New Tuberculosis Drug Development
How Can We Do Better?

	ARTICLE

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In 1985, this journal published a report suggesting that a new fluoroquinolone antibiotic, ofloxacin, might be useful for the treatment of tuberculosis (1). An accompanying editorial discussed impediments to the development of new drugs for tuberculosis but concluded that "the potential for significant advances in the near future is certainly promising" (2). At that time, in addition to the fluoroquinolone compounds, several rifamycin derivatives, including rifabutin and rifapentine, were available for clinical trials. It was hoped that these derivatives, with half-lives substantially longer than rifampin, would make possible once-weekly intermittent therapy and, thus, greatly reduce the amount of supervision required for curative treatment.

Unfortunately, the development of new drugs for the treatment and prevention of tuberculosis has been slow. Despite outbreaks of multidrug-resistant tuberculosis (MDR-TB) and calls for new drug development, truly novel compounds which would significantly improve treatment continue to elude us. A review of tuberculosis drug development during the past decade may provide some insight into how we can quicken the pace of progress.

Twelve years after that first report, fluoroquinolone antibiotics have become the most important "second-line" agents for the treatment of patients with MDR-TB, despite the lack of sufficient data to allow Food and Drug Administration (FDA) approval for a tuberculosis indication (3). Their use is based on data from in vitro and animal studies and from several small, nonrandomized, open label clinical trials. The largest randomized trial of a fluoroquinolone for drug susceptible tuberculosis was conducted in Tanzania and found that the sterilizing activity of ciprofloxacin was inferior to that of pyrazinamide and ethambutol together (4).

A newer and promising fluoroquinolone is levofloxacin, the levo-isomer of ofloxacin. Levofloxacin is responsible for the activity of the parent compound (5), and, thus, has double the activity of the parent drug with little increase in toxicity. A study of levofloxacin in HIV-infected patients in the United States was terminated early because of slow patient accrual and did not recruit the number of drug-resistant patients required to demonstrate efficacy, although the drug was found to be safe and well tolerated (6). Outside of the United States there has been little corporate interest in studies of levofloxacin for tuberculosis treatment. Nonetheless, because of its apparent safety and good activity, it may the fluoroquinolone of choice when indicated for tuberculosis treatment.

Of all the fluoroquinolones evaluated in experimental studies, sparfloxacin appeared to have the greatest activity against M. tuberculosis (several-fold greater than either ofloxacin or ciprofloxacin) (7). There was initial corporate resistance to permit clinical evaluation of the drug for tuberculosis, based on two concerns: (1) that the drug, if identified as an antituberculosis drug, might not be approved for the treatment of other, more common indications, and (2) that toxicities not recognized with shorter-term use might become apparent with chronic administration, resulting in withdrawal of the compound or at least significant restriction of its use. Nonetheless, with the assistance of the WHO Global Tuberculosis Programme, plans were made for a European multicenter clinical study of sparfloxacin for the treatment of MDR-TB. However, post-marketing studies in Europe indicated that dose- related phototoxicity occurred in up to 10% of patients receiving the drug, and plans for expanded development of the drug, including the tuberculosis study, came to a halt. The compound has been available in Europe under a "compassionate release" program for the treatment of MDR-TB and has recently been approved by the United States FDA for the treatment of specified acute bacterial infections. Although photosensitization is a major concern, unpublished data from clinical trials suggest that this problem is infrequent in darker-skinned persons and, thus, sparfloxacin may have wider applicability for the treatment of MDR-TB (J. Grosset, personal communication).

In contrast to the experience with fluoroquinolones and tuberculosis is that of the macrolides and Mycobacterium avium complex (MAC) disease. Several factors are responsible for the better success, including the effectiveness of the HIV community in advocating for drug development, the greater market in developed countries for drugs to treat these common HIV-associated opportunistic infections, and the absence of pre-existing effective therapy. Clarithromycin has been shown to be effective in the treatment of disseminated MAC disease (8), and both clarithromycin and azithromycin have been approved for prophylaxis against MAC in HIV-infection (9, 10). However, no macrolide antibiotics with significant in vitro activity against M. tuberculosis have been identified.

We hoped for more from the rifamycin derivatives. Because of increased activity against M. avium complex (MAC) and the common occurrence of disseminated MAC in patients with advanced HIV disease, rifabutin was first studied for the prophylaxis of MAC infection (11), a condition for which FDA approval was granted in 1994. Earlier, there was an expectation that the drug would be of use in some patients with rifampin-resistant tuberculosis, but the data supporting its use for this condition were not strong. Rifabutin has been evaluated in randomized controlled trials of tuberculosis outside the United States (12) and is approved for tuberculosis treatment in a number of countries. Because of relatively little bi-directional drug interaction with indinavir, FDA and the Centers for Disease Control and Prevention (CDC) have suggested that rifabutin be used in place of rifampin for HIV-infected tuberculosis patients for whom an HIV protease inhibitor is indicated (13). Rifabutin was also being evaluated in an international trial for tuberculosis preventive therapy in HIV-infected persons, but the study was terminated early because of slow patient enrollment.

Rifapentine, on the other hand, has been of greater interest as a drug for tuberculosis. Its arduous development history provides important lessons for new drug development. The first lesson is to avoid delay. Because of the long development time and relatively short patent protection, drugs which sit long on the shelf may be of less interest to companies which must answer to their stock holders. Rifapentine was available for clinical studies in tuberculosis as early as 1986, but Merrell Dow's merger with Marion and the subsequent merger to create Hoechst Marion Roussel (HMR) delayed plans for clinical development. With the rising interest in tuberculosis in the early 1990's, clinical trials were initiated. However, nearly a decade of potential experience and profits have been lost.

The second lesson is that any experimental drug to be tested in human studies should meet the highest standards of drug production and safety. A report in this issue of the American Journal of Respiratory and Critical Care Medicine presents the results of the first well documented clinical trial of rifapentine (14). The investigators chose to use drug manufactured in China because "of its [rifapentine's] potential importance and because of delays in its development by Western pharmaceutical companies." Prior to the beginning of the study, the investigators did confirm that the bioavailability of the Chinese product was similar to an earlier formulation of the drug produced by Merrell Dow (15). Unfortunately, during the course of the study it was found that the batches of drug being used were of suboptimal bioavailability (16). This finding makes interpretation of the results difficult.

The finding also raises the question of the appropriate manufacturing standards that should be met before a drug is evaluated in clinical trials. We do not have access to information indicating whether or not the manufacturer of the Chinese product complied with acceptable practice. Clearly, any drug used in human study should meet the international standards specified by the World Health Organization Good Manufacturing Practice (GMP) (17). The conduct of a study of a drug which was not manufactured under GMP has the potential for exposing patients to unknown risks, such as toxicity or therapeutic failure because of inferior potency, as may have been the case in this study. The example of impotent tetanus toxoid in Bangladesh emphasizes the importance of this point (18). In the present study, it was fortunate that the investigators, likely recognizing the well known problems with rifampin bioavailability (19), choose to repeat bioavailability studies on each batch of rifapentine used in the trial. Perhaps this practice should be required for future clinical trials of any drug for which correlation between bioavailability and dissolution test results may not be satisfactory.

A third lesson is that before embarking on costly Phase III trials, it is prudent to determine the optimal dose of the drug to be studied. For rifampin, this was done by the United States Public Health Service (USPHS) Tuberculosis Study 19 which established 600 mg as the optimal dose for most adults (20). For the rifapentine studies, no dose-ranging studies were done, and a 600-mg dose was chosen, based in part on favorable results from clinical trials conducted in China (21). However, a recent study indicates that weekly rifapentine at a dose equivalent to the human dose of 10 mg/kg is modestly inferior to daily rifampin in the treatment of experimental murine tuberculosis (22). Presently, HMR is planning a New Drug Application submission to the FDA for rifapentine based on results of a study conducted in South Africa and the United States, and CDC is evaluating rifapentine in its USPHS Therapy Study 22. Both of these trials include a continuation phase regimen of once-weekly isoniazid and rifapentine, and the results of these studies are eagerly awaited. If, as the authors of the present report conclude, higher doses are required for optimal efficacy, additional development time will be required. Moreover, plans for studies of rifapentine in tuberculosis preventive therapy may hinge on success in the current treatment studies. Experimental studies have suggested that the combination of rifapentine and isoniazid given once weekly for 3 mo would provide a highly effective preventive regimen (23).

In the past, great advances in tuberculosis treatment and drug development came about through trials conducted in the public sector or as public-private partnerships. Internationally, the British Medical Research Council Tuberculosis Unit set the standard (24). In the U.S., the Veterans Administration (VA) and the USPHS conducted a notable series of clinical trials to evaluate new drug regimens for both the treatment and prevention of tuberculosis (25). In 1960, the CDC assumed a major role in these studies when the USPHS Tuberculosis Division was transferred to CDC.

Unfortunately, United States support for the infrastructure required for these studies gradually diminished, so that the last completed trial, USPHS Study 21, was nearly terminated several times during its course for lack of adequate funding. With the recent increase in federal support for tuberculosis control and elimination, CDC has returned to the private-public partnership model, and has established the Tuberculosis Trials Consortium (TBTC) for the specific purpose of conducting USPHS Study 22 (29). This consortium of clinical investigators required both time and substantial financial resources to establish and support but is now functioning efficiently. Currently new drugs and regimens for both tuberculosis treatment and prevention, new diagnostic tests, and new vaccine candidates are becoming available for clinical investigation. The outstanding success of the effort to sequence the genome of M. tuberculosis promises greatly to accelerate the pace with which new candidate drugs and diagnostics become available (30). Concurrently, the challenges posed by the goal of TB elimination are increasing, as rates of drug resistance increase (31) and as the costs associated with assuring high rates of adherence rise (32). The TBTC now provides a unique and important resource for further clinical studies.

Thanks to continued public sector support for new drug development, it is likely that ten years from now we will have made much more progress. Understanding better the perspectives of the pharmaceutical industry can assist in the promotion of new tuberculosis drug development. Important factors, in addition to potential profit, enter into a company's decision to embark on development of a new product. Innovative collaborative relationships between the public and private sectors, which include sharing of costs, will likely be required to sustain private sector interest in tuberculosis. The recent infusion of funds for tuberculosis control and research, both in the United States and worldwide, present an opportunity which should be enthusiastically pursued.

Division of Tuberculosis Elimination Centers   for Disease Control and Prevention Atlanta, Georgia

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