TB Drug Combinations Move Into Mice

NEW YORK, NY, JULY 8, 2008 – The TB Alliance, in collaboration with The Johns Hopkins University (JHU) and National Jewish Medical and Research Center, is moving its combination testing program into mice.  This step marks the first time such a large set of current and potential tuberculosis (TB) drugs will be tested comprehensively in an animal model of TB.  The results will form the basis and rationale for selecting new, and potentially lifesaving, drug combinations to be studied in humans for their potential to treat both drug-sensitive and drug-resistant TB.

Multi-drug combinations, which can kill Mycobacterium tuberculosis (M.tb) bacteria by hitting multiple targets simultaneously, are the unit of therapy for TB treatment and are necessary to prevent the development of drug resistance.  Therefore, the traditional pathway of drug development — studying one new drug at a time — needs to be complemented with a program that considers multiple new drug combinations.  By including many potential drugs that bind novel targets, the combinations should have the potential for treating both drug-sensitive and drug-resistant TB.

In conventional TB drug development, individual drugs have been added to or substituted into the existing first-line or second-line drug combinations.  "But if you were aiming for an entirely new drug regimen, with two, three or four brand new drugs, it might take 20 or 30 years to go through those combinations in human testing," says Dr. Eric Nuermberger, who with Dr. Jacques Grosset is leading the group at JHU.

The alternative is a methodical study of all potential drug combinations in the mouse model.  "When you can't be entirely rational, you must resort to mechanical combination screening," says Nuermberger.  That is possible in the mouse model, where tens of combinations can be studied in hundreds of mice simultaneously.

This in vivo combination testing builds on lessons learned in the first, in vitro part of this project, which was performed at University of Illinois at Chicago under the direction of Dr. Scott Franzblau.  The in vitro testing yielded clues about which drugs might be antagonistic (working against each other) and which might be synergistic (yielding a result that is greater than the sum of their individual actions).

Based on the in vitro results and limited previous testing in mice, the 80 total possible 3-drug combinations were triaged.  Twelve were eliminated, and the remainder were given varying priorities for further testing.  The work in mice will have three stages: a 4-week preliminary test for the ability to kill M.tb; a more rigorous 4-month test of the time required to eliminate all M.tb in the lungs; and, finally, an analysis of the treatment time required to prevent relapse.  The last of the three tests is labor-intensive but likely the most predictive for assessing new TB treatments.

The in vivo testing is an important advance on the in vitro work, which gave only a static view using constant drug concentrations against a relatively homogenous M.tb population.  The new animal tests will mimic the human condition with fluctuating drug levels (as drugs are gradually metabolized and excreted), drugs concentrating in different tissues, and M.tb bacteria adopting various forms of growth and behavior in different cells and tissues.

TB drug pharmacologist, Dr. Charles Peloquin from the National Jewish Medical and Research Center, is helping Nuermberger's team to match mouse doses with equivalent human doses.  With the newer drugs, the team must still make some educated guesses about dosing.  "However," says Nuermberger, "this project is exploratory.  If we happen to overestimate the exposure you can achieve in humans, that is OK — we are also looking for the potential benefit of a given class of compounds."

Ultimately, the combination testing program may set new standards in the TB drug development process — a process that has not been advanced in the last forty years.

With the insight gained from mouse models, Nuermberger hopes that entirely new combinations of TB drugs may be approved for human trials against both drug-sensitive and drug-resistant diseases, thus boosting the chances of revolutionizing the treatment of TB.