The non-profit Global Alliance for TB Drug Development (TB Alliance) has announced two “pivotal milestones” in its efforts to accelerate the discovery and development of new drugs to combat tuberculosis.

The TB Alliance, which works with public and private partners worldwide on finding drugs that will shorten treatment for tuberculosis, tackle both susceptible and resistant strains, ensure compatibility with antiretrovirals where needed and improve treatment of latent infection, is recruiting for a large-scale Phase III clinical trial in TB patients with moxifloxacin, the fluoroquinolone antibiotic already marketed worldwide by Bayer HealthCare as Avelox or Avalox for other respiratory infections.

The Alliance is also launching a Phase IIa trial with PA-824, a TB drug candidate in the nitroimidazole class originally developed by US biotechnology company Chiron (now part of Novartis).

The moxifloxacin Phase III programme, called REMox TB, is being led by investigators from University College London and the British Medical Research Council in the UK. Recruitment for the global study will begin at six sites in Kenya, South Africa, Tanzania and Zambia. It will look at whether each of two four-month regimens substituting moxifloxacin for one of the current standard TB treatments (ethambutol or isoniazid) is as effective as the routine six-month regimen in terms of failure and relapse.

Moxifloxacin, which has a different mechanism of action from current first-line drugs for tuberculosis and has demonstrated activity in vitro and in vivo against Mycobacterium tuberculosis, the bacillus that causes TB, is the first drug in the TB Alliance portfolio to enter a pivotal registration trial.

First novel candidate
PA-824 is the first novel TB drug candidate developed by a not-for-profit organisation to reach clinical trials, the Alliance notes. It gained worldwide exclusive rights to the compound and its analogues for the treatment of TB under a 2002 agreement with Chiron, which also ensured the technology would be made available royalty-free in endemic countries.

The short-term potency of PA-824 given as monotherapy is being evaluated in a Phase IIa Early Bactericidal Activity (EBA) study in tuberculosis patients. Enrollees at two sites in Cape Town, South Africa, will receive either PA-824 or the standard four-drug TB treatment for 14 days. If the results are positive, PA-824 will advance to Phase IIb trials testing its safety, tolerability and efficacy in combination with other, currently effective drugs.

Phase I studies of PA-824 in healthy volunteers showed the drug to be well tolerated, with no dose-limiting adverse events, the Alliance said.