The Death of TC-5214…

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.

TC-5214 is one such example.

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).

Image — source.

Originally appearing at the All Results Journals

Fedorov, N., Benson, L., Graef, J., Lippiello, P., & Bencherif, M. (2008). Differential Pharmacologies of Mecamylamine Enantiomers: Positive Allosteric Modulation and Noncompetitive Inhibition Journal of Pharmacology and Experimental Therapeutics, 328 (2), 525-532 DOI: 10.1124/jpet.108.146910

Lippiello, P., Beaver, J., Gatto, G., James, J., Jordan, K., Traina, V., Xie, J., & Bencherif, M. (2008). TC-5214 (S-(+)-Mecamylamine): A Neuronal Nicotinic Receptor Modulator with Antidepressant Activity CNS Neuroscience & Therapeutics, 14 (4), 266-277 DOI: 10.1111/j.1755-5949.2008.00054.x

New routes to Chagas…

On March 5th 2001, a 37 year old woman went into surgery to have a kidney and pancreas transplant from a donor that had already passed away. Once discharged, she returned to the hospital six weeks later to be treated for a sudden onset of fever (of unknown origin). She would die six months later, on the first week of October.

What turned out to be the first recognised case of a T. cruzi infection through solid-organ transplantation in the Unites States, came after the physician identified the parasites in a peripheral blood smear. Upon identification the physician immediately notified the Centre for Disease Control (CDC). Upon further investigation it was discovered that other patients had received infected organs from the same donor. A 32 year old woman who had received the liver, and a 69 year old woman who received the other kidney. Both organs were found to be infectious. The donor of the infected organs was an immigrant from Central America.

At the time, no protocol or policy was in place for the regular screening of organ donations for T. cruzi — something that was routinely done in Chagas endemic areas. And no test was licensed for screening organ or blood donors. Today, two Chagas tests are available, out of a full complement of 60 that are licensed and routinely used to screen organs and blood donation for a wide range of infectious agents (including HIV, hepatitis, and west nile virus).

After the infection was detected, all three women were treated with nifurtimox — a drug not available in the US at the time. And a drug, over ten years later, still only has a single manufacturer. Today, nifurtimox, a drug that dates back to 1960, is available for US$48 per treatment regimen — the equivalent of a month of a Bolivian miner’s salary.

Of the three women that were infected, it was only the 69 year old woman that would survive the parasitic infection. In the most severe case, it was death as a result of immunosuppression. The woman who received the kidney and pancreas transplants, was the most immunosuppressed of the three patients. She died even after completing a full course (4 months) of treatment with nifurtimox.

Dorsal view of the “kissing bug”, Triatoma infestans

The original organ donor, the immigrant from Central America, most likely acquired Chagas from the triatomine kissing bug. As it bites, the insect carrying the parasite deposits faeces on the victim’s skin, and when the person rubs the bite wound, the faeces containing the parasite enters the bloodstream.

Blood and organ donor screening programs across the Americas and North America have essentially eliminated transmission via this way. However, some cases still turn up. Add to that the lack of awareness of the disease among US healthcare providers complicates the issue.

Chagas, once thought of and regarded as an exotic disease, given little attention, is increasingly being diagnosed in non-endemic areas. In 2009 it was estimated that 300,000 people living in the US were chronically infected with the parasite. In Europe, Chagas has been reported from congenital transmission (from mother to infant), in a recipient of a bone marrow transplant, and among Brazilian immigrants of Japanese origin in Japan.

Patterns of emigration have drastically changed the epidemiology of this disease over the recent decades. Immigration is one reason, but not the only one.

A new study has shown that a high proportion of triatomine bugs collected in Arizona and California had fed on humans, while others were positive for T. cruzi parasite infection. This new study essentially indicates that the potential exists for vector transmission of Chagas disease in the US. Up until now, the most common result of a triatomine bite was an allergic reaction.

Featured image — source

Triatomine image — source

Originally appearing at endtheneglect.org

Weir, E. (2006). Chagas disease: hidden affliction and visible neglect Canadian Medical Association Journal, 174 (8), 1096-1096 DOI: 10.1503/cmaj.051442 Machado, F., Jelicks, L., Kirchhoff, L., Shirani, J., Nagajyothi, F., Mukherjee, S., Nelson, R., Coyle, C., Spray, D., de Carvalho, A., Guan, F., Prado, C., Lisanti, M., Weiss, L., Montgomery, S., & Tanowitz, H. (2012). Chagas Heart Disease Cardiology in Review DOI: 10.1097/CRD.0b013e31823efde2 Stevens, L., Dorn, P., Hobson, J., de la Rua, N., Lucero, D., Klotz, J., Schmidt, J., & Klotz, S. (2012). Vector Blood Meals and Chagas Disease Transmission Potential, United States Emerging Infectious Diseases, 18 (4), 646-649 DOI: 10.3201/eid1804.111396