The US Food and Drug Administration (FDA) today approved pretomanid, a major "breakthrough" treatment for the most drug-resistant tuberculosis (TB) in combination with bedaquiline and linezolid.

This is only the third anti-TB drug approved by the FDA in more than 40 years, according to a press release issued by RTI International, one of the collaborators of the development of this drug.

The pretanid combination treats extensively drug-resistant tuberculosis (XDR-TB), a type of multidrug-resistant tuberculosis (MDR-TB) in the lungs that is resistant to the two most powerful drugs, isoniazid and rifampicin, as well as to fluoroquinolone. and at least one of three injectable second-line drugs (amikacin, kanamycin or capreomycin).

In a press release, the FDA said that the safety and effectiveness of the combination of pre-antimicrobials, taken orally, had been primarily demonstrated in a study involving 109 patients with multidrug-resistant, treatment-intolerant or treatment-insensitive MDR-TB. Of the 107 patients evaluated 6 months after the end of treatment, 95 (89%) had a successful treatment, far exceeding the success rates of available treatments.

Amita Gupta, MD, professor of medicine and assistant director of the Center for Clinical Education in Global Health at Johns Hopkins University in Baltimore, Maryland, said Medscape Medical News there was a lot of anticipation of this ad.

"It's a very exciting development," she said. "It will change the game for these very resistant patients."

There are very few treatments for people with XDR-TB, she noted, the cure rates are very low (one trial in South Africa showed a cure rate of 2% to 22%), the duration of the treatment is usually 2 years, the mortality rate reaches 80%, and the treatments have had serious toxicities.

The New Drug Application (NDA) for pretomanid indicated that prior treatments generally involved the taking of at least five drugs, some intramuscular, other intravenous, with no definite treatment regimen and with side effects that may include deafness, kidney failure and psychosis.

The pretanid treatment is all oral, well tolerated, with a treatment duration of 6 months and a cure rate of 89%, she noted.

The most common side effects with the pre-manicured combination "included nerve damage (peripheral neuropathy), acne, anemia, nausea, vomiting, headache, increased liver enzymes ( transaminases and gamma-glutamyltransferase), indigestion (dyspepsia), rash, pancreatic enzymes (hyperamylasemia), visual impairment, low blood glucose (hypoglycemia) and diarrhea, "said the FDA.

The FDA has also warned that the combination should not be used in patients with hypersensitivity to bedaquiline or linezolid.

Now the question, Gupta said, is whether the population who needs the combination of drugs will have affordable access. She said the less traditional development path would help in this regard.

The FDA has stated that pretomanid was the second drug to be approved as part of the Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD Pathway, established under the 21st Century Treatment Act to make advance the development and approval of antibacterial and antifungal drugs for the treatment of serious infections. population with unmet needs.

Development Collaboration

RTI International, an independent, non-profit research institute, has collaborated with the nonprofit public-private partnership called TB Alliance, developer of Pretomanid. The initial trading partner is Mylan.

The FDA has approved the approval of pretanid tablets at the TB Alliance.

TB Alliance has negotiated licensing agreements to provide affordable pretreatment in low-resource countries.

Doris Rouse, PhD, vice president of global health technologies at RTI International, said Medscape Medical News"The current treatment costs several hundred times more than the proposed plan."

"It's a fast-growing and highly effective model for meeting the pressing health needs around the world, which may not present the commercial interest of a healthier patient." company, "she said. "But when you have the resources of governments and industry, as well as foundations and not-for-profit organizations, you can muster the expertise and resources to market these new drugs."

XDR-TB is extremely rare in the United States: there have been two cases of XDR-TB in the United States in 2017, according to the Centers for Disease Control and Prevention. However, this is not uncommon in Europe and may be "just a plane ride to catch TB," Rouse said.

"This is a major and growing problem worldwide, with 127 countries reporting cases of extensively drug-resistant TB and half a million cases of drug-resistant TB each year," she added.

A "major breakthrough"

Rouse called the announcement a "major breakthrough".

She said that patients needing this medication could have cough, weakness, lack of appetite, weight loss and night sweats.

"I've seen these patients in theaters and it's really a horrible thing to see," said Rouse.

The World Health Organization (WHO) reports that about 6.2% of multidrug-resistant TB cases worldwide have XDR. Detection of XDR-TB is difficult because some countries do not have the resources to test resistance to second-line drugs.

In June, the FDA's Advisory Committee on Antimicrobial Drugs voted 14 to 4, stating that there was "substantial evidence of the efficacy and sufficient evidence of the safety of the pretomanid". as part of a regimen combining bedaquiline and linezolid, in the resistant adult (XDR) or drug-resistant multidrug-resistant tuberculosis (MDR) ".

Pretomanid is a member of a class of compounds called nitroimidazooxazines.

"It has been studied in 20 clinical trials alone or in combination with other TB drugs, and since TB Alliance started to develop the pretomanid in 2002, it has been administered as part of 39 clinical trials to more than 1,200 people in 14 countries "the alliance said in a press release.

Tuberculosis kills more than 1.6 million people a year worldwide, according to the WHO, more than any other infectious disease.

Follow Medscape on Facebook, Twitter, Instagram and YouTube.

.