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Emerging Drugs for Active Tuberculosis

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Emerging Drugs for Active Tuberculosis Emerging Drugs for Active Tuberculosis Ann M. Ginsberg, M.D., Ph.D.1 ABSTRACT Tuberculosis (TB) drug research and development lay largely fallow from the 1960s to the turn of the century. A realization that current treatments for this major public health epidemic are proving inadequate to control the disease and prevent development and spread of drug resistance has stimulated renewed activity during the past 5 to 10 years. As a result, there are now seven drugs in clinical development for TB and many groups working on discovery-stage projects. This article summarizes the published information available on the seven clinical candidates and describes some of the challenges faced by those pursuing research and development of novel TB therapies. KEYWORDS: Tuberculosis, treatment, clinical development, drug resistance Physicians are using the same first-line treatment Global Report on TB4 reports that in 2006 there were regimen for active tuberculosis (TB) today as they have 9.2 million new cases of active TB worldwide and 1.7 since the 1980s.1 This multidrug regimen is highly million deaths, including 200,000 individuals who died efficacious when delivered and taken appropriately, but from HIV-associated TB. These figures represent a it is lengthy, complex, and has the potential for signifi- slowing of progress in control of TB relative to the cant side effects, and therefore challenges patients’ WHO-reported data for the previous 5 years.4 adherence to the recommended treatment. The basic The complexity and duration of current TB treat- regimen recommended by the World Health Organiza- ment regimens are major factors in limiting progress in tion (WHO), American Thoracic Society, U.S. Centers TB control. Successful use of these regimens in the field for Disease Control and Prevention, and Infectious requires a labor-intensive strategy known as directly Disease Society of America2 includes 2 months of observed treatment, short-course (DOTS)5 to ensure intensive, directly observed therapy with isoniazid, high rates of patient treatment adherence and comple- rifampicin, pyrazinamide, and ethambutol (the ‘intensive tion, which has proven difficult for many national phase’’) followed by a minimum of 4 months of isoniazid TB control programs to sustain adequately over long and rifampicin, with treatment administered daily or at periods.4 Failure to achieve patient adherence to the least three times a week (the ‘‘continuation phase’’). This recommended treatment regimen not only lowers cure regimen is highly efficacious when administered under rates, raising both transmission and mortality rates, but trial conditions, demonstrating cure rates of 95% or leads to the development of drug resistant strains of higher, with relapse rates of less than 5% in the first 1 Mycobacterium tuberculosis. Multidrug-resistant TB to 2 years following treatment completion.3 However, (MDR-TB), including its most highly resistant forms, widespread promotion of this treatment regimen extensively drug resistant TB (XDR-TB),6 is increasing through WHO, national TB treatment programs, and in incidence and spreading globally.7 Currently available, other TB control organizations has provided only lim- second-line drugs for treatment of drug resistant TB are ited success in global TB control. The WHO 2008 inherently inadequate; they have limited efficacy and 1Clinical Development, Global Alliance for TB Drug Development, Tuberculosis; Guest Editor, Neil W. Schluger, M.D. New York, New York. Semin Respir Crit Care Med 2008;29:552–559. Copyright # Address for correspondence and reprint requests: Ann M. 2008 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, Ginsberg, M.D., Ph.D., Clinical Development, Global Alliance New York, NY 10001, USA. Tel: +1(212) 584-4662. for TB Drug Development, 40 Wall St., 24th Fl., New York, NY DOI 10.1055/s-0028-1085706. ISSN 1069-3424. 10005 (e-mail: [email protected]). 552 This document was prepared for the exclusive use of Derek Ambrosino. Unauthorized distribution is strictly prohibited. EMERGING DRUGS FOR ACTIVE TUBERCULOSIS/GINSBERG 553 significant associated toxicities, are more difficult to scribed in this product profile are advanced, whereas administer than the first-line drugs, and are far more those that fail to meet key milestones are typically costly.8,9 terminated from further development. Despite a clear need for more field-effective TB treatments (i.e., drug regimens that could be easily administered and adhered to), while demonstrating TARGET PRODUCT PROFILES high levels of safety and efficacy against both drug In the search for improved drugs to treat drug sensitive, sensitive and drug resistant strains of M. tuberculosis, active tuberculosis, the target product profile might the last new class of TB drugs discovered was the include (1) the ability to shorten treatment duration to rifamycins discovered in the late 1950s10 and first 2 months or less (typically defined as potency greater used to treat TB in the early 1960s.1 In the past 10 years than the most active first-line drug, isoniazid, against M. or so, this lack of activity has finally begun to change, tuberculosis growing under aerobic conditions, and/or with efforts in both the public and private sectors (and potency greater than the best current drug, rifampin, frequently involving collaborations between these two under conditions where M. tuberculosis is slowly replicat- sectors) under way to discover and develop improved TB ing; the latter serves as a model of the ‘‘drug-persistent’’ therapies. This article summarizes many of these efforts, state and therefore as a marker of a compound’s potential with a particular emphasis on the most advanced com- to shorten treatment-duration); (2) safety at least as good pounds, which are currently in clinical development. as that of current first-line TB drugs; (3) a novel mechanism of action for TB treatment; (4) oral bioavail- ability; (5) pharmacokinetic–pharmacodynamic profile THE DRUG RESEARCH AND consistent with once-daily or less frequent dosing; (6) DEVELOPMENT PROCESS minimal or no interactions with hepatic cytochrome The process followed throughout the pharmaceutical P450 enzymes (and therefore minimal potential for industry to discover and develop new drugs has been drug–drug interactions, especially with antiretroviral reviewed many times11,12 and will not be described in therapy); and (7) low cost of goods. detail here. Suffice it to say that for TB drug discovery For MDR- and XDR-TB, the target product the research process most often begins either via profile might pose a somewhat lower ‘‘bar’’ because the phenotypic screening of compound libraries against currently available drugs are less effective, have more M. tuberculosis or a surrogate organism, such as associated adverse effects, and are significantly more M. smegmatis or bacille Calmette-Gue´rin (BCG) grow- expensive.14 For this therapeutic indication, then, the ingininvitrocultureunderoneormoreofavarietyof desired characteristics of a new drug might include (1) conditions (such as aerobic, low oxygen, or nitrogen novel mechanism of action (to ensure activity against a starvation, or in infected macrophages) or compound maximum number of strains resistant to the current libraries are screened against a ‘‘target’’ of interest. The drugs); (2) safety profile at least as good and preferably target has typically been a mycobacterial protein be- better than the current second-line TB drugs; (3) ability lieved important for bacterial survival in the host. In to shorten treatment duration and/or improve cure rates some cases, investigators have screened against whole when given in combination with other second-line TB pathways (such as transcription/translation or more drugs; (4) orally bioavailable; (5) pharmacokinetic–phar- recently, electron transport). Once a set of compounds macodynamic profile consistent with once daily or less is identified with activity against the pathogen or target frequent dosing; (6) minimal or no interactions with (‘‘hits’’), they must be winnowed down to identify hepatic cytochrome P450 enzymes; and (7) low cost of ‘‘lead’’ compounds (i.e., compounds that have druglike goods relative to current second-line TB drugs. properties and the potentialtofulfilltheideal‘‘product profile’’ as discussed in the following section). Lead compounds are then optimized, primarily by medicinal EMERGING DRUGS FOR TB: CANDIDATES chemists, working with biologists to identify key struc- IN CLINICAL DEVELOPMENT ture–activity and structure–toxicity relationships. One Seven candidate TB drugs representing five different or more optimized lead compounds are then selected chemical classes are currently known to be undergoing for intensive preclinical testing before selection of a clinical evaluation. These will be described by chemical compound to enter human testing (‘‘clinical develop- class, in order according to stage of clinical development. ment’’; divided into phases I to III,13 leading to regis- tration). Throughout the research and development process, compounds are evaluated in a series of assays Fluoroquinolones: Gatifloxacin and tests to compare them to a predefined, ideal or and Moxifloxacin ‘‘target product profile.’’ Compounds that continue to The furthest advanced of these seven are two drugs demonstrate the potential to fulfill the criteria de- belonging to the family of C8-methoxy fluoroquinolones: This document was prepared for the exclusive use of Derek Ambrosino. Unauthorized distribution is strictly prohibited. 554 SEMINARS IN RESPIRATORY
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