Pipeline of drugs for related diseases

Abstract

Purpose of review For the first time in decades, there are multiple new drugs in the pipeline for the treatment of tuberculosis (TB). In addition, existing drugs are being repurposed or optimized for TB with the goal of shortened treatment duration for drug-sensitive TB and safer, shorter treatments for multidrug-resistant (MDR) TB. In this review, the results of recent trials evaluating novel combination regimens for TB disease and latent TB infection are described. Recent findings High-dose rifamycins (rifampin and rifapentine) and fluoroquinolones directly observed have treatment-shortening potential when used for drug-sensitive TB disease, and a 12-dose once-weekly regimen of rifapentine along with isoniazid effectively treats latent TB. Bedaquiline, an anti-TB drug with a novel mechanism of action, and delamanid, a nitroimidazole, are entering phase 3 trials. Both improve rates of sputum culture conversion among patients with MDR-TB. Other nitroimidazoles and oxazolidinones are in Phase 2 testing, as are combinations involving multiple new chemical entities. Summary With the resurgence of anti-TB drug discovery efforts, we now have a modestly robust pipeline of new anti-TB drugs. Several promising new regimens involving investigational and existing drugs that may be capable of shortening treatment for drug-sensitive TB and improving management of drug-resistant TB are in late-phase clinical evaluation.

Determination of [ 11 C]Rifampin Pharmacokinetics within Mycobacterium tuberculosis-Infected Mice by Using Dynamic Positron Emission Tomography Bioimaging

“…Preclinical as well as clinical studies have demonstrated that rifamycins have dose-dependent activity and that current dosing achieves concentrations that are on the steep part of the dose-response curve (22,23). Rifamycins have significant potential for shortening TB treatment (21,24,25), and recent trials have demonstrated that within the range of doses tested clinically, higher doses of rifamycins improve microbiologic outcomes significantly (26,27). Other clinical studies also suggest that increasing rifampin concentrations can hasten sterilization (28) in TB treatments and that low rifampin concentrations lead to acquired drug resistance (29).…”

Advances in Diagnosis and Treatment of Latent Tuberculosis Infection

“…With limited pharmacological discoveries in the past 4 decades, the advent of new strategies for active TB disease is encouraging for TB prevention and control. 72 Current research trials are investigating the use of the 12-dose INH and RPT regimen by DOT in low-income countries with high TB prevalence, as well as the actual cost-effectiveness and safety of using new regimens in clinical practice. 70 Along with the scientific advancements in diagnostic measures and multipharmaceutical regimens based on the infectious etiology of LTBI, the influence of social determinants of health on LTBI transmission and prevention may be key to global control of LTBIs.…”

Delamanid: A Review of Its Use in Patients with Multidrug-Resistant Tuberculosis

“…Patients with MDR-TB have an increased likelihood of treatment failure or death and are more likely to develop additional drug resistance [10]. Therefore, there is a compelling need for new anti-TB drugs that are more effective and better tolerated, and can shorten the duration of therapy [3,4,7,10]. Shorter treatment duration reduces the cost of therapy, improves adherence and helps prevent drug resistance [7].…”

“…Therefore, there is a compelling need for new anti-TB drugs that are more effective and better tolerated, and can shorten the duration of therapy [3,4,7,10]. Shorter treatment duration reduces the cost of therapy, improves adherence and helps prevent drug resistance [7]. New MDR-TB regimens should include drugs to which resistance is not expected to have developed, thereby avoiding dependence on drug susceptibility testing [4].…”

“…the oxazolidinone linezolid and fluoroquinolones such as gatifloxacin and moxifloxacin) or new (e.g. bedaquiline, posizolid, sutezolid, SQ-109) drugs are currently being investigated in phase II and/or III trials for use in the treatment of MDR-TB, as are novel combination regimens involving drugs in the pre-registration phase and/or those currently used in standard first-line treatment [1,3,4,7].…”