Breakthrough Drug Approved for Drug-Resistant TB

Finally, a new, more-effective drug taken for shorter duration, when used in combination with two others, is here to fight the worst types of tuberculosis.

Pretomanid is only the third anti-TB drug approved by the U.S. Food and Drug Administration in more than 40 years. It is approved to treat Extensively Drug-Resistant (XDR-TB) and treatment intolerant/non-responsive Multidrug-Resistant (MDR) TB.

“We are seeing an increase in XDR-TB, and we need new weapons to attack it,” said Doris Rouse, Ph.D., vice president of global health technologies at RTI International. “I've been in wards with patients that are so emaciated, they won't eat anything, they have fevers, they can't sleep. But with pretomanid, in a regimen that includes two other drugs, bedaquiline [Janssen Therapeutics] and linezolid [Pfizer], we see improvement within a few weeks. This new treatment will help people who have no other good option for a cure.”

Rouse and her team have collaborated closely on the development of pretomanid for almost 20 years with TB Alliance, a non-profit product development partnership that RTI and Rouse helped form in 2000.

This three-drug, all-oral combination for 6 months, called the BPaL regimen, gives patients with XDR-TB a better alternative to the current six-plus drug regimen for 2 years that, in South Africa, for example, only cured 2 to 22 percent of patients. The BPaL regimen cured approximately 9 out of 10 XDR-TB patients in trials conducted in South Africa.

Pretomanid is a small molecule nitroimidazole, a class of novel anti-bacterial agents that work by stopping the growth of anaerobic bacteria, which do not require oxygen for growth, and protozoa, single-cell microscopic animals.

TB is caused by bacteria (Mycobacterium tuberculosis). It primarily affects the lungs, but can also affect the central nervous system, lymphatic and circulatory systems, bones and tissues. It is highly contagious. A person catches TB from another by inhaling only a few germs from the small water droplets in the air expelled when someone with TB coughs, sneezes or spits.

TB is largely controlled today in the U.S., but at the turn of the 20th Century was this country’s leading cause of death, according to the American Lung Association. It was referred to then as “consumption,” and in the 17th and 18th Centuries in Europe caused the “white plague.”

Worldwide today, TB kills more people than any other infectious disease – 1.6 million a year, or more than 4,000 a day – primarily in low-resource countries. XDR-TB is resistant to four of the main drugs, including injectable agents, currently used to treat drug-resistant TB around the world.

With funding from the National Institute of Allergy and Infectious Diseases, Rouse and a team at RTI in 1999 headed up the effort to identify potential new compounds for TB treatment. They identified and conducted due diligence on pretomanid, a compound developed by a small biotech, Pathogenesis.

TB Alliance acquired the license to pretomanid, then known as Pa-824, in 2002. RTI assisted TB Alliance in planning and managing the preclinical studies needed for development and preparing the successful Investigational New Drug (IND) application to FDA in 2005, leading to the start of clinical trials that year.

RTI has served as a regulatory contact for TB Alliance since the pretomanid IND was submitted to FDA in 2005.

“We’ve worked on this new drug for 19 years, and it hasn’t always been an easy path,” added Rouse. “But as I’ve always said, ‘One of the main ingredients for successful drug development is blessed stubbornness.’ This public-private partnership is an excellent model for meeting unmet needs, especially those that are in low-resource countries that may not have the commercial attraction of other diseases.”

TB Alliance is now targeting adoption and availability of pretomanid as part of the BPaL regimen in countries with a high unmet need for XDR-TB treatments.