Tuberculosis

PaMZ Combination Regimen Shortens and Simplifies Tuberculosis Treatment

An oral regimen combining the new drug pretomanid (PA-824) with the older moxifloxacin and pyrazinamide -- known as PaMZ for short -- has the potential to reduce the duration of treatment for drug-sensitive and even some drug-resistant tuberculosis (TB), according to findings from a study published in the March 17 online edition The Lancet. Nearly twice as many patients treated with the PaMZ regimen had undetectable TB in cultured sputum compared to those taking standard therapy.

Rodney Dawson from the University of Cape Town in South Africa, Carl Mendel of the TB Alliance, and colleagues conducted a Phase 2b TB treatment trial with more than 200 previously untreated participants -- 20% of whom were HIV-positive -- at 8 sites in South Africa and Tanzania between March 2012 and July 2013 (NC-002/NCT01498419). Results were previously reported in part at the 2014 International AIDS Conference last summer in Melbourne.

A total of 181 patients with drug-sensitive TB were randomly assigned to receive a daily regimen of either 400 mg moxifloxacin, 100 or 200 mg pretomanid, and 1500 mg pyrazinamide, or else standard therapy using isoniazid, rifampicin, pyrazinamide, and ethambutol, for the first 8 weeks of treatment. An additional 26 people with multidrug-resistant TB received the former regimen.

The researchers found that the pretomanid/moxifloxacin/pyrazinamide regimen "was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment," and results were consistent for the patients with drug-resistant TB.

The new regimen is now advancing to an international Phase 3 trial calledSTAND (Shortening Treatment by Advancing Novel Regimens), conducted by the TB Alliance, that aims to enroll 1500 participants at some 50 sites across Africa, Asia, the Caribbean, Eastern Europe, and Latin America.

Below is an edited excerpt from a TB Alliance press release describing the study and its findings in more detail.

The Lancet: Results of Phase 2b Trial of Novel TB Regimen PaMZ Show Potential to Shorten, Improve TB Treatment

Phase 3 STAND Trial Launches to Advance PaMZ through Final Stage of Testing

New York -- March 17, 2015 -- A new tuberculosis (TB) drug regimen designed to improve options for TB therapy eliminated more bacteria from sputum than standard therapy and did so at a faster rate, according to data from a phase 2b clinical trial published today in The Lancet. These results are published just as the global phase 3 clinical trial, designed to bring this regimen through the last stage of testing, has begun.
 
PaMZ is a three-drug regimen comprised of two candidate drugs that are not yet licensed for use against TB: pretomanid (Pa), formerly known as PA-824, and moxifloxacin (M), and one antibiotic, pyrazinamide (Z), which is approved for use in TB treatment today. The therapy is intended for those patients whose TB infections are sensitive to the three drugs, including people with drug-sensitive and multidrug-resistant TB (MDR-TB).
 
"The results of this trial show the potential for the PaMZ regimen to improve treatment for tuberculosis," said Rod Dawson, MD, head of the Centre for TB Research Innovation at the University of Cape Town, South Africa, and lead author of the paper. "Especially noted is the fact that PaMZ may have a unique application as a potentially shorter, injection-free regimen for a select sub-group of patients with MDR-TB."
 
The Phase 2b trial, known as NC-002, tested PaMZ in an eight-week study that enrolled more than 200 patients and took place at eight sites in South Africa and Tanzania. Nearly twice (71 percent) as many TB patients treated with PaMZ had no TB in their sputum when cultured at the end of the 2-month course of the trial compared to patients treated with standard therapy (38 percent). These results are based on liquid culture, the most sensitive diagnostic method available.
 
Patients in the arm of the trial that tested the effectiveness of PaMZ on MDR-TB responded similarly to those with drug-sensitive TB. However, the study group for MDR-TB was small. When added to evidence from pre-clinical and earlier studies, PaMZ shows the potential to treat drug-sensitive TB and some patients with MDR-TB in four to six months.
 
"PaMZ is the first regimen under development to treat both drug-sensitive TB and MDR-TB," said Mel Spigelman MD, President and CEO of TB Alliance, the trial’s sponsor. "If successful, PaMZ could be a shorter, simpler, and safer treatment that would enable the scale-up of treatment."
 
Twenty percent of the TB patients enrolled in NC-002 also were co-infected with HIV. The PaMZ regimen appeared to be effective independent of HIV status.
 
Limitations in standard TB treatment remain a strong barrier to TB control. The treatment and cure of a typical case of drug-sensitive TB currently takes between six and nine months. People with drug-resistant TB require a minimum of 18 to 24 months of treatment. This more extensive therapy requires more than 14,000 pills and daily injections for at least 6 months. The long duration of MDR-TB treatment, combined with the pain and side effects that treatment causes, are major obstacles to access. Only 20 percent of all MDR-TB patients receive any treatment, and of those who do, less than half (48 percent) will be cured, according to the World Health Organization’s 2014 Global Report.
 
On the basis of these and other data, TB Alliance and its partners have launched a global phase 3 clinical trial named STAND (Shortening Treatment by Advancing Novel Drugs) in patients who are currently considered to have either drug-sensitive or multidrug-resistant TB.
 
Enrollment has begun in the STAND trial. STAND researchers expect to enroll 1,500 patients in 15 countries in Africa (Kenya, South Africa, Tanzania, Uganda, Zambia), Asia (China, Malaysia, Philippines, Thailand), Caribbean (Haiti), Eastern Europe (Georgia, Russia, Ukraine), and Latin America (Brazil, Peru) in this study. PaMZ will be tested in STAND as a 4- and 6-month treatment for drug-sensitive TB and a 6-month treatment for drug-resistant TB, and also enroll those co-infected with HIV. Each patient will be followed for two years starting from the beginning of treatment. The STAND trial partners with many of the communities in which the study is conducted through its robust community engagement program.
 
If successful in this Phase 3 trial, the PaMZ regimen would eliminate the need for injectable drugs and reduce the cost of MDR-TB therapy by more than 90 percent in those patients whose TB organisms are sensitive to the three drugs. It also promises to be compatible with commonly used HIV drugs, helping the millions of people co-infected with TB/HIV.

About TB Alliance

The Global Alliance for TB Drug Development (TB Alliance) is a not-for-profit organization dedicated to finding faster-acting and affordable drug regimens to fight tuberculosis. Through innovative science and with partners around the globe, we aim to ensure equitable access to faster, better TB cures that will advance global health and prosperity. TB Alliance operates with support from Australia Department of Foreign Affairs and Trade, Bill & Melinda Gates Foundation, European Commission, Global Health Innovative Technology Fund, Irish Aid, National Institute of Allergy and Infectious Disease, UNITAID, United Kingdom Department for International Development, United States Agency for International Development, and the United States Food and Drug Administration. For more information please visit tballiance.org.

3/24/15

Reference

R Dawson, AH Diacon, D Everitt, CM Mendel, et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. The Lancet. March 17, 2015 (Epub ahead of print).

Other Source

TB Alliance. The Lancet: Results of Phase 2b Trial of Novel TB Regimen PaMZ Show Potential to Shorten, Improve TB Treatment. Press release. March 17, 2015.