In July 2009, the FDA slapped varenicline (Chantix), a partial agonist α4/β2 NNR smoking cessation drug, and bupropion (Zyban), a competing drug, with a black box warning. Both had been banned for use by pilots and air traffic controllers the previous year because, out of 6 million plus prescriptions written, a few hundred people had suicidal thoughts and some acted upon them. The FDA noted that while people with underlying psychiatric conditions should not take these drugs, not all people who experienced symptoms had a psychiatric history. On the other hand, nicotine withdrawal can precipitate depression.“Existing NNR drugs are not very selective compounds,” commented Daniel Timmermann, Ph.D., Vice President, Director of CNS Pharmacology, NeuroSearch. “What we are trying to do at NeuroSearch is to create very selective compounds.” NeuroSearch and Abbott's two NNR compounds for ADHD in phase 2 and for cognitive function in phase 1 stemmed from a 5 year collaboration between the two companies, with Abbott responsible for the clinical development under a license agreement.NeuroSearch/Abbott's ADHD compound is a full agonist of α4/β2. “At a very basic level, you can say that what we believe to be the mechanism of action of NNR modulation in ADHD is partly based on the ability of the NNR agonist to enhance dopaminergic and noradrenergic transmissions in the basal forebrain,” said Timmermann.According to Timmermann, neurotransmission based on these transmitter systems is aberrant in the basal forebrain in ADHD patients. By enhancing these neurotransmitters, NNR selective compounds can correct the imbalance as well as augment cognitive function. “There is a host of clinical studies deriving from many years back that uniformly show agents capable of activating nicotinic receptors, namely the α4/β2 subtype, are good for enhancing attention,” said Timmermann.Targacept's ADHD AZD-3480 drug has a mechanism of action comparable to ABT-894, noted Timmermann. NeuroSearch's NNR compound ABT-560 also targets α4/β2 receptors. The company's earlier stage NNR drug candidates target α7, the second most common type of NNR receptor found in the mammalian brain, which is also associated with cognitive function.While patients have been dosed in clinical studies lasting several weeks or months, the effects of long-term use remain unknown. “This has been a conundrum in nicotinic receptor research for many years: how can you activate these receptors permanently with agonists when you know from various cell-based systems that these receptors are prone to become desensitized upon prolonged exposure to agonists,” Timmermann said. “To tell you the truth, there is really not a uniform solution to that problem. However, it does appear to be dose dependent. There has really been a highly competitive race in last 5 years to see who would reach the clinic first with some of these compounds.”
