PA-824

PA-824 is an experimental drug that is undergoing testing as a potential treatment for TB. Like OPC-67683, PA-824 is a nitroimidazole that has demonstrated bactericidal and sterilizing activity against drug-resistant and non drug-resistant TB. PA-824 has also shown activity against both active and latent TB. In a 2002 agreement with the former biotechnology company Chiron, the TB Alliance was granted exclusive rights to develop the drug as a treatment for TB. The TB Alliance is currently carrying out phase II clinical testing on PA-824. How it works ------------ PA-824 is a nitroimidazole. It is a prodrug, which means it needs to be activated before it becomes effective against TB bacteria. PA-824 is activated by either a bacterial enzyme or a cofactor, which is a compound that binds to a protein. This activation is the reason why PA-824 does not attack human cells. Human cells lack the bacterial enzyme and cofactor needed to convert PA-824 into its active form. PA-824 kills bacteria by inhibiting the synthesis of certain proteins and cell wall lipids (i.e. fat molecules) that are needed by bacteria for survival. Researchers believe that PA-824 acts this way against replicating, aerobic (i.e. requiring oxygen) bacteria only. PA-824 is also active against latent TB bacteria. In a latent state, bacteria are anaerobic and either non-replicating or replicating very slowly. In 2008 researchers from the National Institute of Allergy and Infectious Diseases (NIAID) found that PA-824 kills latent bacteria by releasing a gas called nitric oxide (NO), which poisons the bacteria. NO gas is produced naturally by specific immune cells after they engulf TB bacteria; this is one way the body fights TB infection. But this immune response is sometimes not sufficient to eliminate an infection. PA-824 mimics the body's natural immune response, but it is more specific and only releases the gas upon entering the TB bacteria. While PA-824 was originally designed to act against active, aerobic bacteria, this NO mechanism explains how PA-824 is also active against latent, anaerobic bacteria. TB bacteria in their latent state are surrounded by immune cells in structures called granulomas. Oxygen levels are low inside granulomas, so these structures are said to have an anaerobic environment. Researchers determined that NO gas is released in greater quantities in an anaerobic environment. Understanding how PA-824 acts against latent bacteria may help investigators design other TB drugs that use this same mechanism in low-oxygen conditions.[^Mohit] Pre-clinical studies -------------------- Pre-clinical studies demonstrated that PA-824 has potent bactericidal and sterilizing effects against drug-resistant and drug-susceptible TB. The drug’s Minimum Inhibitory Concentration (MIC, or the lowest concentration at which it is effective against bacteria) was found to be between 0.015 and 0.25 µ/ml for drug-sensitive strains and between 0.03 and 0.53 µ/ml for drug-resistant strains. A study in 2005 using the mouse model found that when PA-824 was used alone, it exhibited bactericidal activity during the intensive phase of therapy that was similar to an equivalent dose of isoniazid in humans. When combined with isoniazid, PA-824 prevented the selection of isoniazid-resistant mutants. Researchers were surprised to find that PA-824 also demonstrated potent activity during the continuation phase of therapy, during which it eliminated bacteria that had survived the initial two-month intensive phase.[^Sandeep] This is likely because the bacteria that outlast the intensive phase treatment inhabit an anaerobic environment that facilitates bactericidal action by PA-824.[^Lenaerts] Other studies using the mouse model demonstrated that PA-824, when administered by itself, had bactericidal activity slightly greater than rifampicin (20mg/kg), and comparable to moxifloxacin (100 mg/kg) and isoniazid (25 mg/kg). PA-824 administered alone also showed comparable activity to combination therapy with rifampin and isoniazid in mice and in vitro.[^Lenaerts2] Early studies incorporated PA-824 into standard combination therapies of first-line drugs to investigate its interaction with these drugs and its potential to shorten the current six-month treatment programme. Researchers found some evidence that PA-824 could potentially lead to a shorter regimen. A 2006 study replaced isoniazid with PA-824 in the first-line combination of isoniazid, rifampin, and pyrazinamide. Researchers found that this substitution led to a more rapid conversion to sputum-negative, and had more potent sterilizing effects – as demonstrated by significantly lower bacterial counts after two months of treatment. However, there was no difference in the proportion of mice that relapsed following treatment. Researchers were "unable to establish a clear role for PA-824 in a treatment-shortening regimen." [^Nuermberger] A 2008 study reported that the novel combination of PA-824, moxifloxacin, and pyrazinamide cured mice more rapidly than the first-line regimen of rifampin, isoniazid, and pyrazinamide. PA-824, moxifloxacin, and pyrazinamide in a combination regimen had potent sterilizing activity that accelerated the rate of conversion to sputum-negative. This suggested that PA-824 may substitute well for rifampicin during intensive phase therapy. Researchers concluded that, if these results are applicable to humans, "regimens containing this combination may radically shorten the treatment of multidrug-resistant tuberculosis." [^Nuermberger2] Pre-clinical studies on PA-824 revealed some other notable characteristics of the drug. Researchers found that PA-824 has a narrow spectrum of action; while it kills TB bacteria, it does not act against other types of bacteria. This has important implications for TB treatment, because it means that TB bacteria will not be able to develop resistance to PA-824 as a result of the medication being used widely as a treatment for other bacterial infections. Additionally, PA-824 may be particularly effective against latent TB bacteria when used in combination with moxifloxacin, a 2005 study suggested. This study examined the activity of various drug combinations against latent TB. Researchers were surprised to find that the combination of PA-824 (100 mg/kg) with moxifloxacin (100 mg/kg) was at least as active as the current treatment of isoniazid therapy.[^Nuermberger3] Phase I trials -------------- In phase I trials of PA-824 in healthy volunteers, no serious side effects were reported. A 2009 trial evaluated the safety and efficacy of PA-824 in two escalating-dose clinical studies, one single-dose and one multiple-dose study. The drug was well-tolerated in 58 healthy individuals who were given PA-824 for a period of 7 days, and no adverse events occurred. Pharmacokinetic properties of the drug supported a regimen of one dose per day.[^Ginsberg] Phase II trials --------------- The development of PA-824 experienced a setback when the U.S. Federal Drug Administration (FDA) put the medication on clinical hold following reports of PA-824 causing cataracts in monkeys. Phase I trials, however, found no evidence of this side-effect in human patients, most likely because the dose administered in animal studies far exceeded the comparable dose given to human patients. The FDA removed the clinical hold in July 2009. The following month, a phase II trial was initiated to examine the Early Bactericidal Activity (EBA) of PA-824. An EBA study investigates a drug's ability to quickly kill TB bacteria when administered alone. A randomized, controlled EBA study was conducted at two sites in South Africa and coordinated by Stellenbosch University, the University of Cape Town and the Global Alliance for TB Drug Development. TB-infected patients were separated into five different groups, with about 15 patients per group. Four groups received one of four oral doses of PA-824: 200, 600, 1,000, or 1,200mg per day for a period of 14 days. For the control group, 8 patients received the standard first-line TB treatment. Results were published in 2010. As researchers expected, PA-824 showed promising bactericidal activity. The results confirmed that PA-824 "could someday be incorporated into a regimen to treat drug-susceptible and drug-resistant TB more quickly and effectively." [^Diacon] However, investigators were surprised to find that each of the four PA-824 doses resulted in an essentially the same EBA, with a steady decrease in the number of TB bacteria in the sputum (~0.1 log drop in CFU per day for 14 days, as compared with 0.148 for the standard regimen). This means that maximum effectiveness was seen at the lowest dose tested: 200 mg. The lack of difference in bactericidal activity between 200 mg and 1200 mg contradicted pre-clinical studies in mice, where the activity of PA-824 was dose-dependent (i.e. increased with increasing doses). Researchers recommended more studies to test lower doses of the drug.[^Tyagi] A study published in 2011 conducted more experiments in mice and in vitro to examine the activity of lower doses of PA-824 against TB bacteria. Some of the bacterial cultures used were isolated from human patients. This study confirmed the earlier finding that 200 mg/day of PA-824 in humans is sufficient to achieve maximum bactericidal effects. The study showed that PA-824 could be active against TB bacteria in doses as low as 50 or 100 mg/day in humans. Based on pharmacokinetic results, researchers postulated that human patients require relatively lower doses of the drug than mice because PA-824 has a longer half-life in humans.[^Ahmad] Future developments ------------------- The TB Alliance is leading the development of PA-824 as a treatment for TB. A second EBA study was commenced in 2009 to explore the activity of PA-824 at lower doses (50 to 200 mg/day), but results have not yet been published. Another EBA study that will evaluate PA-824 as part of a novel three-drug combination is currently in its planning stages.[^Wingfield] Advocacy issues --------------- - The TB Alliance gained global exclusive rights to PA-824 and related compounds for the treatment of TB in an agreement with Chiron (now part of Novartis) in 2002. This agreement ensured that the technology would be made available royalty-free in endemic countries, and it was the first such arrangement between a private company and a nonprofit organization. - According to a TB Alliance statement, in 2007 the U.S. FDA approved a request for orphan drug designation for PA-824. The Orphan Drug Act is designed to reduce the costs of developing and registering drugs for some diseases and conditions that are rare in the U.S. The designation confers a number of benefits for the development of PA-824, including a waiver of the nearly $1 million fee usually paid on submission of a New Drug Application. The European Union has just approved similar Orphan Medical Product status for PA-824. The FDA also has granted PA-824 fast-track designation, which is designed to expedite the application and review process for products that have the potential to address a serious or life-threatening condition.[^TBAlliance] - Coordination between future research efforts to develop PA-824 and OPC-67683 is warranted due to the chemical similarities between these two nitroimidazole compounds. - It is taking an extraordinarily long time to push the drug through clinical trials. [^Mohit]: Joshi, Mohit. Experimental Drug Shows Promise Against Latent TB Bacteria. Top News Health. 28 Nov 2008. [^Sandeep]: T Sandeep. Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2005 June; 49(6): 2289-2293 [^Lenaerts]: AJ Lenaerts et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models. Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301 [^Lenaerts2]: AJ Lenaerts et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models. Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301 [^Nuermberger]: E Nuermberger et al. Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2006 Aug; 50(8): 2621-2625 [^Nuermberger2]: E Nuermberger et al. Powerful Bactericidal and Sterilizing Activity of a Regimen Containing PA-824, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2008 Apr; 52(4): 1522–1524 [^Nuermberger3]: E Nuermberger et al. Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model. Am. J. Respir. Crit. Care Med. 2005; 172: 1452-1456 [^Ginsberg]: AM Ginsberg et al. Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects. Antimicrob Agents Chemother. 2009 Sept; 53(9): 3720-3725 [^Tyagi]: S Tyagi et al. Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2005 June; 49(6): 2289-2293 [^Diacon]: AH Diacon et al. Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients. Antimicrob Agents Chemother. 2010 Aug; 54(8): 3402-3407 [^Ahmad]: A Ahmad et al. PA-824 Exhibits Time-Dependent Activity in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2011 Jan; 55(1): 239–245 [^Wingfield]: Wingfield, Claire. Tuberculosis Treatment Pipeline. I-Base, HIV Treatment Bulletin. July 2010. [^TBAlliance]: TB Alliance. TB Alliance Advances Two Drugs In Clinical Trials On Path To Faster, Better Tuberculosis Treatments. 11 August 2007.