The development and approval of bedaquiline and delamanid was a major breakthrough in anti-tuberculosis drug development, a field that had been stagnant for decades. The slow progress in research and development is a consequence of many factors, including lack of funding, scarce economic interest from pharmaceutical companies, and complacency of national governments. It is, however, undeniable that drug development is a lengthy and costly process, and particularly so in the case of antimycobacterials. The recent and almost concomitant availability of a number of new and re-purposed drugs provides an historical window of opportunity to improve tuberculosis treatment, which may not present itself again for many years.
Figure 23. Pipeline of clinical and preclinical development of new anti-tuberculosis drugs.
Provided by the Working Group on New TB Drugs (www.newtbdrugs.org).
74 Indeed, the current pipeline of new anti-tuberculosis drugs in development (Figure 23) may seem rich at a first glance. However, when investigated in detail, the overall outlook is much less promising. Apart from bedaquiline and delamanid, the only other compound that is undergoing Phase III of clinical development is pretomanid. However, pretomanid is a nitroimidazole like delamanid and is very likely to share the same resistance mechanism. The two nitroimidazoles will be therefore alternative but not be used in combination. Among compounds in Phase II of clinical development, two (delpazolid and sutezolid) are oxazolidinones like the re-purposed drug linezolid. These drugs have the same resistance mechanism as linezolid and are mainly being studied to identify a less toxic alternative to linezolid. SQ109 is a novel 1,2-ethylene diamine small molecule with a distinct mechanism of action. However, after having shown promising activity in vitro and in animal studies,145,286 a 14-day EBA study reported no activity of SQ109 alone or in combination with rifampicin.287 In addition, in a recent multi-arm multi-stage study testing different treatment regimens including high-dose rifampicin, ethambutol, moxifloxacin, and SQ109, the arms containing SQ109 were dropped for insufficient efficacy.288 The clinical development of this drug is therefore likely to be discontinued by the company. Macozinone is a piperazinobenzothiazinone derivative that inhibits DprE1, an enzyme that is essential for the biosynthesis of the cell wall. Although officially at Phase II of clinical development due to a small study that has been performed in the Russian Federation and whose results are still unpublished, the drug is currently being tested in a Phase I study in Switzerland. In conclusion, there are currently no innovant anti-tuberculosis drugs in Phase II or III of clinical development. Clinicians treating drug-resistant tuberculosis cannot therefore expect any new breakthrough in terms of new chemotherapy agents, at least for the next few years.
Table 13. Characteristics of the main clinical trials testing new and shorter combinations for
FQ-S = fluoroquinolone-susceptible; SLI-S = susceptible to second-line injectables; MDR-TB = multidrug-resistant tuberculosis; DS-TB = drug-susceptible tuberculosis; DR-TB = drug-multidrug-resistant tuberculosis; Bdq
= bedaquiline; Dlm = delamanid; Pa = pretomanid; HRZE = isoniazid, rifampicin, pyrazinamide, and ethambutol; SoC = standard-of-care; mo = months; TTP = time to culture positivity; TCC = time to culture conversion.
Table 14. Characteristics of the main clinical trials testing new and shorter combinations for fluoroquinolone-resistant MDR-TB.
FQ-R = fluoroquinolone-resistant; MDR-TB = multidrug-resistant tuberculosis; Bdq = bedaquiline; Dlm = delamanid; Pa = pretomanid; SoC = standard-of-care; mo = months.
75 Conversely, innovation is expected to come in the next years in the form of the identification of new, shorter MDR-TB treatment regimens including new and re-purposed drugs. A relevant number of Phase II and Phase III clinical trial are ongoing or starting soon and are summarised in Table 13 for fluoroquinolone-susceptible MDR-TB and in Table 14 for fluoroquinolone-resistant XDR-TB. For fluoroquinolone-susceptible MDR-TB, there are four pivotal Phase III clinical trials that are currently ongoing, and that have the potential to revolutionize the currently-recommended treatment. These trials are testing different combinations including at least one and up to two new drugs among bedaquiline, delamanid, and pretomanid; the total duration of tested treatment is six to nine months, and the control is represented by WHO-recommended standard-of-care regimen. Two trials, both sponsored by Médecins Sans Frontières, have an innovant design that aims at increasing the scientific yield while minimizing the sample size.289,290 The first, TB-PRACTECAL (clinicaltrials.gov:
NCT02589782), is a multi-arm, multi-stage trial that tests three experimental regimens: one or two of the experimental arm will be dropped based on the culture conversion rate at 8 weeks, while the other one/two arm/s will be continued until the end of the follow-up. The second, endTB (clinicaltrials.gov: NCT02754765), is a six-arm Bayesian response-adaptive trial, a design that is prevalently used in oncology trials: in Bayesian randomization, the patients’
likelihood of being randomized to each experimental arm is linked to the performance of the arm at interim outcomes (week 8 and week 39) and re-assessed every month of recruitment.291,292 The number of studies recruiting fluoroquinolone-resistant MDR-TB patients is smaller. Among them, only two are controlled trials, and therefore having reasonable ambitions of conducting to a change in treatment recommendations. One is the aforementioned trial TB-PRACTECAL, which is however not powered to draw any specific conclusion on fluoroquinolone-resistant MDR-TB population. The other is endTB-Q, a trial testing a four-drug regimen containing bedaquiline, delamanid, linezolid, and clofazimine, given for six and nine months, respectively, in two experimental arms.
Overall, it is crucial that the rapid implementation of new drugs and regimens, as soon as they will be supported by sufficient evidence, will be provided together with support from national programs and international agencies to promote training programs and antimicrobial resistance awareness campaigns. The optimal management of each individual patient, together with systematic surveillance of drug resistance and quick adaptation to epidemiological changes in the population, is the key to avoid the quick spread of drug resistance which has led to the failure of many efforts to control tuberculosis in the past.293,294
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