TB Alliance Launches Groundbreaking Preclinical TB Drug Combo Study; Prepares to Advance Two New TB Drugs to Phase II and III Trials in Patients

July 8, 2007

The TB Alliance is launching an innovative approach to accelerating the identification and development of new, optimized, combination drug regimens for TB. In active TB, all therapy must involve multiple drugs to prevent the development of resistance. The new, aggressive strategy will survey potential TB drug combinations in preclinical models - well before clinical evaluation - an approach that has never been employed previously in TB drug development. This new plan has the potential to significantly decrease the time it will take to develop novel optimized, combination therapies for TB.

At the same time, the TB Alliance is preparing to move PA-824 -- its first novel TB drug candidate -- into TB patients for the first time later this summer, while also working with its partners to advance moxifloxacin -- another new TB treatment option with the potential to shorten treatment time -- into large scale, Phase III clinical trials starting this fall.

A New R&D Approach for Regimens

Mycobacterium tuberculosis (M. tb.), the bacillus that causes TB, is a complex, resilient organism, and new, better TB treatments will still require multiple drugs to be taken in combination to optimize efficacy and prevent development of drug-resistance. An optimized 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 HIV.

The conventional approach to TB drug 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 Phase IIB and III. All told, a regimen consisting of completely new drugs would require more than twenty-four years of clinical 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. To jump start this new, aggressive approach, the TB Alliance has just selected two research grantees to begin evaluating anti-TB compounds in combination in preclinical models.

The study will be a comprehensive survey of potential drug combinations, including currently available drugs and drugs in clinical trials. One research team has been selected to screen in vitro the potential synergistic and antagonistic effects of various drug combinations against M. tb., under both replicating and non-replicating conditions. Another research team will then evaluate the most promising combinations in vivo for potential pharmacokinetic interactions and for optimal efficacy. The initial in vivo work will be done in a mouse model system.

After promising combinations have been identified with the potential for shortening therapy to three months or less, the most potentially efficacious combinations would be confirmed in a secondary animal infection model. The best new regimens will then be moved into preclinical development, followed – if merited – by clinical trials in humans. In the meantime, any necessary Phase I trials will be conducted for the individual drugs, as well as combination pharmacokinetic interaction and safety studies in healthy volunteers.

To advance this new paradigm of drug combination development, the TB Alliance has initiated discussions with regulatory agencies including, but not limited to, the U.S. Food and Drug Administration, the European Medicines Agency and the South African Medicines Control Council. The TB Alliance’s “Open Forums on Key Regulatory Issues in TB Drug Development" will also continue in support of these discussions, and other issues related to accelerating TB drug development and approval.

Stage is set for two clinical milestones

The TB Alliance and its partners are preparing to advance two promising clinical candidates into the next phase of research in TB patients.

PA-824, from the initial compound class brought into the TB Alliance’s portfolio, is poised to enter Phase II trials as early as next month. Moxifloxacin, already approved for other indications, including the treatment of acute respiratory infections, is on track to enter Phase III trials this fall to evaluate its efficacy as a replacement for either of two drugs in the current four-drug TB regimen.

PA-824 is a nitroimidazole, a novel class of anti-bacterial agents for the treatment of TB. As a potential TB drug, it has many attractive characteristics — most notably its novel mechanism of action, its activity in vitro against all tested drug-resistant clinical isolates, and its activity as both a potent bactericidal and sterilizing agent in mice. With the completion of several Phase I trials in healthy volunteers, PA-824 will enter a Phase II Early Bactericidal Activity study in TB patients in South Africa.

Moxifloxacin is a fluoroquinolone, a subset of the quinolone class of antibiotics. Developed by Bayer HealthCare AG, moxifloxacin has demonstrated efficacy for the treatment of acute respiratory and some skin infections. It also has an excellent safety record, having been used more than 60 million times, in 104 countries. Moxifloxacin's mechanism of action differs from those of the first-line drugs currently used to treat tuberculosis, and it has demonstrated activity against M. tb. in both in vitro and in vivo studies.

The REMoxTB Phase III clinical trial will be led by investigators at the University College London and the British Medical Research Council as part of a global clinical trial program coordinated by the TB Alliance and Bayer Healthcare AG. Animal studies and early studies in humans suggest that moxifloxacin has the potential to reduce treatment duration to four months or less. The REMoxTB trial will assess whether a four month regimen, with moxifloxacin replacing one of two current drugs, isoniazid or ethambutol, can be considered non-inferior when compared with the standard six month regimen. The first Phase III clinical trial sites are in Kenya, South Africa, Tanzania and Zambia, with additional research sites expected.