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

It is only the third TB drug approved by the FDA in more than 40 years, according to a news release from RTI International, one of the collaborators in the drug's development.

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

The FDA said in a news release that the safety and effectiveness of the pretomanid combination, taken orally, was primarily demonstrated in a study of 109 patients with extensively drug-resistant, treatment‑intolerant, or nonresponsive MDR-TB. Of the 107 patients who were evaluated 6 months after the end of therapy, 95 (89%) had successful treatment, far exceeding success rates of available treatments.

Amita Gupta, MD, professor of medicine and deputy director of the Johns Hopkins University Center for Clinical Global Health Education in Baltimore, Maryland, told Medscape Medical News there was much anticipation of this announcement.

"This is a very exciting development," she said. "It will be a game changer for these highly resistant patients."

There are very few treatments for people with XDR-TB, she noted, cure rates are very low (a trial in South Africa showed 2%-22% cure rates), treatment duration is typically 2 years, mortality rates are as high as 80%, and treatments have had severe toxicities.

The New Drug Application (NDA) for pretomanid said previous treatments have typically involved taking at least five drugs, some intramuscular, some intravenous, with no defined regimen and with side effects that can include deafness, renal failure, and psychosis.

The pretomanid regimen, on the other hand, is all-oral, well tolerated, has a treatment duration of 6 months, and cure rate of 89%, she noted.

The most common adverse reactions observed from the pretomanid combination "included damage to the nerves (peripheral neuropathy), acne, anemia, nausea, vomiting, headache, increased liver enzymes (transaminases and gamma-glutamyltransferase), indigestion (dyspepsia), rash, increased pancreatic enzymes (hyperamylasemia), visual impairment, low blood sugar (hypoglycemia), and diarrhea," the FDA said.

The FDA 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 that needs the drug combination will have affordable access to it. She said the less traditional path of development will help in that regard.

The FDA said pretomanid is the second drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD pathway, established under the 21st Century Cures Act to advance development and approval of antibacterial and antifungal drugs to treat serious infections in a limited population with unmet need.

RTI International, an independent, nonprofit research institute, collaborated with the nonprofit public-private partnership called the TB Alliance, the developer of pretomanid. The initial commercial partner is Mylan.

The FDA granted the approval of pretomanid tablets to the TB Alliance.

The TB Alliance has negotiated license agreements enabling an affordable price for pretomanid in low-resource countries.

Doris Rouse, PhD, vice president of global health technologies at RTI International told Medscape Medical News, "The current treatment is many hundreds of times more in cost than the proposed regimen."

"This is a growing and very successful model for addressing pressing global health needs that may not have the commercial attractiveness for a company to invest in," she said. "But when you have the resources of governments and industry and nonprofits and foundations, you can bring together the expertise and the resources to take these new drugs to market."

XDR-TB is extremely rare in the United States: There were two cases of XDR-TB in the US in 2017, according to the Centers for Disease Control and Prevention. However, it's not rare in Europe and can be "just a plane ride away to get tuberculosis," Rouse said.

She added, "It is a major and growing problem around the world as 127 countries have reported cases of XDR-TB and there are half a million cases of drug-resistant TB annually."

Rouse called today's announcement "a major breakthrough."

She said patients needing this drug may have coughing, weakness, lack of appetite, loss of weight, and night sweats.

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

The World Health Organization (WHO) reports that about 6.2% of the MDR-TB cases worldwide have XDR-TB. Detection of XDR-TB is difficult because some countries lack the resources to test for resistance to second-line drugs.

In June, the FDA's Antimicrobial Drugs Advisory Committee voted 14-4 that there was "substantial evidence of the effectiveness and sufficient evidence of the safety of pretomanid as part of a combination regimen with bedaquiline and linezolid, in adults for the treatment of pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis."

Pretomanid is a member of a class of compounds known as nitroimidazooxazines.

"It has been studied in 20 clinical trials alone or in combination with other anti-TB drugs. Since TB Alliance began development of pretomanid in 2002, it has been administered in a clinical trial setting to more than 1,200 people in 14 countries," the alliance said in a news release.

TB kills more than 1.6 million people a year globally, according to WHO, more than any other infectious disease.

4th China Pharma IP Summit 2019 (CPIPS2019) organized by Shanghai YIP Events, Supported by Pharma IP Right Research Committee of Chinese Pharmaceutical Association, which will be held on 23rd-25th , Oct at Primus Hotel Shanghai Hongqiao China this year. which presents an unrivalled gathering of in-house patent counsel from established and fledgling pharmaceutical and biotechnology companies coming together to listen to updates on patent prosecution and enforceability from global jurisdictions, 
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