Treatment of tuberculosis New drugs ... - Stop TBC...Sep 23, 2014  · Diacon et al. NEJM 2009 8.7% culture negative 47.5% culture negative n = 24 n = 23 Adding TMC207 to a 5-drug

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.”