Negative results in antidepressant treatment: The death of TC-5214

Targacept Incorporated is a biopharmaceutical company that is in the business of creating a new class of drugs that treat multiple diseases and disorders of the nervous system.

The drugs they design and engineer selectively target the neuronal nicotinic receptors (NNRs) that are widely distributed throughout nerve cells of the central nervous system. TC-5214 is one such class of compound. In fact, over the last ten years more than 1000 articles have been published describing the use of these types of compounds (mecamylamines) as a pharmacological tool to confirm the involvement of nicotinic receptors in various physiological and pharmacological effects.

In the winter of 2008, a paper was published that spoke to the potential therapeutic benefit of modulating activities of these NNRs in the central nervous system. Functional NNRs are widely distributed in the brain, and numerous studies have shown that mecamylamine blocks nicotinic-induced mnemonic effects in normal and aged animals and in humans. TC-5214 (or mecamylamine) acts as a noncompetitive NNR antagonist, and showed some positive effects in a number of animal models of depression and anxiety.

The forced swim test (the behavioural despair test or the Porsolt test) is a test frequently employed as a measure of the effect of antidepressant drugs on the behaviour of lab mice or rats. The procedure is simple. The mice are subjected to two trials during which they are forced to swim in an acrylic glass cylinder filled with water. One from which they cannot get out. The first trial, lasting 15 minutes, is followed by a second after 24 hours, lasting just 5 minutes. The measure is the time that the animal spends without moving in the second trial. And this immobility time is decreased by antidepressants.

With immobility taken as a behavioural correlate for a negative mood. TC-5214 was active in the forced swim test in rats and it was also active in the behavioral despair test in mice. The researchers concluded that their results support a novel nicotinic cholinergic antagonist mechanism for antidepressant and anxiolytic (anti-anxiety) effects and highlighted the potential of NNR antagonists as therapeutics for the treatment of anxiety and depression.

Today, TC-5214, representing the most promising drug in the Targacept Inc. pipeline, has come to a screeching halt after it failed the final two clinical trials for major depressive disorder. TC-5214 was positioned to be an add-on treatment to existing anti-depressants.

Targacept's TC-5214 compound previously failed two short-term Phase 3 clinical trials in 2011, showing no significant difference in patients when compared to a placebo. The company needs two successful results to pursue Food and Drug Administration's approval of the compound. As such, with this recent failure, the pursuit of TC-5214 as a possible treatment has been abandoned.

This fail of a drug happens all the time. But this one arouses a certain facet of the discussion. Namely, the difficulty in reproducing clinical trial results across different countries. TC-5214 showed outstanding results in Phase 2b clinical trials in India, but that level of excitement failed to be reproduced in the USA (the only country that counts for FDA approval).

All too often, experimental drugs post stellar results from studies conducted in Russia, India and other less developed regions, leading to inflated stocks for the company and misplaced hopes. Only to blow up after the data cannot be replicated in the United States or Europe. The valuation of a small innovation biotech like Targacept rises and falls with the rise and fall of its negative data.

 References: 1) doi:10.1124/jpet.108.146910. 2) doi:10.1111/j.1755-5949.2008.00054.x

Written by Dr. Charles Ebikeme for The All Results Journals.