Otsuka Novel Products GmbH

Tuberculosis (TB) is the leading cause of mortality by an infectious disease worldwide. Despite national and international efforts, the world is not on track to end TB by 2030. Antibiotic treatment of TB is longer than for most infectious diseases and is complicated by frequent adverse events. To counter emerging Mycobacterium tuberculosis drug resistance and provide effective, safe drug treatments of shorter duration, novel anti-TB medicines, and treatment regimens are needed. Through a joint global effort, more candidate medicines are in the clinical phases of drug development than ever before.

To review anti-TB medicines and treatment regimens under clinical evaluation for the future treatment of drug-susceptible and drug-resistant TB.

Pre-clinical and clinical studies on novel anti-TB drugs.

Description of novel protein synthesis inhibitors (oxazolidinones and oxaboroles), respiratory chain inhibitors (diarylquinolines and cytochrome bc1 complex inhibitor), cell wall inhibitors (decaprenylphosphoryl-β-d-ribose 2'-epimerase, inhibitors, thioamides, and carbapenems), and cholesterol metabolism inhibitor currently evaluated in clinical trials and novel clinical trial platforms for the evaluation of treatment regimens, rather than single entities.

A large number of potential anti-TB candidate medicines and innovations in clinical trial design for the evaluation of regimens, rather than single medicines, provide hope for improvements in the treatment of TB.

Antimicrobial susceptibility testing, based on clinical breakpoints that incorporate pharmacokinetics/pharmacodynamics (PK/PD) and clinical outcomes, is becoming a new standard in guiding individual patient therapy as well as for drug resistance surveillance. However, for most antituberculosis drugs, breakpoints are instead defined by the epidemiological cutoff values of the MIC of phenotypically wild-type strains irrespective of PK/PD or dose.

Although delamanid has been approved for the treatment of multidrug-resistant TB (MDR-TB) in numerous regions, in areas where it is not yet registered it can be accessed as part of salvage therapy (in particular for those patients with limited treatment options)viathe Otsuka compassionate use programme. Here we present the analysis of interim treatment outcomes by 24 weeks of more than 200 MDR-TB patients globally who received delamanid under this programme.

We evaluated treatment efficacy with respect to culture negativity at 24 weeks, as well as the safety profile of delamanid, in an MDR-TB patient cohort treated under compassionate use between 2014 and 2019.

Among patients who received delamanid as part of a multidrug regimen, 123 (61%) out of 202 had extensively drug-resistant TB (XDR-TB), 66 (33%) out of 202 had HIV co-infection and 34 (17%) out of 202 were children aged between 6 and 17 years. Of those patients who were culture positive at delamanid treatment initiation and who completed 24 weeks of delamanid treatment in combination with other anti-tuberculosis (TB) drugs, culture negativity was achieved in 116 (79%) out of 147 cases. The corresponding rates of culture negativity for patients with XDR-TB and HIV co-infection, as well as the paediatric subgroup were 69 (77%) out of 90, 44 (92%) out of 48 and 20 (80%) out of 25, respectively. QT interval prolongation was the most frequently observed serious adverse event and was reported in 8% of patients receiving delamanid. Overall, treatment safety outcomes did not reveal any new or unidentified risks.

The use of delamanid combined with other active drugs has the potential to achieve high rates of culture negativity in difficult-to-treat drug-resistant TB cases, with a favourable safety profile.