Tobacco use is now recognized as the single most responsible cause of avoidable death worldwide representing approximately 10% of all deaths globally. The burden of disease and negative economic impact of tobacco addiction on society is staggering. Smoking-related diseases account for ~$160 billion annually. Smokers who quit before the onset of tobacco-related illness can largely avoid the increased mortality risk. Nevertheless, ~80% of smokers attempting to quit will relapse within the first month of abstinence. Nicotine is the major psychoactive agent and principal reinforcing component in tobacco smoke, responsible for addiction. It is estimated that the annual market for smoking cessation agents is approximately $2.5 Billion.

Current therapies are ineffective and have notable health concerns

Development of efficacious smoking cessation aids is considered the most cost-effective intervention possible within a modern health-care system. Although clinically efficacious, current smoking cessation agents have limited utility. In smokers attempting to quit, ~23% treated with Chantix and ~16% treated with Zyban remain abstinent after 1 year, compared with ~9% of those treated with placebo. Pharmacotherapy is therefore an effective strategy to aid smoking cessation, but there is considerable risk of relapse even when treated with the most efficacious medications currently available. Chantix and Zyban must also now carry “black box” warnings on their labeling because of reported serious mental-health events associated with their use. This highlights the pressing need to develop safer and more effective therapeutics.

Orexin 1 Receptor and Tobacco addiction

Orexin-A (OXA) and orexin-B (OXB), also known as hypocretin-1 and hypocretin-2, are neuropeptides hypothesized to play a central role in the integration of metabolic, circadian and stress signals. OXA and OXB specifically activate the orexin-1 (OX1) and orexin-2 (OX2) receptors, which are family A G-protein coupled receptors (GPCRs). Selective blockade of OX1 has been shown to stop addiction to nicotine, psychomotor stimulants such as cocaine, opiates and alcohol, and also to prevent relapse to these drugs during abstinence.

EORA: Therapeutic for treatment of nicotine and other addiction

EORA compounds are highly specific orexin-1 receptor antagonists. It has been shown in the most relevant in vivo animals models to effectively block nicotine addiction AND cue-instated relapse. In contrast to therapeutics blocking upstream and abundant nicotine receptors, which can lead to many unwanted side effects, OX1 is a downstream receptor, localized in the hypothalamus and acts directly on the motivational properties of addiction. Just as effectively, it has also been shown to block cocaine addiction and cue-instated relapse. Preclinical studies have shown that EORA101 and backup compounds are orally bioavailable, brain penetrant, and non-toxic. We are currently at the stage of IND enabling studies, with anticipated IND submission for smoking cessation in mid 2015. A therapeutic that blocks dual orexin-1 and 2 pathways (Suvorexant, Merck) has been shown to be completely safe in large scale Phase III human trials for a different indication, demonstrating the safety of blocking the pathway and further reducing risk of our compound development. PCT for EORA101 and EORA class compounds were filed in February 2013 and assigned to Eolas Therapeutics. Immediate additional indications include: treatment of cocaine, opiate, and alcohol addictions.