Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is the leading cause of death from an
infectious disease globally. The widespread and ever-increasing resistance to TB drugs is reducing the effectiveness of treatment and jeopardizing TB control. New effective drugs with acceptable safety profiles are needed to turn the tide. Since the early 1990s, Otsuka
Pharmaceutical Co., Ltd. has had a TB
drug development program that resulted in the selection and development of
delamanid (OPC-67683, Deltyba®), a first-in-class bicyclic
nitroimidazole.
Delamanid was initially approved by the European Medicines Agency (EMA) in 2014 for the treatment of adult pulmonary multi-
drug resistant (MDR)-TB when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. It has since been approved by several other countries/regions. In this review, we describe the history of
delamanid's development, including the screening process, in vitro and in vivo characterization, as well as various clinical studies.
Delamanid possesses potent activity against replicating, dormant, and intracellular MTB bacilli, and is bactericidal in mouse and guinea pig TB models.
Delamanid resistance mechanisms have been attributed to genes in the F420-dependent deazaflavin
nitroreductase bio-activation pathway, found in mycobacterium species but not in common bacterial or mammalian cells. Published susceptibility testing results from 744 clinical isolates from
delamanid-naïve patients indicate that the natural resistance rate to
delamanid is very low (1.3%).
Delamanid is largely metabolized by
albumin in serum, and to a much less extent by
cytochrome P450 enzymes. Furthermore, it neither inhibits nor induces
P450 enzymes. In terms of efficacy,
delamanid demonstrated activity in an early bactericidal activity trial in
drug susceptible pulmonary TB patients and increased 2-month sputum culture conversion rates when added to an optimized background regimen in MDR-TB patients in a phase 2b global clinical trial. In addition, recent results outside clinical studies show favourable responses in highly resistant TB patients including extensively
drug resistant (
XDR)-TB when treated with
delamanid-containing regimens in routine programmatic settings. The primary safety concern with
delamanid is QTcF interval prolongation, although this observation has thus far not been associated with any clinical
cardiac events. Overall,
delamanid appears to be a well-tolerated and safe anti-TB
drug when compared to other drugs used to treat MDR-TB.