Strategic Initiatives

Evaluation of New Drug Combinations Mycobacterium tuberculosis (M.tb) is a complex, resilient organism, and it is important to recognize that new, better TB treatments will still require drugs taken in combination. A novel combination therapy should significantly reduce TB's six month treatment time, be effective against drug-resistant strains, and be compatible with anti-retroviral therapy used to treat patients with TB-HIV co-infection. But the conventional approach to drug combination development evaluates potential compounds sequentially, substituting them individually into the existing regimen. Each alteration is studied in clinical trials, which take at least six years to complete. All told, a regimen of new drugs would require more than twenty-four years of development — too long to wait.

To meet this challenge, the TB Alliance is promoting a new paradigm for TB drug development that would significantly shorten the time required for new regimens. This new method has the potential to develop even a totally novel combination therapy in as little as six years.

Under the new approach, each potential drug compound would be assessed individually through Phase I and Early Bactericidal Activity trials. At the same time, all potential combinations would be evaluated in preclinical models. This would first involve identifying any two agents' potential in vitro synergistic and antagonistic effects against M.tb, under both replicating and non-replicating conditions, in the lab. Potential drug combinations would then be evaluated in vivo for potential pharmacokinetic interactions, and prioritized for efficacy studies in mice. Promising combinations with significant efficacy would be further evaluated for their sterilizing activity. Once up to five combinations have been identified with the potential for shortening therapy to less than three months, the two or three most effective combinations would be confirmed in a secondary animal infection model. The most effective new regimens would then be moved into clinical trials in humans: Phase I trials for pharmacokinetic interaction and safety studies in healthy volunteers, followed by Phase II and III trials in patients.

In order to advance this new paradigm of combination development, the TB Alliance has initiated discussions with regulatory agencies including, but not limited to, the U.S. Food and Drug Administration and the European Medicines Agency. The first two "Open Forums on Key Regulatory Issues in TB Drug Development" have been held, and more are planned. The TB Alliance is also in discussions with other TB drug sponsors, to make new and existing compounds available for combination testing.

The Alliance has developed a comprehensive handbook that brings together information on a total of 27 compounds, including all drugs approved to treat tuberculosis, compounds in clinical development for TB, and some approved drugs being investigated for potential use in TB, such as moxifloxacin. Referenced data include physical characteristics, basic biology, efficacy and safety in humans, and absorption, distribution, metabolism and excretion (ADME).

The Handbook was developed as a resource for the TB drug research community, and is available free of charge. It will be updated periodically. Researchers are encouraged to send comments and suggestions to

To download the handbook, click here.

Identification of Biomarkers Phase I-III TB drug clinical development programs currently require a minimum of six years — far longer than trials for other infectious diseases. New drugs and drug combinations must prove safe for human use, and they must demonstrate their efficacy against Mycobacterium tuberculosis, which requires months of treatment. This is followed in Phase III clinical development by one to two years of post-treatment evaluation, so that patients can be monitored for relapse rates. Trial costs are high, and each additional month of testing, while essential, delays the introduction of new medicines that could save lives.

The TB Alliance is working to streamline the clinical development process through the identification of biomarkers for TB. Biomarkers are biological features or substances that can be used as indicators of treatment effectiveness. For example, HIV/AIDS drug development was revolutionized by the validation of biomarkers like viral load and CD4 counts, which dramatically shortened the duration of clinical trials.

The TB Alliance hopes to identify two types of potential biomarkers. The first type would provide an early indication of a candidate drug's potential efficacy during Phase I or II testing. The second type would be surrogate markers of efficacy, for use as primary endpoints — limiting the need to monitor for relapses. This latter type could shorten the duration of pivotal Phase III trials. The TB Alliance is collaborating on this project with Colorado State University and BG Medicine, a biotechnology company specializing in the identification of biomarkers. BG Medicine employs a proprietary platform that utilizes genomics, transcriptomics, proteomics, and metabolomics, to identify specific markers of a disease process or cure.

The biomarkers study, initiated by the TB Alliance in 2005, includes the analysis of in vitro culture supernatant samples and plasma from TB infected mice, with and without treatment over a predetermined length of time. The study is currently in its final stages; once a number of candidate molecules have been identified, they will be matched with the disease process. They will first be validated, by demonstrating their utility in predicting cure versus relapse in a murine (mouse) infection model.

Once these assessments have been completed, potential biomarkers will be ranked according to their ability to predict drug efficacy, and cure versus relapse. The TB Alliance will develop assays based on the prioritized markers, for use with archived human clinical samples. This will determine the presence of these markers in human disease. The end goal of this project is to validate biomarkers for human TB, so that they may be used in clinical trials for novel TB drugs.

The use of biomarkers is a safe and proven scientific method; once potential markers are identified, they are rigorously tested and must be approved for use by regulatory authorities. The process is complex, but the potential rewards are enormous. Successful identification of relevant biomarkers would revolutionize TB drug development, and speed the process of improving treatment for the millions who suffer from TB.

Murine (mouse) Model of Tuberculosis When animals are used to investigate the potential effects of an illness or treatment on humans, it is known as an animal model of disease. Each model is unique — based on the animals used, the disease, and specific research methods. In drug development, animal models are used to test the safety and effectiveness of new medicines before they enter human clinical trials.

As TB drug discovery projects move through the pipeline, animal models of TB are used to demonstrate and compare potential molecules and establish lead candidates for further research. Once a lead candidate has been selected, models can serve multiple purposes, defining the dose response of the individual compound, pharmacokinetic interactions between compounds, pharmacokinetic pharmacodynamic (PK/PD) drivers, optimal dosing regimens, and optimal combinations.

For tuberculosis, the best, validated animal model for predicting drug efficacy in humans is a murine (mouse) model developed by Dr. Jacques Grosset, of the Center for Tuberculosis Research at Johns Hopkins University. Since early 2002, the TB Alliance has collaborated with Johns Hopkins in the establishment and maintenance of a vivarium to house this model, ensuring its availability for ongoing drug research.

In the Grosset mouse model, mice that have been infected with aerosolized Mycobacterium tuberculosis are treated with single drugs or combination regimens for varying periods of time, to determine the ability of these molecules. While no model perfectly mimics the human condition, the murine model appears to be predictive of drug efficacy in man. This conclusion is based upon comparative data with drugs known to be effective in the treatment of TB. Experiments that use this mouse model are therefore expected to provide key data for guiding the development of improved TB regimens comprised of novel treatments.

So far, the Grosset mouse model has been used by the TB Alliance to evaluate its lead drug candidates, moxifloxacin and PA 824.

These animal model studies have led to a number of important findings:

1. Replacing Isoniazid, a current first-line TB drug that is ineffective against MDR-TB, with moxifloxacin yields positive results;
2. Determining the minimum effective dose and minimum bactericidal dose of PA 824; and
3. Evaluating the efficacy of combination regimens containing moxifloxacin and/or PA 824.

These animal model studies led to a number of important findings:

1. Isoniazid, a current first-line TB drug that is ineffective against MDR-TB, could be replaced by moxifloxacin;
2. A moxifloxacin regimen has the potential to shorten the duration of TB therapy for active disease; and
3. A combination that replaces both rifampin and isoniazid with moxifloxacin and PA-824 might be possible, and may have significant benefits.

Clinical Trials Site Assessment Developing drugs to treat a disease that has had no new cure in decades is a constant challenge. Resources are limited and the scientific infrastructure to support laboratory and clinical research is literally being reinvented. Until very recently, clinical trials to evaluate new TB drugs in humans have not been conducted in over forty years. Not knowing the global capabilities to support increasing numbers of TB drug clinical trials, the TB Alliance launched a first-ever comprehensive assessment of clinical trial sites for their potential use in large-scale TB drug trials.

The Clinical Trial Process
Clinical trials are an integral part of the drug development process. Once promising compounds have been identified and thoroughly tested in a pre-clinical setting, carefully conducted trials ensure that they are both safe and effective. In Phase I studies, the new drug or combination is tested in a small group of humans, usually healthy volunteers, to establish how the drug is absorbed and distributed throughout the body. Careful attention is given to the drug's safety, to possible side effects, and to the study of its pharmacokinetics. In Phase II, the drug is given to a larger group of people who are infected with the disease, to determine the appropriate dosage and to determine if it is a safe and effective treatment. Finally, Phase III trials utilize a large number of affected patients to confirm efficacy and tolerability, monitor side effects, and study how best to administer the new treatment. Additional testing is often conducted after the drug has been registered and made available to patients (Phase IV).

Clinical trials for new treatments have certain requirements: a controlled environment, an informed and willing pool of patients or subjects, and the scientific equipment and expertise necessary to closely monitor volunteers. Trial sites must be capable of operating in full compliance with current Good Clinical Practice and Good Laboratory Practice (cGCP/cGLP) — the regulatory standard for clinical research.

The clinical trials site assessment included over 50 sites across the globe: in Africa, Asia, Eastern Europe and North and South America. Potential clinical sites and site laboratories were evaluated for their ability to perform registration-standard Phase II and Phase III TB drug trials. There was a particular emphasis on laboratory capability in handling sputum samples from TB patients, and on a site's ability to conduct cGCP/cGLP-compliant studies.

Initial results from this study are now available to the public. As additional trial sites are evaluated, their results will also be added to the database. This wide-scale evaluation is already proving useful as the TB Alliance continues to expand its clinical trial program. The database is enabling the identification of appropriate sites, and highlighting the infrastructure gaps of sites needing improvements. The TB Alliance sees the clinical trial site assessment project as an important contribution to the scientific infrastructure needed to support clinical TB research. This information may speed the advancement of new treatments for TB and, in the long run, save lives.

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