Important advances in TB drug development
Nathan Geffen, CSSR
Three recent studies have significantly advanced TB drug development.
Delamanid for MDR TB
Delamanid (formerly known as OPC-67683) is a nitroimidazole and is one of two new drugs in this class used to treat TB. It inhibits the synthesis of mycolic acid, a component of the TB bacterium cell wall. It is being developed by the Japanese pharmaceutical company, Otsuka.
In June the company published the results of a large Phase II trial in the New England Journal of Medicine. The trial took place in Philippines, Peru, Latvia, Estonia, China, Japan, Korea, Egypt, and the United States. Patients were randomly assigned to receive a standard background MDR TB drug regimen plus either delamanid 100mg twice daily (n=161), delamanid 200 mg twice daily (n=160) or placebo twice daily (n=160) for eight weeks in hospital. Delamanid is taken with food.
All participants had been diagnosed with multi-drug resistant TB. Nearly all were HIV-negative. The median age was 35. Baseline BMI was 19.6. Nearly 70% of participants had lung cavities. All patients had been previously treated for TB. Of the 481 patients, 402 were sputum-positive using MGIT.
One patient died of TB. Eighteen, 14 and 15 people withdrew from the delamanid 100 mg, delamanid 200 mg and control arms respectively. Fourteen patients, evenly distributed across the arms, discontinued the study drug because of adverse events.
Except for QT interval, there were no significant differences in adverse events between the arms. QT interval was higher in the 200 mg group (13.1%) than in the 100 mg group (9.9%), which was higher than the placebo group (3.8%). There were no clinical events associated with QT interval.
Delamanid exposure increased less than proportionally with the dose. The half-life plasma concentration of delamanid was 38 hours after patients stopped taking the drug.
The main finding of the study was that patients who received delaminid 100 mg and 200 mg had a 45.4% and 41.9% sputum conversion rate (using MGIT) respectively after two months compared to 29.6% in the placebo arm (p=0.008 for the 100mg and p=0.04 for the 200 mg comparisons).
The authors explain that a second large, randomised, controlled trial of six months of treatment with delamanid as part of a full background drug regimen and including patients with HIV on ART has started. It is designed to provide data on 30 months of follow-up of patients.
Possible shorter TB regimen using PA-824
One of the aims of the TB Alliance is to develop shorter, more effective and safer TB treatment regimens. But there are many possible drug regimens, especially with several new agents in the pipeline, and each can take years to test. Iteratively adding single agents to the standard regimen and testing these in clinical trials would be an extremely costly and time-consuming way to identify an optimal new regimen. The question then is how to identify the most promising regimens for large, long, expensive trials.
Andreas Diacon of Stellenbosch University and a team from several research institutions published an article in the Lancet describing a phase 2a trial. This has received wide publicity because it has provided a clever way forward for identifying new TB regimens to take into large trials. 
TB patients at hospitals in Cape Town were randomised to several regimens. The effect of the regimens was measured using 14-day early bactericidal activity (EBA). This was done to identify the most promising regimen (or regimens) to test further. EBA was measured using MGIT from sputum samples collected daily from patients.
To be included patients had to be 18 to 65 years old. They had to weigh 40 to 90kg, be smear-positive, have a chest radiograph consistent with TB and be able to produce sputum.
The following regimens were tested:
- Bedaquiline 700 mg on day 1, 500 mg on day 2 and 400 mg daily thereafter.
- The same as above plus PA-824 200 mg daily.
- The same as the bedaquiline alone regimen plus pyrazinamide 25 mg/kg daily.
- PA-824 200 mg daily plus pyrazinamide 25 mg/kg daily.
- PA-824 200 mg daily, pyrazinamide 25 mg/kg daily and moxifloxacin 400 mg daily.
- Standard isoniazid, rifampicin, pyrazinamide, ethambutol regimen dosed according to body weight.
PA-824 is a new TB drug being developed by the TB Alliance. Like delanamid, it is a nitroimidazole.
Of the 173 patients screened, 85 were included in the trial. Of these 15 were randomly allocated to each arm, except for the standard regimen, to which 10 were allocated.
Half the patients reported adverse events, though most were mild and not drug-related. Fourteen patients completed their regimens in arms 1 to 4, 12 completed regimen 5 and all 10 completed the standard regimen. Five of the seven withdrawals were due to elevated ALT. One PA-824-moxifloxacin-pyrazinamide patient had a QT interval that met withdrawal criteria. One had an altered consciousness experience due to newly diagnosed neurocysticercosis. All of these (except the patient with neurocysticercosis) withdrawals were asymptomatic.
All patients had TB that was susceptible to the treatment regimens they were on.
The key finding of the trial was that the mean 14-day EBA of the PA-824-moxifloxacin-pyrazinamide regimen (0.233, standard deviation 0.128) was significantly higher than the bedaquiline regimens (bedaquiline 0.061 [SD±0.068], bedaquiline-pyrazinamide 0.131 [SD±0.102], bedaquiline-PA-824 0.114 [SD±0.050]).
The PA-824-moxifloxacin-pyrazinamide EBA was not significantly different from the PA-824-pyrazinamide (0.154 [SD±0.040]) and standard regimen (0.14 [SD±0.094]).
The authors conclude that the PA-824-moxifloxacin-pyrazinamide regimen is potentially suitable for treating drug-sensitive and MDR TB. They propose further clinical trials for this regimen. But they also state that the bedaquiline-PA-824 and PA-824-pyrazinamide had comparable EBAs with the standard regimen and therefore “could become important building blocks of future regimens”. They make the important point that, a “regimen not containing isoniazid and rifampicin would represent a substantial step towards a new regimen with low interaction potential suitable for both fully drug-susceptible and MDR tuberculosis. With this study the path to the construction of new regimens becomes clearer.”
Sutezolid (PNU-100840) is a new oxazolidinone. This is the same class of drug as linezolid. These drugs prevent bacterial proteins from being made by interfering with an enzyme that binds with bacterial ribosomes. 
The 2012 i-Base/TAG Pipeline Report explains that sutezolid appears to be more potent against TB than linezolid in vitro, in ex vivo whole blood cultures, and in mice. The report also explains that a whole-blood study predicted that sutezolid, SQ109 and bedaquiline, would be additive and should be tested as part of a novel combination regimen. 
The results of a phase 2 study conducted in South Africa were described in an oral abstract by Robert Wallis of Pfizer and colleagues at the IAS 2012 conference. Sputum positive patients were randomly assigned to, either sutezolid 600mg twice daily (n=25), 1200 mg once daily (n=25), or the standard South African first-line regimen (isoniazid, rifampicin, ethambutol and pyrazinamide, n=9) for the first 14 days of treatment. Only 7% of the patients were HIV positive (not yet on ART) and 20% were women. 
All volunteers completed the trial. There were no treatment-related serious adverse events. There was also no effect on the QT interval. Seven patients on the sutezolid arms had transient asymptomatic ALT elevations.
At baseline, the mean log colony forming units per millilitre (CFU/ml) was 6.95. The mean time to detection using MGIT was 116 hrs. Using 90% confidence intervals, all three treatment arms reduced colony forming units and increased time to MGIT detection significantly, but the standard regimen improvements were significantly greater. The actual reductions are depicted graphically in the abstract and so the exact values are not given. These appear to be approximately as follows:
Time to MGIT detection: approximately 75 hours longer for the sutezolid regimens versus 160 hours for the standard regimen.
CFU/ml reduction: approximately 1.2 log for sutezolid versus 2.8 log for standard.
The authors concluded that further studies of the drug are warranted.
This is one of the most exciting and fast-moving periods in TB drug development since the 1960s. Delamanid has arguably leapfrogged bedaquiline to the front of the new drug pipeline. But both are important.
Both drugs must be put swiftly through the remaining studies needed for regulatory approval, which includes providing plans for paediatric development, and both drugs must be made available for pre-approval access to patients with drug-resistant TB who are being treated at well-run TB facilities. They also need to be tested together. The Global TB Community Advisory Board has written to Otsuka raising these issues and Otsuka has replied in detail with their plans. [6, 7]
Except for delamanid, the regimens and drugs discussed here are several years away from coming to market. The pace from drug discovery to market for new TB drugs is far too slow. Bedaquiline has been in development since at least 2004 and is still not approved anywhere. According to the Working Group on New TB Drugs the current annual budget for sutezolid is tiny, $250,000 to $1,000,000. The annual budget for PA-824 is significant, $10 million, but nothing close to what would be spent on a blockbuster drug.
Although the TB drug development pipeline has improved, diseases that almost exclusively affect poor people continue to receive dramatically reduced investment from pharmaceutical industry and research institutions compared to medicines that can be more profitably marketed in richer countries.
- Gler MT et al. 2012. Delamanid for Multidrug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2012 Jun 7;366(23):2151-60.
- Diacon A et al. 2012. 14-day bactericidal activity of PA-824, bedaquiline,pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet. 2012 Jul 20.
- Shinabarger D. 1999. Mechanism of action of the oxazolidinone antibacterial agents. Expert Opin Investig Drugs. 1999 Aug;8(8):1195-202.
- Clayden et al. 2012 Pipeline Report.
- Wallis RS et al. 2012. Safety, tolerability and early bactericidal activity in sputum of PNU-100480 (sutezolid) in patients with pulmonary tuberculosis. Oral abstract THLBB02. 19th International AIDS Conference July 22-27, Washington DC.
- Clayden P et al. 2012. Letter by Global TB CAB to Otsuka.
- Carlevaro P. 2012. Response to open letter by Global TB CAB.