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Waging war on TB

Six drug therapies under trial bring new hope to practitioners fighting drug-resistant TB

Waging war on TBIt has been 125 years since Mycobacterium tuberculosis - the bacterium responsible for tuberculosis (TB) - was discovered, but still the disease remains a significant cause of death worldwide.

TB is second only to HIV as the leading cause of death from infectious disease in adults. Following the discovery of effective anti-tubercular drugs such as rifampicin, streptomycin and isoniazid around 50 years ago, it was thought the disease was easily curable.This, unfortunately, has not been the case.

According to the World Health Organisation (WHO), around two billion people are carriers of M. tuberculosis worldwide. Although in the majority of these patients, the bacterium remains dormant, approximately nine million people are diagnosed with active TB annually, of which two million will die from the disease. Of particular concern to practitioners treating the disease is the development of drug-resistant forms of the bacterium.

Drug-resistant TB is the result of interrupted, erratic or inadequate disease treatment. Traditional disease therapy consists of at least 6 months of treatment with four first-line agents such as rifampicin, isoniazid, pyrazinamide and ethambutol. According to the WHO, multi-drug-resistant TB (MDR-TB), one of the two drug-resistant forms of the disease, is defined as having resistance to at least isoniazid and rifampicin, the two most often used and most effective first-line drugs.

In cases of MDR-TB, second-line agents, including capreomycin, kanamycin and amikacin, are used. Extensively-drug- resistant TB (XDR-TB) is defined by the WHO as a strain resistant to any fluoroquinolone and at least one of three injectable second-line drugs, in the presence of MDR-TB. For this reason, treatment of XDR-TB is complicated, difficult and long.

Over 35 countries throughout North and South America, Africa, Asia and Europe have now confirmed reports of XDR-TB. This rise in drug-resistant forms of the disease is a global problem.

In the 44 years since the discovery of rifampicin, few new drugs have been developed to treat TB. Until the last decade or so, when the onset of a global TB epidemic and the appearance of drug-resistant strains was witnessed, there was very little reason for the private sector to invest in such projects.

The majority of tuberculosis cases were also restricted to the world's poorest countries. However, somewhat of a resurgence has occurred of late, with six agents from five different drug classes undergoing clinical trials (moxifloxacin, gatifloxacin, SQ109, PA824, OPC67683 and TMC207 - formerly R207910) and many other potential candidates undergoing preclinical development.

Rifapentine, a rifamycin derivative approved by the FDA in 1998, was the first new anti-TB agent approved in 25 years. Accordingly, there has been a specific emphasis on the development of new treatments which have reduced dosing regimens and which are effective against MDR- and XDR-TB. This is to address both the issues that lead to the development of drug-resistant TB and to improve the treatment of such cases.

Moxifloxacin, a broad-spectrum methoxyquniolone developed by Bayer and approved since 1999 for a variety of bacterial infections, is used as a second-line treatment for TB in specific circumstances. A phase II trial of moxifloxacin, conducted in collaboration with the TB Alliance, is currently investigating its efficacy in treating MDR-TB.

An orally administered formulation of the fluoroquinolone gatifloxacin is in phase III trials as a fixed combination with rifampicin, isoniazid and pyrazinamide. This is being done in collaboration with the WHO. Phase II results suggest this combination may enable a reduction in the recommended treatment time, from the current six months to four months, potentially improving patient compliance and providing at least an equal or better outcome in reducing the risk of the occurrence of drug resistance.

Tibotec Pharmaceuticals is developing TMC 207 (originated by Johnson & Johnson) as a monotherapy and/or combination therapy specifically for MDR-TB. One of a new class of anti-tuberculars, TMC 207 is a diarylquinolone. It is thought to have potential in this indication due to its unique mechanism of action - the inhibition of the enzyme ATP synthase (or ATPase), the energy source for M. tuberculosis. The drug is poised to enter a phase II trial that will compare it to a standard background treatment regimen.

In addition to moxifloxacin and various preclinical programmes, the TB Alliance is developing PA 824, a nitroimidazole in phase I trials. This targets both dormant and active TB. The Alliance is also in discussions with Otsuka Pharmaceutical for the joint development of the latter's lead TB product candidate, OPC 67683, an inhibitor of mycolic acid synthesis. POPC 67683 has already completed a phase II trial in South Africa.

The last of the six potential TB drug candidates in clinical development is Sequella's SQ109. The compound, which is being developed in collaboration with the US National Institutes of Health that discovered it, has completed a phase I trial and was granted fast track status by the US FDA in January 2007 for its potential to improve and shorten the current treatment regimen.

Although the prevalence and mortality rates of TB in general have declined, the emergence of MDR- and XDR-TB remains a real concern in terms of effectively treating and controlling the disease. The efforts of organisations such as the WHO, with their DOTS (Directly Observed Treatment, Short course) programme and Stop TB Strategy, have increased global awareness of TB. This has helped to re-initiate interest in the development of new effective drug therapies, without which tuberculosis would remain a significant, worldwide threat.

The widely acknowledged TB epidemic obviously cannot be resolved only through the development of new drug therapies. Preventative recommendations and programmes, as laid out by the WHO and other agencies, aim to combat the development of such strains in the future. However, treating these cases (in the present) with the lack of effective, more efficient and tolerable therapies, still represents a very real problem. It seems that with the recent resurgence of interest in this market and the subsequent progression of six new anti-TB drug therapies into clinical development, a drug offering reduced treatment duration, better overall tolerability and improved efficacy against MDR-and XDR-TB, may soon be a welcome reality.

Around nine million people are diagnosed with active TB annually

Table 1: Recently launched products

Generic name

Trade name (company)

Indication

Country

Bevacizumab

Avastin; Roche

First-line treatment for metastatic breast cancer in combination with chemotherapy

UK

Rituximab

Reditux; Dr Reddy's

Non-Hodgkin's lymphoma

India

Finasteride
(generic substitution)

Actavis Group

Benign prostatic hypertrophy

US

Pipeline was written by Claire Pouwels of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight.

For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733

7th August 2007

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