The compound, called R207910, belongs to a new family of anti-TB agents called diarylquinolines (DARQ) and appears to have better, and more differentiated antibiotic properties than currently used drugs for TB, individually and in combination. R207910 was better at clearing infection from the lungs of mice than the triple cocktail regimen currently recommended by the World Health Organization (WHO). Also, cocktail regimens containing R207910 cleared infection in mice in half the time than the currently used regimen.
"The drug acts through a novel mechanism of action, and is therefore active against all multi-drug resistant (MDR) strains of TB tested so far," says Dr. Koen Andries, D.V.M., Ph.D., Distinguished Research Fellow, Antimicrobial Research at J&JPRD. "A combination including R207910 but excluding rifampin, one of the current TB drugs, looks especially promising. A combination excluding rifampin would be compatible with anti-HIV drugs, making it suitable for treating patients co-infected with HIV and TB."
The World Health Organization (WHO) has declared TB a global health crisis. TB now infects one-third of the world's population and causes close to nine million new cases of active TB and 2 million deaths each year. Unfortunately, many TB strains have become resistant to several antibiotics used today to treat the disease. More than 300,000 new cases of multi-drug-resistant TB per year are detected, mainly in Eastern Europe and Central Asia.
"For a long time, there has been a move to find a drug that is safe and effective and completely cures the patient in a shorter time," Andries says. "A new drug that could shorten or simplify effective treatment of TB would dramatically improve TB control programs."
No new anti-TB drugs have been brought into the clinic in the past 40 years, and although doctors have effective first-line TB drugs that work, there have been difficulties getting these medicines to the patients who need them as well as effectively treating patients with drug resistant disease.
One out of three people in the world are infected with latent TB. Even in the developed world, one out of twenty carry the TB bacillus. In some developing countries, one in two people are infected. A carrier of latent TB has a 10 percent life-long risk to develop TB. However, in HIV patients, that risk is 10 percent per year.
"That is the main reason why there is now such a resurgence of tuberculosis in countries that were previously hit by HIV," Andries says. "The HIV epidemic has worsened the TB epidemic substantially."
TB is currently treated with a cocktail of antibiotics, including rifampin, isoniazid, and pyrazinamide, which must be taken for six to nine months. The TB symptoms disappear after several weeks, and patients begin to feel healthy. However, to completely clear the infection, they must continue therapy at least four more months. This is often difficult, especially for people living in remote areas in developing countries, and discontinuing treatment prematurely increases the risk of developing resistant bacteria.
To ensure compliance, TB patients are monitored under the DOT (Directly Observed Treatment) program, with patients taking their cocktail of medicines each day under the supervision of a healthcare worker.
R207910 Study Findings
"Our findings suggest that at least in mice, R207910 seems to have the desired properties of simplifying and shortening the treatment duration, and perhaps, more," says Andries. In bacterial cell cultures, R207910 was effective against many different strains of mycobacteria, including strains that are resistant to other drugs. The drug is bactericidal, meaning that it kills the TB bacilli.
In mouse models, the studies showed that a cocktail regimen containing this compound reduced bacterial load after one month to the same level as the currently used regimen after two months of treatment, shortening normal treatment time by 50 percent. After two months treatment with the R207910 containing cocktail, no TB bacilli could be isolated from the lungs anymore, a finding that the French group that did those studies called "unprecedented".
The mouse studies also show that this new compound quickly enters the bloodstream and is actually concentrated in lung cells-which harbour the TB bacilli-killing the bacilli soon after they enter the body. Also, R207910 lingers in the body for days continuing to kill bacilli even when administered only once a week in mice.
R207910 is unique in the way it works. The compound attacks an enzyme called ATP synthase, the energy source for the bacterium. Given its new mechanism of action and apparent impact on drug resistant strains of TB, according to Andries, R207910 could lead to a shift in the current treatment paradigm for tuberculosis. "Preliminary data show R207910 has the desired properties we need and holds a great deal of promise," he said.
However, Koen added, considerable work needs to be done to fully determine this compound's clinical potential. Since the compound seems to be safe and well tolerated in Phase I studies with healthy human volunteers, R207910 will now be tested in humans with active pulmonary TB.
Dr. Andries' coauthors are Peter Verhasselt, Hinrich Göhlmann, Jean-Marc Neefs, Hans Winkler, Jef Van Gestel, Philip Timmerman, and Didier de Chaffoy at Johnson & Johnson Pharmaceutical Research and Development, LLC in Beerse, Belgium; Jerome Guillemont at Johnson & Johnson Pharmaceutical Research and Development in Val de Reuil, France; Min Zhu at Johnson & Johnson Pharmaceutical Research and Development, LLC in Raritan, NJ; Ennis Lee, and Peter Williams at Johnson & Johnson Pharmaceutical Research and Development, LLC in High Wycome, UK; Emma Huitric and Sven Hoffner at Swedish Institute for Infectious Disease Control in Solna, Sweden; Emmanuelle Cambau, Chantal Truffot-Pernot, Nacer Lounis, and Vincent Jarlier at Pitié-Salpêtrière School of Medicine in Paris, France. Nacer Lounis is currently at Johns Hopkins University School of Medicine in Baltimore, MD.
The study was supported by Johnson & Johnson Pharmaceutical Research and Development, and animal work in Paris was also supported by annual grants from Association Française Raoul Follereau, INSERM and, Ministère de l'Education Nationale et de la Recherche.
About R207910
A French chemist from the Johnson & Johnson pharmaceutical group synthesised the substance; and the team in Beerse, Belgium discovered its anti-TB action. The compound has been transferred to its sister company, Tibotec, whose lead compounds are for HIV/AIDS, for clinical development.
About Johnson & Johnson Pharmaceutical Research & Development
Johnson & Johnson Pharmaceutical Research & Development, (J&JPRD) is part of Johnson & Johnson, the world's most broad-based producer of healthcare products. J&JPRD, with its headquarters in Raritan, New Jersey (USA), has sites throughout Europe and the United States. J&JPRD leverages drug discovery, drug evaluation, and drug development in a variety of therapeutic areas to address unmet medical needs worldwide. The company's major therapeutic areas of focus include hematology, oncology, infectious disease, obesity and metabolic disorders, neurology and psychiatry, pain and women's health.
About Tibotec
Tibotec is a pharmaceutical research and development company with headquarters in Belgium and operating subsidiaries in the United States and Ireland. The company, like J&JPRD, is a subsidiary of Johnson & Johnson. Tibotec's lead development compounds are for the treatment of HIV/AIDS and the pandemics of TB and HIV/AIDS are closely intertwined. Drug interactions between HIV/AIDS drugs and TB drugs are particularly problematic.
(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the Company's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99(b) of the Company's Annual Report on Form 10-K for the fiscal year ended December 28, 2003. Copies of this Form 10-K are available online at www.sec.gov or on request from the Company. The Company assumes no obligation to update any forward-looking statements as a result of new information or future events or developments.)
For more information on Johnson & Johnson, please visit the Company's website at http://www.jnj.com.
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