OPC-67683

OPC-67683 (also known as delamanid) is an experimental drug that has shown potent activity against drug-resistant and drug-susceptible TB. Along with another experimental medication called PA-824, OPC-67683 belongs to a class of drugs called nitroimidazoles. Interest in nitroimidazoles arose because of research into another antibiotic called [metronidazole](http://www.medicinenet.com/metronidazole/article.htm "Metronidazole"). The Japanese company Otsuka Pharmaceutical has been investigating this class of compounds for more than a decade. Early clinical trials demonstrated OPC-67683 to be a potent bactericidal and sterilizing drug. It is currently undergoing phase II trials to determine its role in TB treatment. How it works ------------ OPC-67683 kills TB-causing bacteria by disrupting the cell wall. It does so by preventing the synthesis of a molecule called mycolic acid, an essential mycobacteria cell wall component. Isoniazid also works by preventing the synthesis of mycolic acid. The difference between OPC-67683 and isoniazid lies in the type of mycolic acid molecule that each drug inhibits. OPC-67683 inhibits the synthesis of methoxy- and keto-mycolic acid but not a-mycolic acid. Isoniazid acts on all subclasses of mycolic acid.[^Tomioka] Pre-clinical trials ------------------- A study in 2006 conducted by Otsuka Pharmaceutical showed that OPC-67683 has potent activity against drug-resistant and drug-susceptible TB _in vitro_ and in mice. For the in vitro component, researchers tested the drug’s ability to inhibit bacterial growth in dishes of both drug-susceptible and MDR TB bacteria. Using the mouse model, researchers administered OPC-67683 to TB-infected mice, some of which were immunocompromised. The results from the in vitro and mouse models demonstrated that OPC-67683 was more potent at a smaller concentration than other first-line TB drugs. The in vitro experiment showed it to be effective against drug-susceptible and MDR TB bacteria at a low concentration of 0.006-0.024 µ/ml. Whereas no TB bacteria colonies were found after 4 months of treatment with the OPC-67683-containing regimen, colonies were still detected after 6 months of treatment with the standard intensive phase regimen. The mouse model showed OPC-67683 to be effective at low doses in vivo. It reduced the number of bacteria in the lungs of normal and immunocompromised mice at lower concentrations than the standard first-line drugs. The combination of OPC-67683 (2.5 mg/kg) with rifampicin (5 mg/kg) and pyrazinamide (100 mg/kg) eradicated TB bacteria more quickly - by at least 2 months - than the current intensive phase regimen of rifampicin (5mg/kg), isoniazid (10mg/kg), ethambutol (100 mg/kg), and pyrazinamide (100mg/kg). These early results, if reproducible in human patients, suggest that OPC-67683 could potentially shorten TB treatment time. [^Matsumoto] Another study in 2007 investigated the in vitro sterilizing activity of OPC-67683, i.e. its ability to completely eliminate an infection, against drug-susceptible bacteria. Researchers found that, at the highest dose levels tested (1.0 µg/ml), OPC-67683 was superior to isoniazid and equal to rifampicin.[^Saliu] These pre-clinical studies revealed some potentially important attributes of OPC-67683. Firstly, the drug was found to have no cross-resistance with any other first-line TB drug. In addition, OPC-67683 is likely safe and effective when used in combination with antiretrovirals. Researchers found that OPC-67683 had no effects on a specific class of liver enzymes (called cytochrome P450 enzymes) that metabolize antiretrovirals. In addition, these liver enzymes did not affect the activity of OPC-67683. This indicates OPC-67683 is unlikely to cause problems or lose its effectiveness when given with drugs that are metabolized by this enzyme. These studies also found that the killing of TB bacteria by OPC-67683 is concentration-dependent. Unlike other first-line medications like isoniazid and rifampicin, which are effective against TB bacteria regardless of the drug concentration, OPC-67683 is only bactericidal at a minimum threshold concentration. Researchers postulated that this may be because, at low concentrations, OPC-67683 is metabolized by TB bacteria to an intermediate compound with slightly different chemical properties. According to the authors of the 2007 study, this chemical transformation could account for the observation that, in some TB bacterial cultures, OPC-67683 at low concentrations lost its effectiveness against the bacteria after 4-5 days. Interestingly, these studies also found that OPC-67683 is highly effective against intracellular bacteria, i.e. bacteria hidden within human cells, and therefore could be used to fight latent TB. TB is remarkably difficult to kill because bacteria are able to hide in different parts of the body, including white blood cells called macrophages. TB bacteria hiding in cells are in a latent state. While researchers are currently investigating exactly where and how bacteria hide in the body, they do know that OPC-67683 is effective against intracellular bacteria. The 2006 study determined that the in vitro intracellular activity of OPC-67683 was better than that of isoniazid and PA-824 and, at a concentration of 0.1 μg/ml, as good as that of rifampicin at a concentration of 3 μg/ml. This intracellular activity is believed by researchers to be an indication that OPC-67683 could be used as a treatment for latent TB.[^Matsumoto] OPC-67683 has another potentially useful property: it is effective against both aerobic and anaerobic bacteria. When TB bacteria are in an aerobic state, they require oxygen for survival and are active and self-replicating. In an anaerobic state, TB bacteria do not use oxygen and are often found hiding inside cells. Experts believe that this anaerobic state is similar to the state of TB bacteria that survive TB treatment with first-line drugs. First-line medications rifampicin and isoniazid are active against aerobic but not anaerobic bacteria, while metronidazole is active only against anaerobic bacteria. Researchers have postulated that, because OPC-67683 is active against bacteria in both states, it could be used to treat both active and latent TB, and to shorten the duration of the standard treatment programme. [^Anderson] Phase I trials -------------- Phase I and Early Bacterial Activity (EBA) studies of OPC-67683 have been completed. Studies of the drug in doses of up to 400mg showed that it was tolerated well by healthy volunteers, and no serious side effects were reported.[^Shi] A phase I trial was undertaken by researchers at the University of Stellenbosch in South Africa to examine the EBA of OPC-67683. Results were published in July 2011. In this study, 48 patients infected with drug-susceptible pulmonary TB were randomly assigned to receive OPC-67683 at a dose of 100, 200, 300 or 400 mg daily for 14 days. Sputum was collected from these patients and analyzed to determine OPC-67683’s EBA, i.e. its bactericidal effects early on in treatment. Researchers found that the average EBA of all dosages of OPC-67683 was significant from day 2 onward, meaning that it didn’t begin eliminating TB bacteria prior to the second day of treatment. The EBA of OPC-67683 did not differ significantly between dosages, although patients who received a dose of either 200 or 300 mg experienced a slightly greater decline in the number of TB bacilli in their sputum than those who received 100 mg or 400 mg of the drug. The effectiveness of the medication appeared to plateau at 300 mg, which researchers believed was due to limited absorption in doses exceeding 300 mg. Overall, the medication was tolerated well in patients, with no serious side effects.[^Diacon] Phase II trials --------------- Phase II clinical trials are currently being planned and undertaken to test the safety and efficacy of OPC-67683 in patients. A phase II study was conducted by Otsuka Pharmaceutical to evaluate the effectiveness of OPC-67683 in the treatment of MDR TB. It was completed in October 2010 but results have not yet been published. In this study, researchers randomly assigned a group of 481 patients infected with MDR TB to one of three groups. Group 1 received an Optimized Background Regimen (OBR, which refers to the standard treatment programme) for MDR TB in addition to 100 mg of OPC-67683 twice daily. Group 2 received the OBR plus 200 mg of OPC-67683 twice daily. Group 3 received the OBR in addition to a placebo. The study lasted for 56 days. Researchers are examining the results to determine how effective OPC-67683 was at inducing patients to convert to sputum-negative during the 56 days of treatment, and whether the medication caused any adverse side effects.[^Otsuka] Another phase II study led by Otsuka Pharmaceutical is active but not yet recruiting participants. This study aims to assess the safety and efficacy of OPC-67683 in patients with MDR TB. OPC-67683 will be given to patients at a total dose of 500-800 mg per day. Researchers will evaluate the medication’s safety and side effects in patients during a period of nine months, and the rate of sputum culture conversion over a period of 24 weeks. The study is expected to be completed by December 2011.[^Otsuka2] Future developments ------------------- Otsuka is currently planning a phase III clinical trial that is expected to be completed in 2015. This will be a multicenter, randomized, placebo-controlled trial conducted globally at approximately 15 different sites qualified to treat MDR TB. There will be two parallel groups of patients in this study. In the first group, MDR TB infected patients will receive either the standard MDR treatment programme (OBR) plus a placebo, or the OBR plus 100 mg of OPC-67683 twice daily for 2 months followed by 200 mg once daily for 4 months. For the second group, researchers will examine the safety and efficacy of OPC-67683 in a group of HIV positive patients taking antiretrovirals.[^Otsuka3] Although early studies demonstrated OPC-67683 to be a potentially effective treatment for both drug-resistant and drug-susceptible TB, Otsuka Pharmaceutical has chosen to direct its initial focus on testing the drug as a treatment for MDR TB. Given that the current success rate for treating MDR TB is only about 70%, the drug will likely be licensed more quickly as a treatment for MDR TB. Otsuka has committed to conducting clinical trials for OPC-67683 once the drug has been licensed for drug-resistant TB.[^Boogaard] Advocacy Issues --------------- - More clinical information is needed to determine the effectiveness of OPC-67683 as a treatment for MDR and XDR TB in addition to drug-tolerant and latent TB. Its optimal formulation has yet to be established. - It is recommended that more resources be committed to clinical trials on TB medications. Research is hampered by issues such as a dearth of investigators experienced in conducting TB trials that adhere to international standards for clinical research, and by a lack of such internationally accepted standards. Larry Geiter from Otsuka Pharmaceutical acknowledged that investigators have yet to agree even on research methods within TB trials, such as a standard way to cultivate TB bacteria in the laboratory. There is also a lack of formal guidelines for benchmarks to be fulfilled by researchers seeking to secure drug licenses. For example, the U.S. FDA has yet to publish formal guidelines on TB drug licensing, guidelines that are well established for other diseases like hypertension.[^Anderson] - If phase II data shows OPC-67683 is likely effective, it should be offered on a compassionate care basis to people with MDR and XDR TB in conjunction with TMC207 and standard MDR TB treatment. [^Tomioka]: H. Tomioka et al. Antituberculous Drug Development and Novel Drug Targets: Present Status of the Development of New Antimycobacterial Agents. Expert Rev Resp Med. 2008; 2(4): 455-471 [^Matsumoto]: M Matsumoto et al. OPC-67683, a Nitro-dihydro-imidazooxazole Derivative with Promising Action Against tuberculosis In Vitro and in Mice. PLoS Med. 2006 Nov; 3(11): 466 [^Saliu]: OY Saliu et al. Bactericidal Activity of OPC-67683 Against Drug-Tolerant Mycobacterium tuberculosis. J Antimicrob Chemother. 2007 Nov; 60(5): 994-8 [^Matsumoto]: M Matsumoto et al. OPC-67683, a Nitro-dihydro-imidazooxazole Derivative with Promising Action Against tuberculosis In Vitro and in Mice. PLoS Med. 2006 Nov; 3(11): 466 [^Anderson]: Anderson, Tatum. Working for the ‘Dark Side’ Against TB. TropIKA.net. 29 Jan 2009. [^Shi]: R Shi et al. Development of New Anti-tuberculosis Drug Candidates. Tohoku J. Exp. Med. 2010; 22(1): 97-106 [^Diacon]: AH Diacon et al. Early Bactericidal Activity of Delamanid (OPC-67683) in Smear-Positive Pulmonary tuberculosis Patients. Int J Tuberc Lung Dis. 2011 Jul; 15(7): 949-954 [^Otsuka]: Otsuka Pharmaceutical. A Placebo-controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB). Clinical Trials.gov: A Service of the U.S. National Institutes of Health. 31 Aug 2011. [^Otsuka2]: Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis. Clinical Trials.gov: A Service of the U.S. National Institutes of Health. 22 Jun 2011. [^Otsuka3]: Otsuka Pharmaceutical. Safety and Efficacy Trial of Delamanid for 6 Months in Patients With Multidrug Resistant Tuberculosis. 26 Aug 2011. [^Boogaard]: J van den Boogaard et al. New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Antimicrobial Agents and Chemotherapy. 2009 Mar; 53(3): 849-862 [^Anderson]: Anderson, Tatum. Working for the ‘Dark Side’ Against TB. TropIKA.net. 29 Jan 2009