June 15, 2005 A promising new drug candidate that may be effective against both actively dividing and slow-growing Mycobacterium tuberculosis (M. tb) has begun testing in humans, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, announced today. The novel antibiotic, PA-824, may shorten the time needed to treat tuberculosis (TB), a contagious disease that claims approximately two million lives worldwide each year. In partnership with the non-profit New York-based Global Alliance for TB Drug Development (TB Alliance), NIAID contributed to the drug candidate's preclinical safety and efficacy testing in animal models. Now, a clinical trial to assess PA-824's safety, sponsored by the TB Alliance, has opened at a medical clinic in Lincoln, NE.
"The rapid movement of PA-824 through the development pipeline is a testament to the successful partnership between NIAID and the TB Alliance. It marks a significant milestone in progress toward our goal of making treatments for TB more effective and shorter in duration," notes NIAID Director Anthony S. Fauci, M.D.
One-third of the global population--some two billion people--is infected with M. tb. A person may remain latently infected and harbor the bacteria, in a non-growing or slow-growing form, for decades with no symptoms. However, if the immune system is weakened by age, HIV or other infections, M. tb may be re-activated and the active form of the disease may emerge. Although most common in other countries where HIV prevalence is highest, approximately 14,000 cases of active TB are reported to the Centers for Disease Control and Prevention each year in the United States.
While TB is curable with antibiotics, the drug regimen is arduous and lengthy. The World Health Organization's current recommendation for treatment of active TB includes the administration of up to 4 drugs for at least 6 months. PA-824 differs from most currently available TB drugs because it appears to attack M. tb in both the bacterium's actively dividing and slow-growing stages. For this reason, researchers hope PA-824 will significantly reduce the time needed to cure TB.
In 2000, C. Kendall Stover, Ph.D., of Pathogenesis Corporation, and his co-authors, including NIAID scientist Clifton E. Barry, III, Ph.D., published the first evidence of PA-824's potential TB-fighting abilities. In 2002, the TB Alliance acquired exclusive worldwide rights to PA-824 from the California-based biotechnology firm, Chiron Corporation.
NIAID provided support to the TB Alliance for continued development of PA-824 through the Institute's Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) (www.taacf.org). TAACF, established by NIAID in 1994, conducts prescreening and efficacy testing of potential anti-TB drugs at no cost to those who submit the compounds.
For PA-824 development, NIAID support included
"Several characteristics of PA-824 that emerged during preclinical testing give us reason to be optimistic about its possible effectiveness against TB in humans," says Dr. Barbara Laughon, Ph.D., chief of the Complications and Co-infections Branch of NIAID's Division of AIDS. In addition to activity against both actively dividing and slow-growing M. tb, PA-824 also shows evidence of being active against both drug-sensitive and multi-drug-resistant TB. Also, in animal testing, single doses of the compound administered orally traveled rapidly to such target organs as the lung and spleen. With support from both the TB Alliance and NIAID, Jacques Grosset, M.D., and William Bishai, M.D., Ph.D., of The Johns Hopkins University in Baltimore, found PA-824 to have bacterial killing effects similar to frontline TB drugs isoniazid and rifampin in animal models of infection. Finally, PA-824's apparent lack of interaction with certain liver enzymes means it may be safe for use by people co-infected by HIV and TB. Currently, such individuals may experience adverse effects when taking both rifampin (to treat TB) and antiretroviral drugs (to treat HIV).
"The announcement that a novel TB drug candidate has entered human trials is cause for celebration in the TB community. It underscores the value of public-private partnerships and the crucial role of NIAID's TB drug development contract mechanism in preparing PA-824 for this stage," says Dr. Laughon.
Adds Maria C. Freire, Ph.D, president and chief executive officer of the TB Alliance, "We worked creatively and smartly with our partners, donors and contractors, combining our ability to move the technology forward with the expert management of RTI International and all of NIAID's contributions. The result is that a promising TB compound moved into human trials in near-record time."
NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.
The Global Alliance for TB Drug Development (TB Alliance) is a nonprofit public-private partnership with an international mandate to revolutionize TB control through the discovery and development of new, affordable therapeutic regimens that will shorten and simplify treatment of active disease, overcome multi-drug resistant TB and enable the simultaneous therapy of HIV/AIDS and TB. More information at www.tballiance.org.
References: AJ Lenaerts et al. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrobial Agents and Chemotherapy. doi:10.1128/AAC.49.6.2294-2301 (2005).
S Tyagi et al. Bactericidal activity of the nitroimidazopyran PA-824 in a murine model of tuberculosis. Antimicrobial Agents and Chemotherapy. doi:10.1128/AAC.49.6.2289-2293 (2005).
CK Stover et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405: 962-66. doi:10.1038/35016103 (2000).
News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
For more information on TB visit NIAID's "Focus on TB" Web site at http://www.niaid.nih.gov/Newsroom/FocusOn/TB/default.htm.
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