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FDA approves treatment for highly drug-resistant forms of TB

TuberculosisPretomanid, a novel compound developed by the non-profit organisation TB Alliance, has been approved by the US Food & Drug Administration (FDA) for treating some of the most drug-resistant forms of tuberculosis (TB). The new drug was approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway) as part of a three-drug, six-month, all-oral regimen for the treatment of people with extensively drug-resistant TB (XDR-TB) or multidrug-resistant TB (MDR-TB) who are treatment-intolerant or non-responsive (collectively “highly drug-resistant TB”).

The LPAD pathway was established by FDA as a tool to encourage further development of antibacterial and antifungal drugs to treat serious, life-threatening infections that affect a limited population of patients with unmet needs.

“FDA approval of this treatment represents a victory for the people suffering from these highly drug-resistant forms of the world’s deadliest infectious disease,” said Dr Mel Spigelman, president and CEO of TB Alliance. “The associated novel regimen will hopefully provide a shorter, more easily manageable and highly efficacious treatment for those in need.”

The three-drug regimen consisting of bedaquiline, pretomanid and linezolid – collectively referred to as the BPaL regimen – was studied in the pivotal Nix-TB trial across three sites in South Africa. The trial enrolled 109 people with XDR-TB as well as treatment-intolerant or non-responsive MDR-TB. Nix-TB data have demonstrated a successful outcome in 95 of the first 107 patients after six months of treatment with BPaL and six months of post-treatment follow-up. For two patients, treatment was extended to nine months. The new drug application contains data on 1,168 people who have received pretomanid in 19 clinical trials that have evaluated the drug’s safety and efficacy. Pretomanid has been clinically studied in 14 countries.

TB, in all forms, must be treated with a combination of drugs; the most drug-sensitive forms of TB require six months of treatment using four anti-TB drugs. Treatment of XDR-TB or treatment-intolerant/non-responsive MDR-TB has historically been lengthy and complex; most XDR-TB patients currently take a combination of as many as eight antibiotics, some involving daily injections, for 18 months or longer. Prior to recent introduction of new drugs for drug-resistant TB, the World Health Organisation (WHO) has reported estimates for treatment success rates of XDR-TB therapy at approximately 34% and about 55% for MDR-TB therapy.

“Until very recently, people infected with highly drug-resistant TB had poor treatment options and a poor prognosis,” said Dr Francesca Conradie, principal investigator of the Nix-TB trial. “This new regimen provides hope with 9 out of 10 patients achieving culture negative status at 6 months post-treatment with this short, all-oral regimen."

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. TB Alliance acquired the developmental rights to the compound in 2002. It has been developed as an oral tablet formulation for the treatment of TB in combination with bedaquiline and linezolid, two other anti-TB agents, and is now indicated for use in a limited and specific population of patients. Adverse reactions reported during the Nix-TB trial of the BPaL regimen include hepatotoxicity, myelosuppression, as well as peripheral and optic neuropathy. Please see additional safety information in the Important Safety Information below and in the accompanying pretomanid Full Prescribing Information.

Pretomanid is only the third new anti-TB drug approved for use by FDA in more than 40 years, as well as the first to be developed and registered by a not-for-profit organization. Pretomanid was granted Priority Review, Qualified Infectious Disease Product, and Orphan Drug status. As a product development partnership, TB Alliance has collaborated with and received significant support from numerous governments, academia, philanthropic institutions, the private sector, civil society organisations and other partners over the course of pretomanid’s development.

Pretomanid is expected to be available in the US by the end of this year. In addition to the US FDA, TB Alliance has submitted pretomanid as part of the BPaL regimen for review by the European Medicines Agency and has provided data to the World Health Organisation for consideration of inclusion in treatment guidelines for highly drug-resistant TB.


Not everyone is celebrating this news. According to a NPR report, Médecins Sans Frontières (Doctors Without Borders) has concerns about a critical bottom-line issue: How much will the drug cost in poor and middle-income countries, where most TB patients reside? The report says the stakes are so high because the difference between the new regimen and the current drug regimen is so dramatic.

Sharonann Lynch, HIV & TB policy adviser at MSF, agrees that the new drug treatment is "a very important milestone in the development of TB drugs." But, she says, "we are very anxious about when we will see this drug getting into countries, when we will see this drug getting into bodies."

She says that drugs for TB have a history of getting approved by the FDA or other formal body only to be priced out of reach for those who need them most. "The game-changing aspect will be the affordability, frankly," Lynch adds. And pricing information for pretomanid is not yet available, even though Lynch says she has repeatedly asked for it.

The report says the TB Alliance’s stated mission is to ensure accessibility of drugs. But it granted the first manufacturing license of pretomanid to Mylan, a global pharmaceutical company. "We seem to be moving into a for-profit model," Lynch says.

Julie Knell, a spokesperson for Mylan, says that Mylan has not yet announced its launch price for pretomanid in lower- and middle-income countries in part because pricing discussions had been put on hold pending FDA approval. "Now that it has been received, discussions can begin," she says. But she notes: "Mylan has historically been a leader in reducing the price of drugs for patients and programs in developing countries; for instance, we've helped reduce the cost of HIV treatment by 80% over the past decade."
With pretomanid, she says, the company hopes to continue its commitment to reducing costs and increasing access for patients in "high burden" countries.

[link url=""]TB Alliance material[/link]
[link url=""]NPR report[/link]

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