Treatment of tuberculosis
New drugs:
Bedaquiline and Delamanid
KIT 23 September 2014
Martin P. Grobusch
Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases,
AMC, University of Amsterdam, Netherlands
Centre de Recherches Médicales (CERMEL), Hôpital Albert Schweitzer, Lambaréné, Gabon
Institute of Tropical Medicine
University of Tübingen, Germany
Institute of Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, South Africa
Tuberculosis: Novel drugs and
treatment strategies
Ma et al. Lancet 2010
Zumla et al. 2014
Zumla et al. 2014
Basic biology:
• Drug target/mechanism: closely related to PA-824
• Inhibition of mycolic acid biosynthesis, killing M. tb. in vitro (mycobacteria-specific)
• Prodrug requiring activation by M. Tb..
• Active against strains resistant against RIF, INH, PZA, STR, ETH
Animal models:
• Orally active in a mouse lung model
• Long-term treatments over 6 mo regimens incl. OPC-67683 were superior to
regimens without, indicating that length of tx could be reduced by 2 mo
• Safety – drug-drug interactions: no CYP enzyme inhibition
• Safety – animal toxicity: ‘no correlation between mutagenicity and antibacterial
properties’
PLoS Medicine 2006
Zumla et al. 2014
TMC207: Phase II, step 1 interim
analysis Diacon et al. NEJM 2009
8.7% culture
negative
47.5% culture
negative
n = 24
n = 23
Adding TMC207 to a 5-drug MDR TB Regime resulted in faster culture
conversion and higher conversion rate at week 8
TMC207 (Bedaquiline) – C208:
Outcome W 24 Diacon A, Pym A, Grobusch MP et al AAC 2012.
AAC 2012
Addition of bedaquiline to a 5-drug MDR-TB Tx regimen results in long-term,
more rapid and higher culture conversion
“Overall, 10 of 79 (13%) in the bedaquiline group and 2
of 81 patients (2%) in the placebo group died (p= 0.02).
In the bedaquiline group, deaths occurred during study
treatment in 1 and after week 24 in 9 patients (median
after last dose 49.1 weeks).
In 6 patients, the deaths were attributed to tuberculosis.
No deaths were considered to be related to the study
drugs...nor was there any associations between deaths
and bedaquiline concentrations or a [prolonged] QTc
interval.”