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The power of positive partnering
January 2010
by Lori Lesko  |  Email the author


WINSTON-SALEM, N.C.—What if you could get the soothing effect of nicotine without the health risks of smoking a cigarette? London-based pharmaceutical giant AstraZeneca is banking on TC-5214, Targacept Inc.'s late-stage investigational product for major depressive disorder, to do more than that.
For this reason, AstraZeneca and Targacept, a clinical-stage biopharmaceutical company based in Winston-Salem, N.C., the heart of tobacco country, have combined forces to develop and commercialize TC-5214, a nicotinic channel blocker that is thought to treat depression by modulating the activity of various neuronal nicotinic receptor (NNR) subtypes.
TC-5214 recently completed a Phase IIb clinical trial, and will take the next step when AstraZeneca and Targacept jointly design a global Phase III clinical program in 2010, with the goal of filing a new drug application with the U.S. Food and Drug Administration (FDA) in 2012.  
If successful, the partnership has the potential to become a $1 billion deal. The collaboration, announced Dec. 3, calls for AstraZeneca to make an upfront payment to Targacept of $200 million and up to an additional $540 million if specified development, regulatory and first commercial sale milestones are achieved. Targacept will also be eligible to receive up to $500 million if specified sales related milestones are achieved—as well as significant, stepped double-digit royalties on net sales worldwide.
AstraZeneca has agreed to cover 80 percent of the cost of the initial global development program, with Targacept assuming the remaining 20 percent.
AstraZeneca will also fund the costs of global commercialization of TC-5214, and will assume Targacept's manufacturing and supply agreements with third parties in relation to TC-5214.  
J. Donald deBethizy, Targacept president and CEO, says AstraZeneca will help his company meet its goal of advancing TC-5214 into late-stage development and bringing a new mechanistic approach for the treatment of depression to the millions of patients who do not respond well to first-line antidepressant therapy.  
Alan Russo, Targacept CFO, adds, "We've had good success with our TC-5214 trials. More than half of the people diagnosed with depression are not helped by first-line antidepressant drugs … and the 80/20 agreement will give us less financial risk."
Serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of drugs for depression, but many patients fail to respond adequately, Russo says. The NIMH STAR*D study suggests that approximately 63 percent of patients do not achieve remission with first-line SSRI treatment. It is hoped that TC-5214 will fill that void.
"The opportunity to improve treatment in depression is a large one, both commercially and in terms of benefits for patients," says David Brennan, AstraZeneca's CEO. "It's an area both AstraZeneca and Targacept know well. I'm pleased to be adding another late-stage project to our pipeline."  
AstraZeneca spokesperson Emily Denney says the company "already had a successful collaboration with Targacept, which began back in 2005, focusing on the development of clinical stage candidates for the treatment of cognitive function associated with various diseases. We were already in close contact, so this was a natural partnering opportunity for both companies."
TC-5214 "complements AstraZeneca's neuroscience portfolio, and shows our commitment to building on our long-standing experience in neuroscience," Denney says. "This new alliance broadens the collaboration between AZ and Targacept."  
Three product candidates in the collaboration are currently in clinical development; including AZD3480 for attention deficit/hyperactivity disorder (ADHD), AZD1446 planned for Alzheimer's disease, and TC-5619 for cognitive dysfunction in schizophrenia.
Scientific evidence suggests that depressive symptoms are associated with an overstimulation of NNRs and other receptors in the brain that are activated by the neurotransmitter acetylcholine, Denney says. This overstimulation is referred to as increased cholinergic tone. TC-5214 has properties that modulate forms of NNR subtypes thought to be involved in the increased cholinergic tone associated with depression. In particular, TC-5214 blocks certain NNR channels.  
"An innovative approach for the treatment of major depression. TC-5214 is based on its potential effect on NNR and has no effect on the serotonin or noradrenalin receptors and transporters like SSRI and SNRI do," Denney says. "There is potential for significant benefit to patients in an area of great unmet need."  
TC-5214 potentially has a strong market opportunity in both the U.S. and Europe, she says. With depression affecting about 121 million people worldwide, the market for an effective anti-depressant is huge. Major Depressive Disorder (MDD) is the leading cause of disability in the U.S. for people between the ages 15 and 44, and the National Institute of Mental Health (NIMH) estimates that approximately 14.8 million American adults suffer from MDD.  
 In 2000, the total economic burden of treating depression in the United States alone was approximately $83.1 billion, with workplace costs, including missed days and lack of productivity due to illness, accounting for approximately 62 percent of the total economic burden, with treatment costs accounting for approximately 31 percent and suicide-related costs accounting for approximately 7 percent, Targacept reports.

Targacept initiates Phase II study of TC-5619 in cognitive dysfunction in schizophrenia  
WINSTON-SALEM, N.C.—Targacept Inc. also announced last month that it has initiated a Phase II clinical proof-of-concept trial of TC-5619 in cognitive dysfunction in schizophrenia. TC-5619 is a novel small molecule that is highly selective for the alpha7 neuronal nicotinic receptor (NNR), and was discovered by Targacept scientists using Targacept's drug discovery platform, Pentad.  
Targacept expects that the Phase II trial of TC-5619 could be completed by the end of 2010. Following completion of the trial, Targacept's strategic collaborator, AstraZeneca, has the right to license TC-5619 on terms specified in the parties' December 2005 collaboration agreement.
According to Dr. J. Donald deBethizy, president and CEO of Targacept, TC-5619 could be a game-changer for schizophrenia patients, as currently available treatment options do not adequately address the dramatic impact schizophrenia has on cognition for millions of patients. These cognitive impairments play a primary role in the inability of schizophrenic patients to function normally. According to market research firm Business Insights, approximately 7.9 million people with schizophrenia in the world's seven major pharmaceutical markets in 2007.  It has been estimated that up to 75 percent of persons with schizophrenia are cognitively impaired. There is currently no drug approved in the United States or Europe specifically for cognitive dysfunction in schizophrenia.
"The scientific literature is replete with evidence of the key role that the alpha7 NNR plays both in cognitive function and in the psychoses characteristic of schizophrenia," deBethizy says. "TC-5619 is highly selective for the alpha7 NNR, and has to date shown little or no interaction with the 5-HT3 receptor, which is known to be associated with significant limiting side effects that have served as an obstacle to the successful development of other alpha7 NNR modulators."
Code: E011002



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