Target Indication: Obesity, Alzheimer’s Disease and Cognitive Impairment Associated with Schizophrenia
Obesity refers to the excessive accumulation of fat in the body to the point that health is adversely affected. Obesity has been strongly linked to an increased risk of diabetes (type 2), hypertension, coronary artery disease, cancer, and stroke; as a result, obesity is associated with increases in all-cause mortality. According to the World Health Organization, over 300 million adults worldwide are obese, and in the United States, obesity is estimated to affect nearly 60 million Americans, according to the American Obesity Association.*
Although modification of diet and exercise is the cornerstone of obesity treatment, drug therapy that can safely enhance satiety (i.e., feeling "full" with eating) and subsequently reduce the risk for other disorders in obese patients could bring significant clinical benefit.
PRX-07034 is a novel, highly selective, small-molecule antagonist of a specific G-protein coupled receptor (GPCR) known as 5-HT6 being developed for the treatment of obesity, Alzheimer's disease and cognitive impairment associated with schizophrenia.
In April 2007, EPIX announced the results of a Phase 1b multiple ascending dose clinical trial of PRX-07034. The randomized, double-blind, placebo-controlled Phase 1b, multiple ascending dose clinical trial was designed to study the safety, tolerability, pharmacokinetics, and pharmacodynamics of PRX-07034 administered orally once-daily for 28 days in a population of obese, but otherwise healthy, adults (average weight 100kg or 220 pounds). The results indicated that PRX-07034 was well tolerated up to 600 mg once per day and demonstrated predictable pharmacokinetics with dose proportional increases in exposures, and a half-life supporting once-daily administration. In addition, the overall results on cognitive function showed a dose-dependent trend for improvement associated with PRX-07034; for the predetermined endpoint that combines speed and accuracy, there was a dose-dependent effect which was statistically significant (p=0.014 vs. placebo) at the 600 mg dose. The trial included measures to assess potential effects on obesity as well; results indicated that a greater proportion of subjects on drug experienced weight loss during the one month period than subjects on placebo, suggesting pharmacologic activity for obesity.
PRX-07034 has also been shown to enhance cognitive function in preclinical animal models of memory impairment through a dual mechanism of action. PRX-07034 has an effect on both the acetylcholine and glutamate neurotransmitter systems in the brain, which makes PRX-07034 a potentially complementary therapy to cholinesterase inhibitors, a class of drugs approved for the treatment of Alzheimer's disease. Based on encouraging data from preclinical studies, PRX-07034 is expected to have beneficial effects when administered in combination with cognitive-enhancing therapies. Indications are that the human 5-HT6 receptor is found mainly in the central nervous system with little or no expression in peripheral tissues, which may result in greater drug selectivity with fewer side effects.
*Source: World Health Organization 2006 Statistics; American Obesity Association 2005 Statistics
