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12:00 AM
 | 
Nov 21, 2011
 |  BioCentury  |  Product Development

Not depressed yet

One miss by Targacept, AstraZeneca doesn't predict fate of depression drug

If history is any guide, there's no reason to think the failure of Targacept Inc. and AstraZeneca plc's first flexible-dose Phase III trial of TC-5214 automatically means the program is dead. However, the partners probably will have to succeed in two of the remaining three depression trials to have a shot at approval. Two of those are fixed-dose studies - which some data suggest are less likely than flexible-dose studies to succeed.

Even among drugs that prove to be effective, subjective entry criteria and endpoints plus high placebo response rates in major depressive disorder (MDD) trials lead to high failure rates.

A meta-analysis published by FDAresearchers in April in the Journal of Clinical Psychiatry examined 81 efficacy trials testing antidepressants that were ultimately approved in the last 25 years. Only 53% of the studies showed a statistically significant difference from placebo. Most antidepressants thus experience at least one failure in Phase III testing.

This month, Targacept and AstraZeneca joined that club. The partners reported that in the flexible-dose, European Phase III RENAISSANCE 3 trial in 295 patients, TC-5214 as an adjunct to antidepressant therapy missed the primary endpoint of change in Montgomery-Asberg Depression Rating Scale (MADRS) compared to antidepressant plus placebo.

Without detailed data, it is impossible to know whether the lack of separation was due to a high placebo response rate, low efficacy of TC-5214 or some other factor.

According to Michael Thase, professor of psychiatry at the University of Pennsylvania, if the placebo response rate was over 40%, "you could be more confident that this was simply a failed trial and it doesn't accurately gauge whether the compound works or not. But if the placebo response rate is less than 20%, I'd be really worried that this may actually not be a useful compound."

Targacept said it won't release detailed data until 1H12 after all four efficacy trials have read out.

Reason to believe

TC-5214 is the S-enantiomer of mecamylamine hydrochloride, a broad-spectrum non-competitive nicotinic receptor antagonist. It is expected to work in...

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