The power of positive partnering

AstraZeneca, Targacept to design nicotine channel blocker TC-5214 for treatment of major depressive disorder

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WINSTON-SALEM, N.C.—What if you could get the soothingeffect of nicotine without the health risks of smoking a cigarette?London-based pharmaceutical giant AstraZeneca is banking on TC-5214, TargaceptInc.'s late-stage investigational product for major depressive disorder, to domore than that.
For this reason, AstraZeneca and Targacept, a clinical-stagebiopharmaceutical company based in Winston-Salem, N.C., the heart of tobaccocountry, have combined forces to develop and commercialize TC-5214, a nicotinicchannel blocker that is thought to treat depression by modulating the activityof various neuronal nicotinic receptor (NNR) subtypes.
TC-5214 recently completed a Phase IIb clinical trial, andwill take the next step when AstraZeneca and Targacept jointly design a globalPhase III clinical program in 2010, with the goal of filing a new drugapplication 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 tomake an upfront payment to Targacept of $200 million and up to an additional$540 million if specified development, regulatory and first commercial salemilestones are achieved. Targacept will also be eligible to receive up to $500million if specified sales related milestones are achieved—as well assignificant, stepped double-digit royalties on net sales worldwide.
AstraZeneca has agreed to cover 80 percent of the cost ofthe initial global development program, with Targacept assuming the remaining20 percent.
AstraZeneca will also fund the costs of global commercialization ofTC-5214, and will assume Targacept's manufacturing and supply agreements withthird parties in relation to TC-5214.
J. Donald deBethizy, Targacept president and CEO, saysAstraZeneca will help his company meet its goal of advancing TC-5214 intolate-stage development and bringing a new mechanistic approach for thetreatment of depression to the millions of patients who do not respond well tofirst-line antidepressant therapy.
Alan Russo, Targacept CFO, adds, "We've had good successwith our TC-5214 trials. More than half of the people diagnosed with depressionare not helped by first-line antidepressant drugs … and the 80/20 agreementwill give us less financial risk."
Serotonin reuptake inhibitors (SSRIs) are the most commonlyprescribed class of drugs for depression, but many patients fail to respondadequately, Russo says. The NIMH STAR*D study suggests that approximately 63percent of patients do not achieve remission with first-line SSRI treatment. Itis hoped that TC-5214 will fill that void.
"The opportunity to improve treatment in depression is a largeone, both commercially and in terms of benefits for patients," says DavidBrennan, AstraZeneca's CEO. "It's an area both AstraZeneca and Targacept knowwell. 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 in2005, focusing on the development of clinical stage candidates for thetreatment of cognitive function associated with various diseases. We were alreadyin close contact, so this was a natural partnering opportunity for bothcompanies."
TC-5214 "complements AstraZeneca's neuroscience portfolio,and shows our commitment to building on our long-standing experience inneuroscience," Denney says. "This new alliance broadens the collaborationbetween AZ and Targacept."
Three product candidates in the collaboration are currentlyin clinical development; including AZD3480 for attention deficit/hyperactivitydisorder (ADHD), AZD1446 planned for Alzheimer's disease, and TC-5619 forcognitive dysfunction in schizophrenia.
Scientific evidence suggests that depressive symptoms areassociated with an overstimulation of NNRs and other receptors in the brainthat are activated by the neurotransmitter acetylcholine, Denney says. Thisoverstimulation is referred to as increased cholinergic tone. TC-5214 hasproperties that modulate forms of NNR subtypes thought to be involved in theincreased cholinergic tone associated with depression. In particular, TC-5214blocks certain NNR channels.
"An innovative approach for the treatment of majordepression. TC-5214 is based on its potential effect on NNR and has no effecton the serotonin or noradrenalin receptors and transporters like SSRI and SNRIdo," Denney says. "There is potential for significant benefit to patients in anarea of great unmet need."
TC-5214 potentially has a strong market opportunity in boththe U.S. and Europe, she says. With depression affecting about 121 millionpeople worldwide, the market for an effective anti-depressant is huge. MajorDepressive Disorder (MDD) is the leading cause of disability in the U.S. forpeople between the ages 15 and 44, and the National Institute of Mental Health(NIMH) estimates that approximately 14.8 million American adults suffer fromMDD.
 In 2000, the total economic burden of treating depression inthe United States alone was approximately $83.1 billion, with workplace costs,including missed days and lack of productivity due to illness, accounting forapproximately 62 percent of the total economic burden, with treatment costsaccounting for approximately 31 percent and suicide-related costs accountingfor approximately 7 percent, Targacept reports.

Targacept initiates Phase II study of TC-5619 in cognitivedysfunction in schizophrenia
WINSTON-SALEM, N.C.—Targacept Inc. also announced last monththat it has initiated a Phase II clinical proof-of-concept trial of TC-5619 incognitive dysfunction in schizophrenia. TC-5619 is a novel small molecule thatis highly selective for the alpha7 neuronal nicotinic receptor (NNR), and wasdiscovered by Targacept scientists using Targacept's drug discovery platform,Pentad.
Targacept expects that the Phase II trial of TC-5619 couldbe completed by the end of 2010. Following completion of the trial, Targacept'sstrategic collaborator, AstraZeneca, has the right to license TC-5619 on termsspecified in the parties' December 2005 collaboration agreement.
According to Dr. J. Donald deBethizy, president and CEO ofTargacept, TC-5619 could be a game-changer for schizophrenia patients, ascurrently available treatment options do not adequately address the dramaticimpact schizophrenia has on cognition for millions of patients. These cognitiveimpairments play a primary role in the inability of schizophrenic patients tofunction normally. According to market research firm Business Insights,approximately 7.9 million people with schizophrenia in the world's seven majorpharmaceutical markets in 2007.  Ithas been estimated that up to 75 percent of persons with schizophrenia arecognitively impaired. There is currently no drug approved in the United Statesor Europe specifically for cognitive dysfunction in schizophrenia.
"The scientific literature is replete with evidence of thekey role that the alpha7 NNR plays both in cognitive function and in thepsychoses characteristic of schizophrenia," deBethizy says. "TC-5619 is highlyselective for the alpha7 NNR, and has to date shown little or no interactionwith the 5-HT3 receptor, which is known to be associated with significantlimiting side effects that have served as an obstacle to the successfuldevelopment of other alpha7 NNR modulators."

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