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Experimental AD Drugs Target Nicotinic Receptors

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Experimental AD Drugs Target Nicotinic Receptors 64 Neuropsychiatric Medicine C LINICAL P SYCHIATRY N EWS • May 2006 Experimental AD Drugs Target Nicotinic Receptors BY MICHELE G. SULLIVAN Ph.D., the company’s vice president of Mid-Atlantic Bureau neuroscience research. ABT-089 had pro- ceeded to phase II trials in adults with at- new class of drugs under develop- tention-deficit hyperactivity disorder, but ment for Alzheimer’s disease has is now back in the preclinical stage for ad- Ataken a cue from one of the world’s ditional toxicologic studies. The drug also oldest drugs—nicotine. has potential as an Alzheimer’s therapy, The highly selective nicotinic receptor Dr. Sullivan said. agonists (NRAs) have the potential to Although there are no published data on mimic, and surpass, the cognition-en- neuroprotective effects of any of the hancing effects of nicotine without its NRAs in development, studies suggest cardiovascular or addictive side effects. that nicotine blocks the aggregation of Tantalizing evidence suggests that the en- amyloid β on neurons. If NRAs work the gineered molecules could provide a ther- same way, they might reduce or prevent apeutic one-two punch for Alzheimer’s neuronal plaque buildup. patients: immediate cognitive improve- But a study released last year conclud- ment and protection against the amyloid ed that the compounds could actually β plaques and neurofibrillatory tangling worsen the other major component of ADLUBOWSKI that are the disease’s hallmarks. K Alzheimer’s pathology: neurofibrillatory Brains of patients with Alzheimer’s dis- AVID tangling. ease (AD) show another distinct charac- ©D Frank LaFerla, Ph.D., and colleagues teristic: a significant loss of cholinergic Dr. Marwan Sabbagh says nicotinic acetylcholine receptor agonists must boost the administered daily nicotine to mice ge- neurons and acetylcholine receptors, in ad- activity of high-affinity receptors in the brain but not nicotinic receptors elsewhere. netically engineered to develop amyloid β dition to the hallmark plaques and tangles, plaques and neurofibrillatory tangling. Af- said Dr. Marwan Sabbagh, a neurologist A selective nAChR agonist could im- mild cognitive impairment, with a total ter 5 months, their brains showed signifi- and director of the Sun Health Research prove cholinergic function in a couple of 107 patients. According to the company cant accumulation of tau in pyramidal Institute’s Cleo Roberts Center for Clini- ways, Dr. Sabbagh said. The surviving re- Web site, the drug had positive effects on neurons—a preliminary event in tangle cal Research in Sun City, Ariz. “Initially, it ceptors would become more sensitive to cognition. formation—and significant increases in was thought that muscarinic receptors any available acetylcholine. And since Last month, Targacept completed a sec- phosphorylated tau, a protein found in the were selectively affected in Alzheimer’s, nAChRs help modulate the flow of other ond trial in 193 cognitively impaired old- tangles (PNAS 2005;102:3046-51). but now we think that’s not so,” he ex- neurotransmitters, boosting their func- er adults, but company representatives de- “That doesn’t mean that there isn’t a plained. “It seems that the nicotinic re- tion could improve levels of dopamine, clined to comment for this article, saying place for NRAs,” said Dr. LaFerla, codi- ceptors are the ones that go.” norepinephrine, and γ-amino butyric acid they were constrained by the quiet period rector of the Institute for Brain Aging Nicotinic acetylcholine receptors as well. surrounding their initial public stock of- and Dementia at the University of Cali- (nAChRs) are activated by acetylcholine, But since nAChRs are distributed fering in January. fornia, Irvine. “Nicotine is a pretty dirty but they also react to nicotine and struc- throughout many tissues, a compound Memory Pharmaceuticals Corp. of drug and probably has other effects than turally similar molecules. Two types of that attaches nonselectively could be Montvale, N.J., recently announced posi- just binding to the receptor. If you could nAChRs, the α7 and the α4-β2, are rich- loaded with adverse effects. “The chal- tive findings from its phase I trial of MEM come up with a more selective compound, ly distributed in areas of the brain tar- lenge is to develop a selective agonist that 3454 in 48 healthy young subjects. Cogni- you might still see a beneficial effect.” geted by Alzheimer’s. Other types of enhances the activity of the high-affinity tive performance, a secondary end point An Alzheimer’s drug that would provide nAChRs occur in skeletal muscle and gut receptors in the brain, but not the nicotinic of this safety trial, significantly improved quick cognitive benefits and progressive tissue. receptors that occur in the muscles, the in those taking 15 mg daily, said David A. disease modification would have enor- Postmortem studies have shown that gastrointestinal tract, or anywhere else.” Lowe, Ph.D., the company’s chief scien- mous impact, according to Dr. Peter up to 50% of nAChRs are lost in Drug companies are hot on the trail of tific officer. Whitehouse. But disappointment over Alzheimer’s brains. This is apparently re- such compounds. At least three agonists The trial lasted 14 days and tested three past efforts to enhance the cholinergic lated to the buildup of amyloid β plaques, that target receptors involved in cognitive doses (15 mg, 50 mg, and 150 mg). Only system, including today’s cholinesterase which seem to preferentially attach to impairment are in preclinical or clinical the 15-mg dose showed a statistically sig- inhibitors, has provoked concern about the α7 nAChRs, the type most highly ex- trials right now. These three are described nificant effect on cognition. “One partic- this new pharmacotherapy. pressed in the hippocampus and frontal in the following paragraphs. ularly interesting observation was that the “Maybe if the cholinesterase inhibitors cortex, Dr. Sabbagh said in an interview. Targacept Inc. of Winston-Salem, N.C., effect on day 13 was stronger than it was had worked better, we’d be seeing a dif- “High affinity α4-β2 receptors are prefer- a spinoff company of tobacco giant R.J. on day 2,” Dr. Lowe said in an interview. ferent climate for NRAs,” said Dr. White- entially lost in AD but the α7 receptor is Reynolds, is farthest along the develop- “This shows that the effect is sustained.” house, professor of neurology at Case expressed in plaques. This suggests that mental pipeline with its candidate, TC- The company will proceed with a phase Western Reserve University, Cleveland. the biological interaction between the 1734. In 2004, the company completed IIa trial later this year. “It will be a challenge to find drugs with nicotinic receptors and AD pathology is two phase II safety trials of the drug for Abbott Laboratories has a number of an effect size much larger than current complex,” he said. age-associated memory impairment and NRAs in the works, said James Sullivan, cholinesterase inhibitors.” ■ Eleven Deaths Reported in Donepezil Vascular Dementia Trial leven of 648 patients died only for the treatment of mild to vious VaD studies (1.7%) and was donepezil-treated group and the than 5%, and twice the rate of Ewhile taking donepezil (Ari- moderate Alzheimer’s disease in lower than that reported in the placebo group (1.7% vs. 1.1%). placebo, for abdominal pain cept) in a trial of the drug for the the United States. general population of patients Additional analyses of vascular (5.1% vs. 2.5%), anorexia (5.7% treatment of vascular dementia, Those patients taking with vascular dementia. Howev- events such as stroke and my- vs. 2.8%), and nausea (9.9% vs. according to preliminary study donepezil showed improvement er, the mortality rate observed in ocardial infarction for the three 4.3%). results announced by Eisai Co. on measures of cognition, com- the placebo group of this study VaD trials, alone and combined, Eisai has notified regulatory Ltd., the drug’s maker. None of pared with those on placebo. (0%) was lower than that seen in showed a statistically significant authorities about the mortality the 326 patients taking placebo However, there was no benefit the placebo groups in the com- higher risk of a vascular event in findings, and has reported that during the 24-week trial died. observed on global function, the bined analysis for the two prior the donepezil group, compared the results of the most recent The multicenter, randomized, trial’s other primary measure. VaD studies (2%), and was lower with placebo. vascular dementia study have not double-blind study was conduct- An analysis of adverse events than the rate for the general VaD In the most recent study, over- changed the overall safety profile ed in nine countries and enrolled data revealed that the mortality population. all adverse events were not sig- of the drug, and that the drug’s only people with vascular de- rate of 1.7% for the donepezil In an analysis of all three vas- nificantly different between the benefit-risk profile continues to mentia (VaD), who had no prior treatment group in this trial was cular dementia trials, observed treatment and placebo groups. be favorable for its approved in- diagnosis of Alzheimer’s disease. consistent with that observed in mortality rates were not statisti- Adverse events in the treatment dications. Donepezil is currently approved a combined analysis of two pre- cally significant between the group occurred at a rate greater —Kerri Wachter.
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