and by 2030, it is projected that 42% of the population will be clinically obese. Rates of diabetes have grown significantly as a result. There has been a similar dramatic rise in the rate of obesity in Europe and Asia. Furthermore, the cost of this epidemic is significant. According to the CDC, in 2008 medical costs associated with obesity were estimated at $147 billion. Despite the magnitude of this problem, current approaches to clinical obesity are largely ineffective, and there are relatively few new therapeutic approaches in clinical development.
We are developing compounds designed to treat obesity that act by stimulating a key receptor in the brain that regulates appetite and food intake – the 5HT2c receptor. The role of this receptor in regulating food intake is well understood, and has been extensively studied in both animal models and humans. In 1996, Wyeth Pharmaceuticals launched the anti-obesity drug Redux® (dexfenfluramine), a non-specific serotonin receptor agonist that was used with the stimulant phentermine in a combination commonly known as “fen-phen.” This diet drug combination gained rapid and widespread acceptance in the clinical marketplace, and was shown to be highly effective at regulating appetite, reducing food intake, and causing weight loss. Unfortunately, in addition to stimulating the 5HT2c receptor, fen-phen also stimulated the 5HT2b receptor that is found in the heart. The activation of 5HT2b by fen-phen is believed to have caused significant cardiovascular problems in a number of patients and, as a result, Redux was withdrawn from the market in 1997. In 1996, doctors wrote 18 million monthly prescriptions for drugs constituting the fen/phen combination. In that same year, these drugs generated sales of greater than $400 million, serving as a benchmark for the substantial market opportunity for an effective drug to treat clinical obesity.
Since the withdrawal of Redux from the market, several groups have published research that implicates stimulation of the 5HT2b receptor as the underlying cause of the cardiovascular problems. These findings suggest that highly selective compounds that stimulate the 5HT2c receptor, but that do not appreciably stimulate the 5HT2b receptor, could be developed that maintain the desired appetite suppressive effects without the cardiovascular toxicity. Other approaches to treating obesity are also being explored by various groups.
We initiated a drug development program focused on creating potent and selective compounds that stimulate the 5HT2c receptor, but that avoid the 5HT2b receptor and other receptors, such as 5HT2a. Our specific goal is to develop a once-per-day orally administered pill that reduces appetite by stimulating the 5HT2c receptor, but that does not stimulate the 5HT2b receptor, the 5HT2a receptor, or other receptors that could cause adverse side effects. We have developed a portfolio of compounds that are designed to stimulate the 5HT2c receptor with best-in-class potency and specificity. We have evaluated a number of these compounds in preclinical obesity models, where they have demonstrated significant reductions in food intake. Although these compounds are at earlier stages of preclinical development, we believe they represent promising opportunities for future development. We continue to develop this portfolio of compounds while we also evaluate potential partnering opportunities for the program.
As the data below illustrate, we have successfully developed compounds that show dramatically better compound selectivity than other 5HT2c agonists. Importantly, we have demonstrated that we can achieve this profile across multiple distinct compound backbones (or chemical families), which provides development flexibility. As noted above, compound selectivity is critical to safety and tolerability. When evaluated in weight loss studies, these compounds exhibit superior weight loss to other agents.
Shown below is a comparison of one of our potent and selective 5HT2c agonists (ATH-91385) relative to other agents that have been shown to induce significant weight loss in preclinical diet induced obesity (DIO) models. As a monotherapy, ATH-91385 exhibits comparable weight loss to the combination Topiramate + Phentermine. However, when ATH-91385 is combined with Phentermine, dramatically better weight loss is achieved. Furthermore, when ATH-91385 is combined with both Phentermine and Topiramate, even better weight loss is achieved (~twice as good as Phentermine + Topiramate).
We believe that this program exhibits best in class potential. The company plans to continue to advance the program toward the clinic as we explore partnership opportunities.