Novel TMC207-containing regimens have sterilizing activity …regist2.virology-education.com/2011/4TB_PK/docs/09_Nuerm...Presented at the 4th International Workshop on Clinical Pharmacology

Presented at the 4th International Workshop on Clinical Pharmacology of TB Drugs, 16 September 2011, Chicago, IL, USA

Novel TMC207-containing regimens have sterilizing activity in murine

tuberculosis

R. Tasneen1, S. Li1, C. Peloquin2 K. Adries3, Khisi Mdluli4, Eric Nuermberger1 1Center for Tuberculosis Research, Johns Hopkins University, Baltimore, MD 2College of Pharmacy, University of Florida, Gainesville, FL 3Tibotec BVBA, Beerse, Belgium 4Global Alliance for TB Drug Development, New York, NY


Background

• At least 5 novel drugs* in clinical development have shown the potential to shorten TB treatment in animal models and clinical trials

• The real game changer will be a regimen containing 2 or more novel drugs and capable of curing both DS- & DR-TB in under 6 months

* TMC207, PA-824, PNU-100480, OPC-67683, SQ107


TMC207 (bedaquiline)

• Median MIC = 0.06 µg/ml

• New target: ATP synthase

• Selective activity against mycobacteria

• No cross-resistance

• Sterilizing activity comparable to RIF in mice1

• Shortens time to sputum conversion in MDR-TB

Science 2005; 307:214,

NEJM 2009; 360:2397 1 AJRCCM 2011; 184:732


Early data on TMC207 (J)-containing combinations

AAC 2007;51:1011

Synergistic JZ

is most potent

2-drug combo

No 3-drug

combo better

than JZ alone

No data for addition of the following drugs to JZ:

- clofazimine

- linezolid

- PA-824


Experimental Objectives

Experiment 1

• Determine which 3rd drug(s) improve the bactericidal and sterilizing activity of JZ

Experiment 2

• Compare the sterilizing activity of regimens based on Z plus 2 of the following: P, J, Pa & M

• Compare the sterilizing activity of Z-sparing regimens based on adding JP, PaP or JPa to M


Scheme of Experiment 1

D-13 D0 M1 M2 (+3) M3 (+3) M4 (+3) M5 (+3)

Untreated 6* 6* 3

2HZR/3HR 5 5 5 5 (15) (15)

4JZ 5 5 (15) (15)

3JZP 5 (15) (15)

4JZM 5 (15) (15)

4JZC 5 5 (15) (15) (15)

4JZR 5 (15) (15)

4JZL 5 (15) (15)

4JZPa 5 5 (15) (15)


Lung CFU counts after 1 month

Abbreviations:

R, rifampin

H, isoniazid

Z, pyrazinamide

J, TMC207

Pa, PA-824

M, moxifloxacin

L, linezolid

P, rifapentine

C, clofazimine

Month 2 results: JZ, JZC and JZMC groups were culture-negative;

JZPa (0.70 ± 0.24), RHZ (3.14 ± 0.28)

* p < 0.05 vs. JZ

** p < 0.01 vs. JZ

* * **


Serum PK of J and its M2 metabolite after a single dose of J given alone or with Pa

Treatment group

Proportion (%) with positive M.tb cultures 3 mo after completing treatment for:

2 mo 3 mo 4 mo 5 mo 6 mo

2HZR/3HR ND ND 50% (7/14) 14% (2/14) 0% (0/14)

4JZ ND 0% (0/15) 0% (0/15) ND ND

3JZP 0% (0/15) 0% (0/14) 0% (0/15) ND ND

4JZM ND 6.7%(1/15) 0% (0/15) ND ND

4JZC 0% (0/15) 7% (1/14) 0% (0/15) ND ND

4JZR ND 0% (0/15) 0% (0/15) ND ND

4JZL ND 0% (0/15) 0% (0/15) ND ND

4JZPa ND 6.7% (1/15) 0% 0/13) ND ND

Relapse results of Experiment 1

Isolates from mice in JZx groups relapsing after 3 mos. remained susceptible to J

AAC 2011; accepted



Conclusions for Experiment 1

• JZ exhibited strong bactericidal activity and cured 15 of 15 mice in 3 months, with no selection of resistance

• By CFU cts: M, L, R and P all modestly increased JZ activity; C had a greater additive effect

• Pa had an antagonistic effect when added to JZ, but JZPa was still more effective than RZH and cured 14 of 15 mice in 3 months

• We are unable to confirm whether any drug actually adds sterilizing activity to JZ


Scheme of Experiment 7 D-13 D0 M1 M2 (+3) M4 (+3)

Untreated 6 6 4

2RHZ/3RH 4 4 4 (15)

2PMZ 4 (15) 4 (15)

4PaMZ 4 4 (15) (15)

4JMZ 4 4 (15) (15)

2PaPZ 4 (15) 4 (15)

2JPZ 4 (15) 4 (15)

4PaPM 4 4 (15) (15)

4JPM 4 4 (15) (15)

4JPaM 4 4 (15) (15)


Lung CFU counts at 1 and 2 months

AAC 2011; accepted


Relapse results from Experiment 2

After M1 After M2 After M4

Untreated

2RHZ/3RH 15/15 (100%)*

2JPZ 15/15 (100%) 0/15 (0%)

4JMZ 15/15 (100%) 5/15 (33%) 0/15 (0%)

2PMZ 15/15 (100%) 15/15 (100%)

4PaMZ 15/15 (100%) 10/15 (67%)

2PaPZ 15/15 (100%) 15/15 (100%)

4PaPM 15/15 (100%) 13/15 (87%)

4JPM 15/15 (100%) 7/14 (50%)

4JPaM 15/15 (100%) 7/14 (50%)

*RHZ still had 1.65 +/- 0.23 log CFU in lungs at M4 time point AAC 2011; accepted

p < 0.05

vs. RHZ


Conclusions • Some JZ-containing combinations (eg, JZP, JZM) are

capable of curing mice ≥ 3 months faster than RZH

• Pa has an antagonistic effect when added to JZ, but JZPa was still more effective than RZH

• Z is essential to dramatically shorten treatment with these drugs, but JPaM was still superior to RZH

• JPaMZ may be a very short MDR-TB regimen if Z is active and a short (


Acknowledgments

• Funding: Global Alliance for TB Drug Development

• Drug: Tibotec (TMC), sanofi-aventis (RPT), Global Alliance for TB Drug Development (PA-824, MXF)

• Scientific input: Jacques Grosset

Documents

Novel TMC207-containing regimens have sterilizing activity …regist2.virology-education.com/2011/4TB_PK/docs/09_Nuerm...Presented at the 4th International Workshop on Clinical Pharmacology