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TMC207, New Drug for TB MultiDrug Resistant (MDR) & XDR
(extensively drug resistant)
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Link:
Diarylquinoline TMC207 for MDR Tuberculosis
The new compound TMC207, a diarylquinoline that inhibits mycobacterial ATP synthase, shows promising activity against MDR tuberculosis. In this study, the administration of TMC207 resulted in a shorter time to sputum-culture conversion and a significant increase in the proportion of patients achieving culture conversionto negative. LINK: Free Full Text
2 Editorials in NEJM:
Unorthodox Approach to the Development of a New Antituberculosis Therapy
NEJM June 4 2009
Clifton E. Barry, III, Ph.D.
From the Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
The development of TMC207 represents an important advance in the chemotherapy of tuberculosis. It is perhaps most amazing because of the defiantly unconventional nature of the effort. At virtually every step, from the original discovery of the diarylquinolines by screening for compounds that would kill Mycobacterium smegmatis, a saprophytic distant relative of M. tuberculosis, through the phase 2 study by Diacon et al. reported in this issue of the Journal (ClinicalTrials.gov number, NCT00449644 [ClinicalTrials.gov] ),1 this effort flouted conventional wisdom about how to develop new drugs for tuberculosis.
It is also a humbling case study that is worth some reflection. Those of us in the tuberculosis field turned up our noses at looking for compounds that killed anything less than the real human pathogen, and until recently, the whole notion of screening drugs for their ability to provide activity against whole organisms was somewhat anachronistic. Surely we have advanced in the decades since streptomycin was isolated by Selman Waksman after he performed such a screen. Give us a nice, isolated enzyme with a high-resolution x-ray crystallographic structure, and we will use the armamentarium of modern drug discovery to treat the hard-to-treat tuberculosis. The problem, summed up recently by Payne et al.,2 is that this approach does not work for bacteria. The truly disturbing fact is that we do not understand why. We can develop exquisitely potent and selective inhibitors of virtually any target we choose, but these inhibitors rarely translate into anything with activity useful against whole cells.
The study by Diacon et al. is important for three distinct reasons. First, the diarylquinolines are a new class of drugs that increase the therapeutic options for patients who have multidrug-resistant or extensively drug-resistant tuberculosis, for whom treatment options are often sparse, largely ineffective, and often highly toxic. These patients often have little recourse, and their physicians turn as a last resort to agents such as linezolid that have considerable adverse events after prolonged administration. TMC207 appears not to be associated with serious adverse events, at least during the initial 8 weeks of therapy. Longer-term data, of course, are essential, but for now this is encouraging.
The second reason this is an important study is because of the design. The current four-drug regimen for treating persons with drug-susceptible tuberculosis is overwhelmingly effective. Most trials of new agents have involved swapping out one of the four for a new candidate and measuring the difference. These are large, expensive undertakings because of the numbers required to power such a study. Sentiment has been growing that the inherently poor response of patients to second-line tuberculosis drugs means that a small cohort of patients with multidrug-resistant tuberculosis could provide meaningful outcomes.3,4 In fact, an earlier report by Diacon et al.5 was perhaps the first controlled clinical trial conducted in a population with multidrug-resistant tuberculosis. The phase 2 study of TMC207 reported here is an important step that I hope will serve to dispel the following two prevailing wisdoms: patients with multidrug-resistant tuberculosis are too heterogeneous for such studies because of highly variable regimens of background chemotherapy, and a trial involving patients with multidrug-resistant tuberculosis will limit use of the drug to that population.
It is important to appreciate the distinction between drug development for patients with multidrug-resistant or extensively drug-resistant tuberculosis and a trial involving patients with multidrug-resistant or extensively drug-resistant tuberculosis that is used as a stepping-stone to a larger trial involving patients with drug-susceptible tuberculosis. A trial offers many important lessons for understanding how to formulate large, expensive phase 3 efficacy studies in patients with drug-susceptible tuberculosis and how to determine whether agents are worth that investment. In the field of oncology, testing experimental chemotherapeutic agents in patients who have advanced disease is a standard prelude to efficacy in the target population. Other ongoing studies (ClinicalTrials.gov numbers, NCT00727844 [ClinicalTrials.gov] , NCT00425113 [ClinicalTrials.gov] , and NCT00685360 [ClinicalTrials.gov] ) conducted by several different teams of investigators have embraced this concept, but this trial of TMC207 seems to be the first completed study.
The third reason this is an important study is that one of the largest barriers to the development of new drugs for tuberculosis is the paucity of targets that, when their function is inhibited by drugs, have a positive therapeutic effect in patients. Of the agents currently in use, we have multiple complex prodrugs that have multiple effects, such as isoniazid and pyrazinamide, but designer prodrugs are a tall order (although a rational approach to optimizing prodrugs is emerging with the nitroimidazoles6). Among the highly active drugs are very few known targets: rifampin targets RNA polymerase, the aminoglycosides target the bacterial ribosome, and the fluoroquinolones target DNA gyrase. The target of TMC207 is ATP synthase, which the current study by Diacon et al. validates. Efforts are already under way to create other drugs against this target.
The drug and the trial are very encouraging, but there are some reasons to be circumspect regarding the transition of TMC207 into a mainstream drug for the treatment of persons with drug-susceptible tuberculosis. First, the available safety data are still limited and urgently need to be expanded. Second, there are unresolved problems with the metabolism of TMC207 by a cytochrome P-450 system (CYP3A4) that is strongly induced by rifampin, making it unclear whether TMC207 and rifampin could be effectively coadministered. Rifampin is the most active of the front-line tuberculosis agents, and the choice between it and TMC207 will be difficult if the regimen requires only one of the two. Finally, there are still challenges in addressing the pharmacokinetics of TMC207, which has an unusually long half-life. None of these points detract from the overall value of the current study; they may simply impede the development of TMC207 beyond the population with multidrug-resistant or extensively drug-resistant tuberculosis.
In retrospect, there was a considerable element of luck in the discovery of TMC207 and its target, but there was also a refreshing sense of forward movement. This experience shows that there is always a chance of discovering a new class of molecules, a new therapeutically useful target, and of adopting a new trial design that shows convincing efficacy with the involvement of only 47 patients.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
References
1. Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009;360:2397-2405. [Free Full Text]
2. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 2007;6:29-40. [CrossRef][ISI][Medline]
3. Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 2007;4:e292-e292. [CrossRef][Medline]
4. Sacks LV, Behrman RE. Developing new drugs for the treatment of drug-resistant tuberculosis: a regulatory perspective. Tuberculosis (Edinb) 2008;88:Suppl 1:S93-S100. [CrossRef]
5. Diacon AH, Patientia RF, Venter A, et al. Early bactericidal activity of high-dose rifampicin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob Agents Chemother 2007;51:2994-2996. [Free Full Text]
6. Singh R, Manjunatha U, Boshoff HI, et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008;322:1392-1395. [Free Full Text]
The Global Burden of Tuberculosis - Combating Drug Resistance in Difficult Times
NEJM June 4 2009
Peter R. Donald, M.B., Ch.B., M.D., and Paul D. van Helden, Ph.D.
According to the 13th annual tuberculosis report of the World Health Organization (WHO) - published on World TB Day, March 24, 2009 - there were an estimated 9.27 million new cases of tuberculosis worldwide in 2007 (see interactive graphic).1 Although this figure represents an increase from 9.24 million in 2006, the world population has also grown, making the number of cases per capita a more useful measure of the problem; this figure peaked in 2004 at 142 per 100,000 and fell to 139 per 100,000 in 2007. An estimated 1.32 million people who were not infected with the human immunodeficiency virus (HIV) died of tuberculosis in 2007, as did an estimated 456,000 people who were HIV-positive. Prevalence and mortality rates appear to be falling in all six WHO regions. Thus, the Americas, the eastern Mediterranean, and Southeast Asia appear likely to meet the Millennium Development Goals target, set in conjunction with the Stop TB Partnership and the World Health Assembly, of halving tuberculosis prevalence and tuberculosis-related mortality between 1990 and 2015. This target will probably not be met by the African and European regions. Nevertheless, do the new statistics, at last, represent the turn of the tuberculosis tide and provide reason for cautious optimism?
Some 22 high-burden countries collectively account for 80% of the global tuberculosis burden. In 2007, the countries with the highest prevalence were India (with 2.0 million cases), China (1.3 million), Indonesia (530,000), Nigeria (460,000), and South Africa (460,000); of the estimated 1.37 million cases in HIV-positive persons, 79% were in Africa and 11% in Southeast Asia. Disturbingly, there were an estimated 500,000 cases of multidrug-resistant (MDR) tuberculosis in 2007 (including 289,000 new cases); of these, 131,000 were in India, 112,000 in China, 43,000 in Russia, 16,000 in South Africa, and 15,000 in Bangladesh; 55 countries had reported cases of extensively drug-resistant (XDR) tuberculosis by the end of 2008. These last figures are reason for considerable concern and highlight a potential threat to our ability to treat tuberculosis, both in individual patients and in the context of a treatment program.
In early April in Beijing, at a ministerial meeting of countries with a high burden of MDR or XDR tuberculosis, it was forecast that to achieve the target set out in the Global Plan to Stop TB, treatment of 1.4 million cases of MDR or XDR tuberculosis will be required in the 27 countries with the highest burden between 2009 and 2015. The cost of diagnosing and treating these cases was estimated at $16.9 billion, with annual costs increasing from $700 million in 2009 to $4.4 billion in 2015; the latter figure is 61 times the funding that is available in 2009. In higher-burden regions, the proportion of tuberculosis cases that are multidrug-resistant may range from 1 to 14% or more.2 Of these cases, the proportion that are extensively drug-resistant may be as high as 21%.3 Even in the United States, where the number of MDR cases appears to be declining, the number of XDR cases is increasing. Although countries in Eastern Europe, the former Soviet Union, and China have a large number of MDR cases, reporting suggests that sub-Saharan Africa has a relatively low proportion of drug-resistant cases. However, the incidence of primary drug-resistant cases indicates that these areas may have the highest rates of transmitted MDR tuberculosis in the world.2 Furthermore, we know that reinfection and multiple infection are common in high-incidence areas, and thus that many so-called recurrent cases are the result of a new infection and should be added to the primary cases to give a true picture of the growing burden of transmitted MDR and XDR tuberculosis.
Tuberculosis is a disease of poverty, and the declining incidence in many relatively wealthy areas is not unexpected, but there are other parts of the globe where health systems are defective or simply overwhelmed and cannot cope, because of either a lack of funds and personnel or dysfunctional politics, which lead to the sloppy implementation of directly observed treatment (DOTS) programs and exacerbate the tuberculosis problem. Resistance to any agent emerges rapidly if there is overt or covert monotherapy or noncompliance. Under less than ideal conditions, isoniazid monoresistance also emerges rapidly. And in the absence of isoniazid, our most powerful bactericidal agent, the risk of resistance to rifampin, the next-most-powerful bactericidal agent, increases, since neither pyrazinamide nor ethambutol (nor streptomycin) is particularly effective in preventing resistance in companion drugs. Once MDR tuberculosis has developed, there is little to stop the rapid acquisition of resistance to the remaining agents. Further progression to pre-XDR and XDR tuberculosis becomes only a question of time. Since this process will take place over some months, or even years, the patient remains infectious, and it is not surprising that transmission of MDR and XDR tuberculosis occurs, particularly in communities with a high incidence of HIV infection.
Since we now know that many of the tuberculosis infections in high-incidence countries have been transmitted recently, our failure to contain MDR and XDR tuberculosis also reflects our inability to diagnose the problem quickly enough to prevent transmission while continuing to prescribe an ineffective standardized regimen.4 Individualized therapy could optimize multidrug treatment and limit the further acquisition of resistance. However, in the face of limited resources for the necessary testing and decision making, we have been forced to adopt a standardized approach, which contributes to further treatment failures in MDR tuberculosis. Reinfection is treated as "relapse" according to standardized protocols, and the drugs that are added to the regimen only provide the bacterium with new opportunities for developing additional resistance. The Case Record appearing in this issue of the Journal (pages 2456-2464) provides a vivid example of the deadly consequences of prescribing a standardized regimen in a severely ill patient without knowing the drug susceptibility of the causative organism.5 Recognizing the urgency of this problem, the Stop TB Partnership has defined one of its major objectives as the improvement of laboratory facilities and services and the training of personnel to permit the introduction of new, rapid diagnostic tests for MDR tuberculosis.1
The threat of MDR and XDR tuberculosis could hardly have come at a worse time - in the midst of the worst economic conditions in a century. In theory, the cost burden to developing countries for treatment of MDR and XDR cases may far exceed their total budgets for health care, and aid from the Global Fund to Fight AIDS, Tuberculosis, and Malaria or other sources will be essential for some time if we are to try to control this problem.
On a note of optimism, the Stop TB Partnership has established the Global Laboratory Initiative to promote the availability of new diagnostic tools in countries with a high MDR burden, country-specific budgets are being prepared, and funding could become available through the Global Fund and through UNITAID (an international facility for the purchase of drugs against HIV-AIDS, malaria, and tuberculosis). A number of new antituberculosis agents are in the developmental pipeline, many under the aegis of the Global Alliance for TB Drug Development, and some have already entered clinical evaluation in studies of early bactericidal activity and the treatment of MDR tuberculosis. However, it must be recognized that the development of a new antituberculosis agent is a long, expensive process; if these agents are distributed in places with dysfunctional health services, where the need is probably the greatest, the development of resistance could leave us worse off in a decade than we are now. "Self-supervised DOTS" is not DOTS, and if health systems remain dysfunctional, any new drug will follow the same path to resistance that our current drugs have taken. The tuberculosis tide has turned, but maintaining the momentum will require a financial and political commitment that may be beyond the capability of many struggling communities.
Dr. Donald reports receiving consulting fees from the Global Alliance for TB Drug Development. No other potential conflict of interest relevant to this article was reported.
Source Information
Dr. Donald is an emeritus professor in the Department of Paediatrics and Child Health, and Dr. van Helden a professor and head of the Division of Molecular Biology and Human Genetics, Medical Research Council Centre for Molecular and Cellular Biology, National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Health Sciences, University of Stellenbosch, Stellenbosch, South Africa.
References
1. Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009 (Publication no. WHO/HTM/TB/2009.411.). Geneva: World Health Organization, 2009.
2. Zager EM, McNerney R. Multidrug-resistant tuberculosis. BMC Infect Dis 2008;8:10-10. [CrossRef][Medline]
3. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs -- worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep 2006;55:301-305. [Medline]
4. Millen SJ, Uys PW, Hargrove J, van Helden PD, Williams BG. The effect of diagnostic delays on the drop-out rate and the total delay to diagnosis of tuberculosis. PLoS ONE 2008;3:e1933-e1933. [CrossRef][Medline]
5. van Helden PD, Donald PR, Victor TC, et al. Antimicrobial resistance in tuberculosis: an international perspective. Expert Rev Anti Infect Ther 2006;4:759-766. [CrossRef][Medline]
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