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PA-824

on Tue, 07/17/2012 - 19:45

Last updated July 2012

ACTIVE TB DISEASE

PA-824, like delamanid, is from a new drug class, the nitroimidazoles. In phase II development by the TB Alliance, PA-824 recently was shown to be safe, well tolerated, and efficacious at doses of 100–200 mg daily in a dose-ranging study among drug-sensitive, sputum smear–positive, adult pulmonary TB patients. The TB Alliance will evaluate PA-824 as a component of novel anti-TB regimens for both DS-TB and DR-TB moving forward. These PA-824-containing novel regimens are being tested in the combination studies described further in the next section of this chapter.

The NIAID DMID and the TB Alliance are cosponsoring a phase I thorough QT (TQT) study to evaluate any effects PA-824 will have on cardiac conduction (the rate at which the heart conducts electrical impulses). The clinical trial will also study whether PA-824 and moxifloxacin had additive or synergistic effects on the QT interval. This study will start enrolling in Q4 2012.

The ACTG has opened a phase I safety, tolerability, and pharmacokinetic interaction study of PA-824 and two common antiretrovirals (ARVs). This study, also called A5306, will look at whether PA-824 is safe to use with lopinavir/ritonavir (a boosted protease inhibitor) and efavirenz (a non-nucleoside reverse transcriptase inhibitor) as well as with rifampicin. Given the prevalence of TB/HIV coinfection, these DDI studies between new potential anti-TB agents and commonly used ARVs are essential.

In late 2012, the TB Alliance plans to file an investigational new drug (IND) application with the FDA, and to start a phase I program for its backup nitroimidazole, the new drug candidate TBA354, which is currently in preclinical development.

NOVEL COMBINATIONS TO TREAT ACTIVE TB DISEASE

NC001

The TB Alliance recently completed NC001, the first TB clinical trial to evaluate multiple unapproved new TB drug candidates in combination. This two-week, phase II EBA study tested the three-drug regimen PA-824, moxifloxacin, and pyrazinamide (PaMZ). The PaMZ regimen performed significantly better than the standard of care (HRZE).

The study also tested additional two-drug combinations of PA-824, moxifloxacin, and pyrazinamide and bedaquiline to evaluate their potential as “building blocks” of future regimens. Validating what had been seen in mouse models, pyrazinamide and bedaquiline were synergistic, pyrazinamide and PA-824 had an additive effect, and PA-824 and bedaquiline did not have an additive effect.

The study was also important for helping open up a promising new regulatory pathway for new combination trials. In addition, it demonstrated that EBA studies can distinguish between treatments, not just between doses of the same treatment. NC001 also showed that measuring colony-forming units (which involves comparing the number of remaining viable bacterial cells that can grow into colonies after the experimental and control treatment) and time to positivity (TTP, which measures how long a cultured sputum sample takes to read as positive after therapy, with more effective treatment leaving fewer live bacterial cells and therefore having a longer TTP) gave similar results, helping to validate TTP as a biomarker for treatment response.

NC003

The TB Alliance is also planning study NC003, which will evaluate the EBA, safety, tolerability, and pharmacokinetics of two weeks of once-daily oral dosing of clofazimine alone, pyrazinamide alone, and various combinations of these drugs with PA-824 and bedaquiline, in comparison with standard first-line TB treatment. NC003 will enroll 105 newly diagnosed adults with smear-positive, drug-sensitive pulmonary tuberculosis. The study is expected to begin enrolling patients in late 2012, with results expected in the summer of 2013.


References:

  • Diacon AH, Dawson R, du Bois J, et al. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 2012 Jun;56(6):3027–31. Available from: http://aac.asm.org/content/56/6/3027.abstract. (Accessed 2012 June 26)
  • Murray, Stephen (TB Alliance, New York, NY). E-mail with: Erica Lessem (Treatment Action Group, New York, NY). 2012 May 8.
  • Hafner, Richard (National Institute of Allergy and Infectious Diseases, Bethesda, MD). Conversation with: Erica Lessem (Treatment Action Group, New York, NY). 2012 April 17.
  • Hafner, Richard (National Institute of Allergy and Infectious Diseases, Bethesda, MD). E-mail with: Erica Lessem (Treatment Action Group, New York, NY). 2012 June 4.
  • Murray, Stephen (TB Alliance, New York, NY). E-mail with: Erica Lessem (Treatment Action Group, New York, NY). 2012 May 8.
  • Murray, Stephen (TB Alliance, New York, NY). E-mail with: Erica Lessem (Treatment Action Group, New York, NY). 2012 May 8.