Experimental Drug For Multi-Drug Resistant TB Shows Promise In Trial

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Main Category: Tuberculosis
Also Included In: Clinical Trials / Drug Trials;  Infectious Diseases / Bacteria / Viruses
Article Date: 04 Jun 2009 - 10:00 PDT

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When added to the mix, a new experimental drug known as TMC207 appeared to make a cocktail of background drugs five times more powerful in successfully treating patients with multidrug resistant tuberculosis (MDR-TB).

The study is published in the 4 June issue of the New England Journal of Medicine, NEJM and was the work of Dr David McNeeley and colleagues. McNeeley works for Tibotec, the subsidiary of Johnson & Johnson that is developing the drug.

In the randomized, placebo-controlled phase 2 trial, when added to the background regimen, the new drug shortened the treatment time and cleared 5 times more patients of the TB compared to the background regimen alone.

TMC207 with the background regimen cleared traces of the TB bacteria in the sputum of 48 percent of the patients after 8 weeks, whereas only 9 per cent of patients were clear of TB in the placebo group after this time (the placebo group took only the background regimen of standard TB drugs).

TMC207 is a diarylquinoline, a new type of drug that cuts off the bacteria's energy source by inhibiting production of the bacteria's own ATP, a molecule that behaves like a rechargeable battery inside the living cell.

The news has been welcomed by doctors working with TB and MDR-TB in particular. One of the key problems with treating TB is getting people to stick to their medication schedule, so a drug that shortens the timescale will make it more likely that fewer people will drop out of a programme. It is when patients interrupt or discontinue their medication early that the TB bacteria develops resistance to drugs.

Dr Peter Donald, Professor Emeritus, Stellenbosch University in Capetown, South Africa, where TB is a major public health problem and where this first stage phase 2 trial was conducted, said:

"The results of this study are highly encouraging news for the treatment of tuberculosis."

"Not only is this an agent with a radically different means of action, but it shows potential to shorten the treatment of tuberculosis in the foreseeable future, something the tuberculosis community has been hoping for years."

Treating patients with TB is not simple and MDR-TB is even more difficult. It takes at least 18 more months to treat MDR-TB and for this you need second line drugs because the first line ones don't work any more, the bacteria has become resistant to them. However, there are more side-effects with second line drugs, and these also have to be managed.

Every year just under half a million people find out they have MDR-TB, and 110,000 die from it.

The study is the first part of a two-stage phase 2 trial and involved 47 hospitalized patients who had just been diagnosed with pulmonary MDR-TB. Each patient was randomized to one of two groups: one group (23 patients) was given TMC207 and a background panel of 5 second-line antituberculosis drugs, and the other group (24 patients) was given a placebo with the same background regimen.

The active drug group was given TMC207 at a dose of 400 mg a day for 2 weeks, then 200 mg three times a week for 6 weeks. Six people in each group dropped out early.

Each day patients gave a sputum (spit) sample which was grown as a culture and then tested for TB bacteria.

The results showed that:

• At the end of 8 weeks, more patients were TB culture negative in the TMC207 group than in the placebo group (47.6 versus 8.7 per cent).


• TCM207 also reduced the time to culture conversion: the probability of becoming culture negative on any given day within the 8 weeks of the trial was 11.8 times higher in the drug group than in the placebo group.


• Also, mean sputum colony forming units (CFU) count went down faster in the TMC207 group than in the placebo group (CFU is a measure of the viable bacteria in the sample that the patient gives).


• Most adverse events (bad side effects) were mild to moderate, and of these only nausea was more frequent with TMC207 than the placebo (26 versus 4 per cent).


• One participant in each group experienced a serious adverse event but in neither case was this related to the medication.

Johnson & Johnson, who sponsored the trial, said in a statement that:

"The data obtained validate ATP synthase as a viable target for the treatment of TB."

The second stage trial will take place in South Africa, Peru, Latvia and Russia and the treatment time will be extended to 24 weeks. These results will come out sometime in 2010.

"The Diarylquinoline TMC207 for Multidrug-Resistant Tuberculosis."
Diacon, Andreas H., Pym, Alexander, Grobusch, Martin, Patientia, Ramonde, Rustomjee, Roxana, Page-Shipp, Liesl, Pistorius, Christoffel, Krause, Rene, Bogoshi, Mampedi, Churchyard, Gavin, Venter, Amour, Allen, Jenny, Palomino, Juan Carlos, De Marez, Tine, van Heeswijk, Rolf P.G., Lounis, Nacer, Meyvisch, Paul, Verbeeck, Johan, Parys, Wim, de Beule, Karel, Andries, Koen, McNeeley, David F.
N Engl J Med 4 June 2009 360: 2397 -2405

Additional sources: Johnson & Johnson.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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