AstraZeneca and Targacept, Inc. announced the enrolment of the first patient in the phase II b clinical trial of TC-5214, a nicotinic channel blocker, as a “switch” monotherapy treatment for patients with Major Depressive Disorder (MDD) who do not respond adequately to initial antidepressant therapy.

This study is in addition to the companies’ phase III Renaissance programme for TC-5214 as an adjunctive treatment for MDD. The Renaissance programme is designed to support a New Drug Application (NDA) filing in the US planned for the second half of 2012 and a Marketing Authorisation Application (MAA) filing in Europe planned for 2015. AstraZeneca and Targacept are co-developing TC-5214.

In the phase II b study, patients with MDD who do not respond adequately, based on predefined criteria, to initial open label treatment with one of six commonly used SSRI or SNRI antidepressants will be switched to receive either one of two fixed doses of TC-5214, the active control duloxetine or placebo. Dosing in this double blind phase of the study is twice daily for eight weeks.

The primary outcome measure for the study is change from double-blind baseline at the end of the dosing period for TC-5214 on the Montgomery-Åsberg Depression Rating Scale (MADRS) as compared to placebo. The study is projected to enrol approximately 350 patients into the double blind phase from approximately 75 centres worldwide.

Recent scientific evidence suggests that depressive symptoms are associated with an over stimulation of Neuronal Nicotinic Receptors (NNRs) and other receptors in the brain that are activated by the neurotransmitter acetylcholine. This over stimulation is referred to as increased cholinergic tone. TC-5214 modulates the activity of certain NNRs, which is believed to help normalise cholinergic tone resulting in antidepressant effects.

In 2010, AstraZeneca and Targacept initiated the Renaissance Programme, a group of phase III double blind, placebo controlled studies designed to assess the safety and efficacy of TC-5214 as an adjunct treatment in patients with MDD who did not respond adequately to initial therapy with either an SSRI or SNRI. The programme also includes a long-term safety study in which patients receive TC-5214 or placebo for up to one year. Study design for the phase III adjunctive programme borrows heavily from the positive phase II b clinical trial for TC-5214 conducted by Targacept.

In December 2009, AstraZeneca and Targacept signed a collaboration and license agreement for the global development and commercialisation of TC-5214. The initial goal for the collaboration is to develop TC-5214 as an adjunct treatment for MDD in patients with an inadequate response to an SSRI or SNRI to regulatory approval.

Major Depressive Disorder (MDD) is a highly prevalent and debilitating disease with significant unmet need, affecting approximately 42 million people worldwide, and the global antidepressant market is estimated to be approximately $20 billion today. SSRIs and SNRIs are the most commonly prescribed classes of drugs for depression, but in many cases patients fail to respond adequately. In the NIMH’s large-scale Star D study conducted between 2001 and 2006, approximately 63% of patients did not achieve remission with first-line treatment with the SSRI citalopram hydrobromide.

Targacept is developing a diverse pipeline of innovative NNR Therapeutics for difficult-to-treat diseases and disorders of the nervous system. NNR Therapeutics selectively modulates the activity of specific neuronal nicotinic receptors, a unique class of proteins that regulate vital biological functions that are impaired in various disease states.

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease.