TB Alliance Portfolio Update November 2003

November 23, 2003

The TB Alliance has assembled a portfolio of promising anti-TB compounds and is overseeing their development. The compounds, which were carefully selected through TB Alliance business development initiatives including requests for proposals (RFPs), span the lead identification, lead optimization, and preclinical development phases. The portfolio reflects the TB Alliance strategy to engage expertise and resources in every discipline worldwide from academia, industry and public laboratories.

PA-824 & Analogs. PA-824, the first TB Alliance compound acquired through an exclusive license deal with Chiron Corporation in June 2002, has moved briskly through the R&D pipeline reaching several important milestones in preclinical development. These milestones addressed key issues of compound synthesis, toxicology and preclinical efficacy. If extensive animal toxicology studies in the next year are similarly successful, the TB Alliance will be able to enter Phase I clinical trials.

MJH-98-I-81 is an analog of isoniazid and a lead compound from the research project at Dr. Michael Hearn’s laboratory at Wellesley College. Through a two-year research project with the TB Alliance, Dr. Hearn has synthesized hundreds of distinct molecules. Emphasizing diversity, the goal is to find a path to a new drug using a wealth of existing and novel chemistry. MJH-98-1-81, an analog of isoniazid (INH), the cornerstone of current therapy, has good activity in vitro against M. tuberculosis and a high selectivity index.

KRQ-10018. KRQ-10018, a novel quinolizine compound, is at the lead optimization stage at the Korea Research Institute of Chemical Technology (KRICT) in Taejon, South Korea. Acquired by the TB Alliance in April 2003, KRQ-10018 has demonstrated activity and specificity for tuberculosis. The compound is to be further evaluated for preclinical efficacy.

Quinolzines and Pyridones. Under the same agreement, the Korea Research Institute of Chemical Technology (KRICT) is synthesizing hundreds of quinolizines, quinolone and pyridone compounds. Quinolones, which are structurally similar to the quinolizines, are already on the market for other indications and have great potential for the treatment of TB. Compounds will be further tested in vitro and in vivo for specific activity against TB by KRICT’s partner, the Yonsei University in Seoul.

Moxifloxacin. Moxifloxacin, a quinolone with worldwide regulatory approval and developed by Bayer AG for use in the U.S. for treatment of skin and upper respiratory tract infections and pneumonia, has shown high levels of activity against TB in in vitro models. Research funded by the TB Alliance has affirmed moxifloxacin’s early promise for shorter therapy through in vivo experiments in a mouse model developed by Dr. Jacques Grosset of the Johns Hopkins University. Through a collaboration facilitated by the TB Alliance, the CDC TB Trials Consortium has undertaken a Phase II clinical trial to determine the acceptability and short-term efficacy of a moxifloxacin-containing regimen.

Murine Models. Dr. Jacques Grosset, a researcher at the Johns Hopkins University, is widely recognized for his mouse model of tuberculosis which closely mimics human disease, allowing drug candidates to be tested prior to clinical trials. In research funded by the TB Alliance, Dr. Grosset’s mouse model affirmed the in vitro activity of moxifloxacin against M. tuberculosis. Moxifloxacin, a quinolone developed by Bayer AG, is now being tested in a Phase II clinical trial organized by CDC TB Trials Consortium and in a collaboration facilitated by the TB Alliance. The support of the TB Alliance also helps ensure that the murine model, a platform technology, will continue to be available for other TB drug development studies.

Clinical Trial Capacity. The TB Alliance is supporting the standardization of a network of 15 global sites in Africa, Asia and South America. The network is managed by Dr. Amina Jindani, a leading authority on TB clinical trials, based at the International Union Against Tuberculosis and Lung Disease (IUATLD). Dr. Jindani is evaluating the efficacy of TB therapy using WHO-recommended fixed dose combinations (FDCs), where four drugs are combined in a single pill. By training staff and upgrading laboratories, Dr. Jindani’s project can also provide the TB community with a set of potential clinical trial sites and establish guidelines for clinical trials to be used with potentially new anti-TB drugs.

Other Projects under Negotiation. In addition to the compounds listed above, the TB Alliance is currently in discussion with public, private and academic facilities about partnering on the development of other compounds.