TB Alliance, Mylan Announce Collaboration to Commercialize Pretomanid

Non-profit drug developer, TB Alliance, and pharmaceutical company, Mylan announced a global collaboration to make the experimental drug pretomanid accessible for use in two investigational drug regimens for pulmonary tuberculosis (TB).

TB, a bacterial infection transmitted through the air, is a challenging disease to treat, often requiring treatment through a combination of antibiotics. It also is the leading cause of death among people with HIV/AIDS2 and accounts for more than 1 in 4 fatalities from antimicrobial resistance annually. TB occurs in every part of the world. In 2017, the largest number of new TB cases occurred in the Southeast Asia and Western Pacific regions, followed by the African region. There is a growing resistance to available drugs, which means the disease is becoming deadlier and more difficult to treat. There were 558,000 cases of drug resistant TB in 2017.

Multidrug resistant - (MDR) and extensively drug resistant- (XDR) TB are forms of the disease caused by bacteria that do not respond to first-line anti-TB drugs. Current treatments, therefore, consist of combinations of many different drugs, which may need to be taken for up to two years. Patients may take as many as 20 pills a day, resulting in numerous side-effects and often creating a significant economic burden.4 Drug sensitive - (DS) TB treatment, which consists of treatment with up to four drugs daily for six to nine months, has traditionally fared better with a global treatment success rate of approximately 82%; however, rising rates of resistance are complicating treatment and necessitating different options.

"The TB drug pipeline is showing significant promise as we progress in our goal to provide transformative benefit to people with TB," said Mel Spigelman, President and CEO of TB Alliance. "We are determined to take steps now to ensure that pretomanid, if approved, will be able to reach patients in need as part of an appropriate treatment regimen."

"For more than a decade, Mylan has led the charge in accelerating access to high quality and affordable antiretrovirals for people living with HIV all over the world," Mylan CEO Heather Bresch said. "We look forward to collaborating with TB Alliance to bring that same level of commitment and innovation to the millions of people suffering from tuberculosis, many of whom also have HIV. The drug regimens under development represent an important step in transforming the TB treatment landscape."

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. TB Alliance began preclinical development of pretomanid in 2002, and it has since studied pretomanid in 20 clinical trials alone or in combination with other anti-TB drugs. Pretomanid has been administered in a clinical trial setting to more than 1,200 people in 14 countries.

The two pretomanid-based regimens under development include:

For XDR-TB and MDR-TB that is treatment-intolerant or non-responsive: All oral, six- to nine-month treatment regimen consisting of bedaquiline, pretomanid and linezolid (BPaL regimen)

For DS-TB and MDR-TB: All oral, four- and six-month treatments, respectively, consisting of bedaquiline, pretomanid, moxifloxacin and pyrazinamide (BPaMZ regimen)

TB Alliance is currently advancing the development of pretomanid in three ongoing late-stage clinical trials. The Nix-TB and ZeNix trials are evaluating the BPaL regimen for treatment of XDR-TB and related highly resistant forms of TB, while the SimpliciTB trial is evaluating the BPaMZ regimen for the treatment of DS-TB in four months and MDR-TB in six months.

The BPaL regimen has been studied in the ongoing Phase 3 Nix-TB trial, an open-label, single arm trial. Nix-TB participants with XDR-TB and treatment-intolerant or non-responsive MDR-TB were treated with bedaquiline, pretomanid and linezolid over six months, extended to nine months in some cases, with the intent to cure. In interim results from the first 75 participants presented at the 2018 Union World Conference on Lung Health, 89% of the trial participants had a favorable outcome with their clinical infection resolved and sputum cultures negative for TB after six months of treatment and six months of post-treatment follow-up.

The BPaMZ regimen is being studied in the ongoing late-stage SimpliciTB clinical trial, initiated in 2018, for the treatment of both DS- and MDR-TB. The BPaMZ regimen was previously evaluated in TB Alliance's Phase 2b study called NC-005, in which people with MDR-TB who were treated with the BPaMZ regimen cleared TB bacteria from their lungs up to three times faster than drug-sensitive TB patients treated with the standard first-line treatment (HRZE).

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