Are pretomanid-containing regimens for tuberculosis a victory or a victory narrative?

Around 10 million people become sick with tuberculosis, and more than 1·2 million people die from the disease each year.1WHOGlobal Tuberculosis Report.https://www.who.int/tb/publications/global_report/en/Date: 2019Date accessed: October 31, 2019Google Scholar WHO has proposed some ambitious targets in their End TB Strategy,2WHOThe End TB Strategy.http://www.who.int/tuberculosis/strategy/end-tuberculosis/en/Date accessed: August 25, 2019Google Scholar and global leaders committed to reaching these targets within the next decade. As these deadlines approach, the rhetoric has increased but has produced seemingly little progress, creating an air of desperation among all cadres engaged in the fight against tuberculosis. New drugs are needed urgently, and for the past 20 years the investigational compound known as PA-824—later named pretomanid—has been a promising therapeutic candidate against tuberculosis.3Stover CK Warrener P VanDevanter DR et al.A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis.Nature. 2000; 405: 962-966Crossref PubMed Scopus (894) Google Scholar Although a pretomanid-containing regimen was approved by the US Food and Drug Administration (FDA) under its Limited Population Pathway on Aug 14, 2019, it has been in the news headlines since 2014, when reports from a phase 2b study of its use in combination with moxifloxacin and pyrazinamide for treating all forms of tuberculosis led to the popular press referring to pretomanid as a “major breakthrough”.4Scott S Tuberculosis treatment breakthrough could dramatically speed up cure, researchers say.https://www.abc.net.au/news/2014-07-21/major-breakthrough-in-tuberculosis-treatment--researchers-say/5610308Date: July 25, 2014Date accessed: September 14, 2019Google Scholar Media coverage of another pretomanid-containing regimen, known as Nix-TB, had a similar message. Nix-TB is a 6-month, three-drug (pretomanid, bedaquiline, and linezolid) regimen that has so far been assessed in 109 people with highly resistant forms of tuberculosis in an uncontrolled study (NCT02333799), showing an 89% treatment success. The FDA approval of the Nix-TB regimen has offered the tuberculosis field hope and, for many, has signalled a step forward. For others, because the approval of this drug is based on an uncontrolled, non-randomised study in 109 patients, it risks lowering the evidentiary standards required for new tuberculosis medicines.5Global TB Community Advisory BoardResearch, regulatory, and access considerations regarding pretomanid.http://tbonline.info/posts/2019/5/18/research-regulatory-and-access-considerations-rega/Date accessed: September 20, 2019Google Scholar More data are needed on the safety and efficacy of pretomanid-containing regimens, and such data can be found in the paper published in The Lancet Respiratory Medicine by Conor Tweed and colleagues.6Tweed CD Dawson R Burger DA et al.Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial.Lancet Respir Med. 2019; (published online Nov 12)https://doi.org/10.1016/S2213-2600(19)30366-2Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar This phase 2b study, was a partially randomised trial that included a non-randomised group for patients with rifampicin-resistant tuberculosis and was designed to assess four different treatment regimens, three of which contained pretomanid. Participants with drug-susceptible tuberculosis were randomly assigned to receive standard of care with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) or a combination of pretomanid, bedaquiline, and pyrazinamide, with two different dosing strategies used for bedaquiline. People with rifampicin-resistant tuberculosis all received a regimen containing bedaquiline, pretomanid, pyrazinamide, and moxifloxacin. The study was an 8-week trial and its primary efficacy endpoint was daily percentage change in the time to sputum culture positivity in liquid media. Safety was also assessed in each group. The study was not placebo-controlled or blinded (except for the microbiology laboratory staff), and the sponsor was involved in the design, execution, and interpretation of results. 180 participants with drug-susceptible tuberculosis and 60 people with rifampicin-resistant tuberculosis were enrolled in the study. The pretomanid-containing groups showed significantly higher bactericidal activity against drug-susceptible tuberculosis, with daily percentage changes in time to sputum culture positivity being 5·17% (95% Bayesian credibility interval 4·61–5·77) for the group with the daily dose of bedaquiline, 4·87% (4·31–5·47) for the group with the loading dose of bedaquiline, and 4·04% (3·67–4·42) for the HRZE group. The pretomanid-containing regimens, however, were also associated with a worse safety profile than the HRZE group for people with drug-susceptible tuberculosis. Of the 13 participants who had to stop receiving study treatment due to safety concerns, 11 were in the pretomanid-containing groups (9% of 119 participants who received pretomanid) and only two were in HRZE group (3% of 61 patients who received HRZE). Because people in the rifampicin-resistant tuberculosis group were not randomly assigned and received a different regimen, it is difficult to interpret the findings from this group. The authors conclude that the pretomanid-containing regimens are promising candidates for shortening treatment duration of both drug-susceptible and rifampicin-resistant tuberculosis. A phase 3 trial of the moxifloxacin-containing regimen (SimpliciTB, NCT03338621) has already been launched.7Global Alliance for TB Drug DevelopmentTrial to evaluate the efficacy, safety and tolerability of BPaMZ in drug-sensitive (DSTB) adult patient and drug-resistant (DR-TB) adult patients.https://clinicaltrials.gov/ct2/show/NCT03338621Date accessed: September 14, 2019Google Scholar It is difficult, however, to draw conclusions about treatment shortening potential on the basis of 8-week studies of bactericidal activity. For example, in multiple phase 3 trials of fluoroquinolone-based treatment shortening that were launched on the basis of 8-week data, all trials failed to show non-inferiority.8Imperial M Nahid P Phillips P et al.A patient-level pooled analysis of treatment shortening regimens for drug-susceptible pulmonary tuberculosis.Nat Med. 2018; 24: 1708-1715Crossref PubMed Scopus (141) Google Scholar Tweed and colleagues6Tweed CD Dawson R Burger DA et al.Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial.Lancet Respir Med. 2019; (published online Nov 12)https://doi.org/10.1016/S2213-2600(19)30366-2Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar suggest that the pretomanid-containing regimens for the treatment of drug-susceptible tuberculosis should be pursued on safety grounds, reporting that “part of the global effort to move beyond HRZE should be motivated by the need for alternative therapies with fewer side-effects.” However, safety issues seen in this trial with the pretomanid-containing regimens for drug-susceptible tuberculosis—most notably liver toxicity—are of concern. A similar study9Dawson R Diacon A Everitt D et al.Efficacy 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, partially randomized trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis.Lancet. 2015; 385: 1738-1747PubMed Scopus (197) Google Scholar assessing pretomanid, moxifloxacin, and pyrazinamide for drug-susceptible tuberculosis, the STAND trial (NCT02342886), also showed promise in an 8-week assessment, but when rolled out to phase 3 it did not show non-inferiority compared with the HRZE group (although this could be due in part to a truncated sample size) and was put on a temporary clinical hold after reports of high frequency of hepatotoxicity and three treatment-related deaths.10Global Alliance for TB Drug DevelopmentShortening Treatment by Advancing Novel Drugs (STAND).https://clinicaltrials.gov/ct2/show/results/NCT02342886?view=resultsDate accessed: September 14, 2019Google Scholar The early efficacy reported in the 8-week trial of Tweed and colleagues showed that the pretomanid-containing regimens had a significantly higher early bactericidal activity than did the HRZE regimen and that there might be a role of pretomanid in the treatment of people with drug-susceptible tuberculosis. The safety and independent contributions of pretomanid to pretomanid-containing regimens, however, are not well understood. Given the evidence base available to us currently, can we claim pretomanid a victory? We think more research is needed before pretomanid can be celebrated as a promising treatment for people with tuberculosis. We declare no competing interests. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trialB200PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B200PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes. 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