|Promising New TB Drug Enters Clinical
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
“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,
NIAID provided support to the TB Alliance for continued
development of PA-824 through the Institute’s Tuberculosis
Antimicrobial Acquisition and Coordinating Facility
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
- A contract awarded to Doris Rouse, Ph.D., of RTI
International in Research Triangle Park, NC, that
provided technology transfer assistance and project
management of preclinical testing of the compound
- A contract to Ian Orme, Ph.D., of Colorado State
University that confirmed the efficacy of the compound
in animal models of TB infection
“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.
The National Institutes of Health (NIH) The
Nation's Medical Research Agency is comprised
of 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services.
It is the primary Federal agency for conducting and
supporting basic, clinical, and translational medical
research, and investigates the causes, treatments,
and cures for both common and rare diseases. For more
information about NIH and its programs, visit www.nih.gov.
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.