Novel Antibiotic Shows Promise in Shortening Treatment Duration of Tuberculosis

RARITAN, N.J. -- Scientists at Johnson & Johnson

Pharmaceutical Research and Development (J&JPRD) have identified a novel anti-tuberculosis (TB) compound that works better and faster than the current standard of care in mouse models of TB infection. Also, preliminary studies in healthy human volunteers show that the drug is safe. The findings were published in the Dec. 9, 2004 issue of Science Express, the online version of

the journal Science, and will be published in the Jan. 14, 2005 print edition.

These studies were conducted by scientists at J&JPRD and their colleagues at the

Swedish Institute for Infectious Disease Control in Solna, Sweden, and the

Pitie-Salpetriere School of Medicine in Paris, France.

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 Koen Andries, DVM, PhD, 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.

Andries' coauthors are Peter Verhasselt, Hinrich Gohlmann, 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, N.J.; 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 Pitie-Salpetriere 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 Francaise Raoul Follereau, INSERM and, Ministere de l'Education

Nationale et de la Recherche.

Source: Johnson & Johnson Pharmaceutical Research & Development