Tuberculosis

ICAAC 2012: Experimental Nitroimidazole TBA-354 Shows Promise against Tuberculosis in Early Studies

The experimental nitroimidazole TBA-354, under investigation by the TB Alliance, showed potent activity against Mycobacterium tuberculosis in vitro and in animal studies, according to a presentation this week at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) in San Francisco.

Nitroimidazoles are a promising new class of drugs being developed for treatment of both drug-sensitive and drug-resistant tuberculosis. While 2 first-generation compounds -- PA-824 and OPC67683 -- are undergoing clinical testing, researchers are working to identify next-generation agents that may be more potent and easier to use. In preclinical studies to date, TBA-354 has demonstrated a favorable pharmacokinetic profile with good oral bioavailability.

Below is an edited excerpt from a press release issued by ICAAC describing this research in more detail.

New Molecule Shows Promise against Tuberculosis

San Francisco -- September 9, 2012 -- TBA-354, a new member of the nitroimidazole class, was discovered by the non-for-profit drug developer, the Global Alliance for TB Drug Development (TB Alliance), in partnership with two academic institutions, the University of Auckland and the University of Illinois at Chicago. This compound was discovered by the partnership with the aim to maximize the potential of this emerging class of anti-tubercular compounds for the treatment of both drug-sensitive and drug-resistant tuberculosis (TB).

TBA-354 is more potent against animal models of TB than another compound of the same class, PA-824, which has already shown promise against TB in clinical trials. This advantage of TBA-354 over PA-824 was consistently observed in various models of TB infection conducted in multiple laboratories, and when administered as a single drug or in combination with companion drugs pyrazinamide and moxifloxacin. TBA-354 is predicted to be effective against TB in both drug-sensitive and MDR-TB patients when administered at low once daily or less frequent doses, lending this compound potential as a next generation nitroimidazole anti-tubercular agent.

Accounting for nearly 9 million new active cases and 1.5 million deaths in the world annually, TB is a leading global health threat for which no new drugs have been developed in nearly 50 years. Additionally, drug-resistant forms of TB are emerging with increased frequency as a result of the inadequacies of current therapy. The length and complexity of TB treatment makes treatment adherence extremely challenging in endemic countries.

TBA-354 belongs to the nitroimadazole class. Other drugs from this class have exhibited promising activity against TB bacteria in the lab and in clinical trials -- two of the most advanced new TB drug candidates (PA-824 and delamanid) belong to this class. Having shown greater potency compared to PA-824 and an improved pharmacokinetic profile compared to delamanid, along with other promising properties, TBA-354 offers the potential to shorten and simplify TB treatment further than therapies currently under clinical development. Its increased potency against TB could also reduce the cost, pill size, frequency and/or side effects of treatment with a nitroimidazole by achieving comparable efficacy with less drug amount. Importantly, because it belongs to a novel class of drugs, TBA-354 projects to be effective in treating both drug-sensitive and drug-resistant TB.

TBA-354 was discovered by the TB Alliance in partnership with the University of Auckland and the University of Illinois at Chicago. The TB Alliance is a not-for-profit product development partnership (PDP) that operates like a biopharmaceutical company. The medicinal chemistry that led to discovery of TBA-354 was conducted at the Auckland Society for Cancer Research Center at University of Auckland and the biology was conducted at the University of Illinois at Chicago. Further in-depth profiling of the compound was led by the TB Alliance in collaboration with Johns Hopkins University, University of Illinois at Chicago and RTI International. Financial support for this project was provided by the Bill & Melinda Gates Foundation and UK Aid. The work was presented at ICAAC 2012 in San Francisco on Sept 10th 2012.

TBA-354’s excellent efficacy and pharmacokinetic profile make it a promising candidate to deliver superior bactericidal results from a small daily pill. The evidence of TBA-354’s effectiveness was found in animal models of TB, which, while often predictive, have their limitations. Clinical trials are needed to evaluate TBA-354’s effectiveness against TB in patients. Before proceeding to clinical trials, the safety and tolerability of TBA-354 must be evaluated; these toxicology and safety pharmacology studies are underway and will provide more information concerning the potential of this compound.

One of the major challenges of TB treatment, as well as drivers of drug-resistance remains the length and complexity of current treatment. Defeating the TB pandemic will require new drugs that shorten and simplify treatment. Given the disproportionate skew of the TB burden in the developing world, all new TB treatments must also be inexpensive enough to facilitate scale-up. As the most potent anti-tubercular nitroimidazole under development to date, TBA-354 offers great promise in many ways. Its potency may enable the reduction of length, cost, and side-effects of TB treatment. It is compatible with commonly used AIDS medications in ways that some currently used TB treatments are not. Further, nitroimadzoles have already proven combinable with other experimental TB drugs to form novel treatments regimens with the potential to cure both drug-sensitive and MDR-TB.

9/11/12

Reference

AM Upton. TBA-354: A Next Generation Nitroimidazole for Treatment of Drug Sensitive and Drug-Resistant Tuberculosis.52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Francisco. September 9-12, 2012. Abstract 438.

Other Source

ICAAC/American Society for Microbiology. New Molecule Shows Promise against Tuberculosis. Press release. September 9, 2012.