医薬品医療機器総合機構 · 2018. 4. 5. · OAT organic anion transporter>& w µ ½ å º...

2.5

1

2.5.1 ........................................................................................................................ 5

2.5.1.1 ........................................................................ 5

2.5.1.2 ............................................................................................................ 5

2.5.1.3 .................................................................................................................... 8

2.5.2 .............................................................................................. 12

2.5.2.1 .......................................................................................................................... 12

2.5.2.2 .................................................................................. 12

2.5.2.3 ...................................................................................................................... 12

2.5.2.4 ...................................................................................................................... 13

2.5.2.5 .............................................................................................. 13

2.5.3 .................................................................................................. 14

2.5.3.1 .......................................................................................................................... 14

2.5.3.2 .......................................................................................................... 15

2.5.3.3 .......................................................................................................... 17

2.5.3.4 .......................................................................................... 20

2.5.3.5 .......................................................................................... 20

2.5.3.6 .............................................................................................................. 21

2.5.4 .................................................................................................................. 24

2.5.4.1 .................................................................................................................. 24

2.5.4.2 .......................................................................................... 28

2.5.4.3 .................................................................................................................. 36

2.5.4.4 .......................................................................................... 50

2.5.4.5 ...................................................................................................... 52

2.5.4.6 .............................................................................................................. 53

2.5.5 .................................................................................................................. 56

2.5.5.1 .......................................................................... 56

2.5.5.2 .................................................................. 59

2.5.5.3 .......................................................................................................................... 59

2.5.5.4 ...................................................................................... 64

2.5.5.5 .................................................................. 67

2.5.5.6 .......................................................... 74

2.5.5.7 ...................................................................... 75

2.5.5.8 ...................................................................................................... 77

2.5.5.9 ...................................................................... 77

2.5.5.10 Adverse Drug Reaction ADR .................................................................................... 81

2.5.5.11 .......................................................................................................... 82

2.5.5.12 .............................................................................................................. 82

2.5

2

2.5.6 .................................................................................. 86

2.5.6.1 ...................................................................................................... 86

2.5.6.2 .................................................................................................................. 87

2.5.6.3 .................................................................................. 88

2.5.7 .................................................................................................................................. 91

2.5

3

(1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol

(1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol

1 1

ADR adverse drug reaction AFB acid fast bacillus ALT alanine aminotransferase ARV antiretroviral AST aspartate aminotransferase ATP adenosine 5’-triphosphate 5’- AUC area under the plasma concentration-time curve -AUClast area under the plasma concentration-time curve from the time of dose

administration to the time of last quantifiable concentration 0-

AUCxh area under the plasma concentration-time curve from the time of dose administration up to x h postdose 0 x -

BCRP breast cancer resistance protein BR background regimen C0h predose plasma concentration CFU colony forming unit CI confidence interval CLCR creatinine clearance Cmax maximum plasma concentration CPK creatine phosphokinase CPK-MB creatine phosphokinase muscle-brain isoenzyme -

CYP cytochrome P450 P450 DMID Division of Microbiology and Infectious Diseases DOTS directly observed therapy short course DST drug susceptibility testing DS-TB drug-susceptible tuberculosis FAS full analysis set FDA Food and Drug Administration GGT gamma glutamyl transferase - HIV human immunodeficiency virus

2.5

4

ITT intent-to-treat IUATLD, Inc The International Union Against Tuberculosis and Lung Disease JRD Janssen Research & Development LDH lactate dehydrogenase M2 N-monodesmethyl-bedaquiline N- MATE multidrug and toxin extrusion protein MDRH&R-TB multidrug resistant tuberculosis, resistant to isoniazid and rifampicin, excluding

pre-XDR and XDR pre-XDRXDR-TB

MDR-TB multidrug resistant-tuberculosis MedDRA Medical Dictionary for Regulatory Activities ICH MGIT mycobacterium growth indicator tube MIC minimal inhibitory concentration MIC50 minimal inhibitory concentration to inhibit the growth of 50% of isolates

50% MIC90 minimal inhibitory concentration to inhibit the growth of 90% of isolates

90% mITT modified intent-to-treat M. tuberculosis Mycobacterium tuberculosis OAT organic anion transporter OATP organic anion transporting polypeptide OCT organic cation transporter PMDA pre-XDR-TB pre-extensively drug resistant tuberculosis pre- PT preferred term q.d. once daily 1 1 QTc QT interval corrected QT QTcB QT interval corrected for heart rate using Bazett's formula Bazett QT QTcF QT interval corrected for heart rate using Fridericia’s formula Fridericia

QT SMQ Standardized MedDRA Query MedDRA SOC system organ class STREAM The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for

Patients with MDR-TB TB tuberculosis t.i.w 3 times per week 3 tmax time to reach the maximum plasma concentration TMC207 bedaquiline t1/2,term terminal elimination half-life TSP Tuberculosis Symptoms Profile WHO World Health Organization XDR-TB extensively drug resistant tuberculosis

2.5

5

2.5.1

2.5.1.1

2.5.1.1.1

TMC207 Tibotec

Janssen Research & Development JRD

TMC207 Mycobacterium tuberculosis M. tuberculosis 5'-

ATP ATP

TMC207

2.5.1.1.2

2.5.1.2

2.5.1.2.1

20 2015

1,040 1 2015 1 1

2015 12 31 2015 44,888

10 14.4 2015 18,280

2

7,131 2

MDR-TB

2

1

1 pre- pre-XDR-TB

1 1

XDR-TB

MDR-TB XDR-TB1 WHO 2015 MDR-TB 1

1 WHO MDR-TB RR-TB rifampicin-resistant TB

2.5

6

58 1 230 3 MDR-TB

DST MDR-TB 2015 48 2 MDR-

TB XDR-TB 4 5 6 7 XDR-TB

MDR-TB 2 DS-TB 6 8 MDR-

TB XDR-TB

HIV HIV9 2015

180 HIV 40 1

2.5.1.2.2

WHO 10 International Standards for

Tuberculosis Care 11

12

13 13

MDR-TB

2.5.1-1

6

MDR-TB MDR-TB

DS-TB 6 9 MDR-TB

18

MDR-TB

5

MDR-TB

4

6 18 13

2.5

7

2.5.1-1 *

RMP PZA INH

RMP RFPINH PZA

SM EB

SM EMB EB

LVX LVFX

KAN KM

EVM

ETH TH PAS CS

DLM * 13

WHO 2013 MDR-TB 52% 1

DS-TB 97% MDR-TB

50 75% 14 15 16 10 55%

95% CI 52 58% 4

MDR-TB

MDR-TB

XDR-TB 18

2.5.1.2.3 TMC207

MDR-TB

WHO TMC207 2013 6 MDR-TB

TMC207 17

TMC207 WHO

MDR-TB

MDR-TB

TMC207 2014 7 MDR-

TB

TMC207 MDR-TB

MDR-TB18 19 TMC207

National Institute of Allergy and Infectious

Diseases MDR-TB TMC207

2016 8

2.5

8

2.5.1.3

2.5.1.3.1

SIRTURO® 2005 1 2005 8

MDR-TB TMC207 I 11 IIa

1 TMC207-C202 C202 IIb 2 TMC207-TiDP13-

C208 C208 TMC207-TiDP13-C209 C209

C202 DS-TB 3 25 mg 100 mg 400 mg TMC207 7

C208 MDR-TB

Stage 1 Stage 2

Stage 1 TMC207 8

Stage 2 TMC207

24

C209 MDR-TB

TMC207 24

C208 C209 MDR-TB

FDA Fast Track

2012 12

2014 3 TMC207 MDR-TB

1 40

JRD 0 18

MDR-TB TMC207 Background Regimen BR

II

4 1 12 18

2 5 12 3 2 5 4 0 2

1 2 3 4

The International Union Against Tuberculosis and

Lung Disease IUATLD, Inc

MDR-TB III STREAM

The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients with MDR-TB

Stage 2 TMC207

2.5.1.3.2

TMC207 2015 9

PMDA

2.5

9

MDR-TB II TMC207TBC2001 TBC2001

2.5.1.3.3.1

TBC2001 MDR-TB 1 TMC207

24

5

PMDA 2.5.1.3.3.2

TBC2001 4 24

IIb

TBC2001 6 Week 24

5.3.5.2.4 TMC207TBC2001

2.5.1-2

2.5

10

2.5.1-2 I

(CDE-101)

(CDE-102)

(BAC1003, C104, C109, C110, C117)

Thorough QT (TBC1003)

(C108, C111)

(C112)

IIa

MDR-TB BR (TBC2001)

DS-TB

(C202)

IIb

MDR-TB

BR (C208)

MDR-TB XDR-TB BR (C209)

*BR Background Regimen

2.5.1.3.3

TMC207

2.5.1.3.3.1

PMDA

MDR-TB TMC207

II TBC2001

TMC207 24

PMDA TBC2001 TMC207

48

2.5.1.3.3.2

2.5

11

1 World Health Organization. Global tuberculosis report 2016.

2 . 27

3 World Health Organization. Tuberculosis country profiles - Japan Tuberculosis profile. 2015.

Available from:

https://extranet.who.int/sree/Reports?op=Replet&name=/WHO_HQ_Reports/G2/PROD/EXT/TBC

ountryProfile&ISO2=JP&outtype=html

4 , et al. . . 2012;87(9):565-75.

5 Tuberculosis Research Committee (Ryoken). Drug-resistant Mycobacterium tuberculosis in Japan:

a nationwide survey, 2002. Int J Tuberc Lung Dis. 2007;11(10):1129-35.

6 World Health Organization. Multidrug and extensively drug-resistant TB (M/XDR-TB):2010

global report on surveillance and response. 2010.

7 , et al. 2006 . .

2008;83(12):773-7.

8 Shah NS, et al. Extensively drug-resistant tuberculosis in the United States, 1993-2007. JAMA.

2008;300(18):2153-60.

9 Centers for Disease Control and Prevention. Fact sheets: HIV and Tuberculosis. 2015.

10 World Health Organization. Guidelines for the Programmatic Management of Drug-Resistant

Tuberculosis: 2011 Update. Geneva: World Health Organization; 2011.

11 Tuberculosis Coalition for Technical Assistance. International standards for tuberculosis care. 2nd

edition; 2009.

12 . , 0129

1 , 28 1 29 .

13 . . 3 . : ; 2015.

14 . . . . 2010;47:174-9.

15 . . . . 1998;73(11):665-72.

16 , et al. . . 2005;80(11):687-93.

17 World Health Organization. The Use of Bedaquiline in the Treatment of Multidrug-Resistant

Tuberculosis: Interim Policy Guidance. Geneva: World Health Organization; 2013.

18 , et al. . . 2014;89(11):813-5

19 . . . 2014; 89(7):679-82.

2.5

12

2.5.2

2.5.2.1

TMC207

4

TMC207 TMC207 10 mg/mL 40 mg/mL

TMC207 TMC207 100 mg TMC207

100 mg TMC207

TMC207 100 mg TMC207

N- M2

Cmax AUClast C108

C111

TMC207 TMC207 100 mg

TMC207 120.89 mg C208 C209

II TBC2001

20

2.5.2.2

I II TMC207

C108

C111 C111

2.5.2.3

TMC207

2.7.1-4 2.7.1-5 2.7.1-10

Cmax AUC 2 C108 C111

TMC207

2.5

13

2.5.2.4

MDR-TB

Cmax AUC CV%

MDR-TB

20% 30% MDR-TB

2.5.2.5

TMC207

Cmax

AUC

2

TMC207

MDR-TB

Cmax AUC 30%

2.5

14

2.5.3

2.5.3.1

2.5.3.1.1

TMC207 2

2.5.2.3

M2 89.63 99.99% 99.8%

M2

2.6.4.9.2

In vitro P450 CYP 3A4

M2 CYP M2

4~6 M2 CYP3A4 N- M3

TMC207 0.001%

MDR-TB TMC207

75% 85%

M2 3.7% 7.2%

2.5.3.1.2 TMC207 M2

TMC207 10 700 mg 50 400 mg 1

1 q.d. 14 M2

2.7.2.3.1.4 TMC207 tmax

5 TMC207 q.d. 2

AUC24h 1.90 2.44

M2 t1/2,term

2.5.3.1.3 MDR-TB TMC207 M2

IIb C208 Stage 1 Stage 2 C209 II TBC2001

MDR-TB TMC207 BR

2.7.2.2.2.2.(2) 2.7.2.2.2.2.(3) 2.7.2.2.2.3.(1)

TMC207 400 mg q.d. 2

M2 C0h Cmax Css,avg Week 3 C208 Stage 1

Week 8 C208 Stage 2 C209 TBC2001 Week 24 200 mg 3

t.i.w. Weeks 3 1

C208 Stage 1 TMC207 2

t1/2,term 5.5 M2 t1/2,term 5.3

2.5

15

M2 t1/2,term M2

M2

CAD

M21

CAD CAD

t1/2,term

C208 Stage 2 Week 2 M2

Week 8 16 24

2.5.3.1.4 MDR-TB M2

TMC207 M2

M2 MDR-TB

MDR-TB

DS-TB

2.7.2.3.1.5

2.5.3.2

2.5.3.1.4 HIV

2.7.2.3.1.7

2.5.3.2.1

2.5.3.2.2

Vc/F

Vc/F

164 L 138 L 20%

2.5.3.2.3

AUC168h

34% C209

Week 24

C208 Stage 2

2.5

16

TBC2001 MDR-TB

MDR-TB C208 Stage 1 Stage 2 C209

C208 Stage 1 Stage 2

C209

TBC2001

2.5.3.2.4

C208 Stage 2 C209

2.5.3.2.5 HIV

HIV

II HIV

C208 Stage 2 76 8 C209 203

10 C208 Stage 2 C209 HIV

HIV

HIV

2.5.3.2.6

C112 TMC207

M2 AUClast 19%

M2 AUClast

TMC207

TMC207

2.5.3.2.7

CDE-102 TMC207

0.001%

2.7.2.2.2.1(2)

CLCR CL/F

CLCR 108 mL/min

2.5

17

39.8~227 mL/min

2.7.2.3.1.7(8)

2.5.3.3

M2

I

TMC207 2.5.2.3

2.5.3.3.1

CYP3A4 CYP3A4

2.5.3.3.1

CYP M2 in vitro

CYP3A CYP3A

TMC207

I 5

4 HIV-1 1

MDR-TB IIb C208 Stage 1

TMC207

2.5.3.3.1.1 In vitro

CYP3A4 M2

CYP CYP1A2 CYP2A6 CYP2C8/9/10 CYP2C19 CYP2D6 CYP2E1

CYP3A4 CYP3A4/5 CYP4A CYP1A2 CYP2C9 CYP2C19

CYP3A4 CYP mechanism-based inhibition

M2 CYP2B6 CYP2D6 CYP2C19 CYP3A4 CYP3A4/5

In vitro M2 BCRP MRP2 P-gp

OATP1B1 OATP1B3

M2

M2 OCT1

OCT1 in vivo

2.5

18

In vitro

M2

OAT1 OAT3 OCT2

MATE2-K BCRP OATP1B1

OATP1B3 OCT1 MATE1 M2

MATE2-K BCRP OATP1B1 OATP1B3 OCT1 OAT1 OAT3 OCT2

MATE1

M2 2.7.2.3.1.3.(2)

OAT1 OAT3 OCT2 MATE2-K

in vivo BCRP

MDR-TB

Cmax 8 BCRP

2.5.3.3.1.2

(1) BAC1003

RMP CYP450 CYP3A4

TMC207 RMP 600 mg 1 1

AUC336h 52% 90%CI -57 -46%

TMC207 RMP

CYP3A4 TMC207

(2) C104

TMC207 / 300/2000 mg 1 1

AUC

TMC207

(3) C208 Stage 1 Background Regimen

C208 stage 1 MDR-TB BR

terizidone

TMC207 BR

TMC207

TMC207

2.5

19

2.5.3.3.1.3

(1) C109

CYP3A

TMC207 400 mg 1 1

4 AUC24h 22%

11%

2 TMC207 CYP3A4 14

(2) C110

HIV PI

ARV CYP3A4

CYP3A4 CYP2C9 CYP2C19

TMC207 400/100 mg 1 2

AUClast TMC207

22% 90%CI 11 34% Cmax

TMC207 C0h

21% 90%CI -28 -13%

14% 90%CI -22 -6% TMC207

HIV MDR-TB

TMC207 STREAM

2.5.1.3.1

(3) C117

NNRTI HIV ARV 1

HIV-1 200 mg 1 2

TMC207

TMC207

TMC207

(4) QT

TMC207 ECG QT

QT QT

TMC207 TMC207 QT

ECG

C209

QTcF

2.5

20

2.5.5.5.3.2(4) TMC207

ECG

QT

TMC207

2.5.3.4

IIb

C208 Stage 2 MDR-TB TMC207 400 mg q.d. 2

TMC207 200 mg t.i.w. 22

AUC24h AUC24h AUC24h/

MIC 4

C209 MDR-TB TMC207 400 mg q.d. 2

TMC207 200 mg t.i.w. 22 Cavg

Cavg Cavg/MIC 4

2.5.3.5

C208 Stage 1

QTcF

ECG

C208 Stage 2 1 Grade 4

QT SMQ QTcF

AUC24h

Week 2 400 mg q.d.

Week 3 200 mg t.i.w. M2 QTcF

C209 1 Grade 4

QT SMQ QTcF

Cavg

Week 2 Week 12 Week 24 M2

QTcF

2.5

21

TBC2001 MDR-TB

QTcF

C208 Stage 2 C209

C208 Stage 2 C209

Hy's law3 , 4 Temple's Corollary5 ALT AST

3 ALT AST

ALT AST

2.5.3.6

MDR-TB TMC207

400 mg q.d. 2 200 mg t.i.w. 22

CYP3A4 M2 M2

23% 31% 1/6 1/4

TMC207 10 700 mg 50 400 mg q.d.

14 TMC207

tmax 5

M2 t1/2,term

HIV

TMC207

TBC2001

MDR-TB IIb

C208 Stage 1 Stage2 C209 MDR-TB

C208

C209

IIb C208 C209

TMC207

TMC207 TMC207

TMC207

TMC207

2.5

22

QT TMC207 QT TMC207

TMC207 QT

QT

TMC207

CYP3A4 CYP3A4

CYP3A4

TMC207

- 15 CYP3A4 14

- rifapentine

CYP3A4 CYP3A4

TMC207 TMC207

2.5

23

1 Hanumegowda UM, et al. Phospholipidosis as a function of basicity, lipophilicity, and volume of

distribution of compounds. Chem Res Toxicol. 2010; 23(4): 749-755.

2 Lehr T, et al. Semi-mechanistic population pharmacokinetic drug-drug interaction modelling of a

long half-life substrate and itraconazole. Clin Pharmacokinet. 2010; 49(1): 53-66.

3 Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006; 15:

241-243.

4 FDA Guidance for Industry: Drug-induced liver injury: Premarketing Clinical Evaluation. July

2009.

5 Senior JR. Evolution of the food and drug administration approach to liver safety assessment for

new drugs: Current status and challenges. Drug Saf. 2014; 37(Suppl 1):S9–S17.

2.5

24

2.5.4 TMC207 MDR-TB IIb 2 C208

C209 II 1 TBC2001 IIa 1

C202

C208 MDR-TB Stage 1

Stage 2 Stage 1 TMC207 8

Stage 2 TMC207 24

C209 MDR-TB

TMC207 24 TBC2001 MDR-TB

TMC207 24

TMC207 BR

MGIT

C202 DS-TB 3 25 mg 100 mg 400 mg TMC207

7 CFU

C208 C209 TBC2001

C202 2.5.4.3.3

2.5.4.1

C208 C209 TBC2001

MDR-TB C208

pre-XDR-TB C209

MDR-TB

XDR-TB BR 3

TBC2001 MDR-TB

pre-XDR XDR-TB

BR 4

2.5.4.1.1

C208 TMC207

1 1

C208 Stage 1 TMC207 23 24

intent-to-treat ITT ITT 47 23 48.9% TMC207

10 13 Week 104

17.0% 14.9%

C208 Stage 2 TMC207 80 81

160 TMC207 79 81 ITT

2.5

25

ITT 160 60 37.5% TMC207 29 31 Week 120

9.4

8.1% 6.3%

160 99 61.9% TMC207 50 49

1 Rollover Rollover 2.7.6.12.2.1.(1)10)

Rollover

2.7.6.12.2.3

C209 233 TMC207 233 ITT ITT

54 23.2%

7.3% 5.2% 4.7% C208

Stage 2

IIb 2.7.3.3.1.1(1)

IIb 1

ITT ITT

C208 Stage 1 Stage 2 C209 DST

XDR-TB C208 Stage 1 Stage 2 DS-TB MGIT

modified intent-to-treat

mITT 2.5.4 IIb

mITT

IIb ITT mITT

2.7.3.3.1.1(2)

TBC2001 6 TMC207

2 4

FAS

6 Week 24

Week 24 2.5.4.2.1.4

5 2 TMC207

2.5.4.1.2

IIb TBC2001 TMC207

2.7.2.5 1

IIb ITT C208

Stage 1 9.0 C208 Stage 2 C209

25.0 C208 Stage 1 Stage 2

C208 Stage 1 ITT

63.0 TMC207 85.1

C208 Stage 2 ITT

2.5

26

TMC207 91.7 94.1 C209

95.6 C208 Stage 2

TBC2001

40.0 25.0 50.0 38.0 24.0

48.0 48.5 33.0 81.0

24 6 5

2 TMC207

2.5.4.1.3

IIb mITT ITT

C208 Stage 2 HIV

Grade 1 3 TMC207


IIb ITT C208

Stage 1 74.5% C208 Stage 2 63.1% C209 64.4% C208

Stage 1 55.3% Stage 2 35.0% Stage 1 42.6%

Stage 2 25.6% C209 38.2%

32.2% C208 Stage 1 Stage 2

C209 3

IIb C208 Stage 1 85.1% C208 Stage 2 80.0% C209

63.5% 2cm

Grade 1 3 C208 Stage 2 48.1%

C209 18.5%

C208 Stage 2 TMC207 34.0 g/L 15 49 g/L 31.0 g/L 19 41 g/L

C209 38.0 g/L 17 49 g/L C209

C208 Stage 2

C208 Stage 2

C209

C208 Stage 2 C209

HIV C209

4.0% C208 Stage 1 12.8% Stage 2 15.0% C208 Stage 2

TMC207 10.1 % 19.8% HIV

IIb HIV CD4

250×106 cells/L ARV

DST MDRH&R-TB pre-XDR XDR-TB

2.5

27

pre-XDR-TB C208 Stage 1 5 1 C208 Stage 2

3 1 C209 MDRH&R-TB pre-XDR-TB XDR-TB

2 1 1 XDR-TB C208 Stage 5% XDR-TB

C209 16.3% C209

87.1%

TBC2001 6 3

Pre-XDR-TB XDR-TB 2 cm

2 33.3% Grade 1 1 16.7%

2.5.4.1.4

IIb TBC2001 TMC207 MIC 7H11

7H9

2.5.4.1.4.1 TMC207

IIb TMC207 MIC 7H11

C208 Stage 1 78.0% C208 Stage 2 86.1% C209 76.6%

0.06 g/mL MIC50 50% MIC

0.06 μg/mL MIC90 90% MIC 0.12 μg/mL

C208 Stage 1 Stage 2 TMC207 MIC

2.7.3.3.1.4(2)

TBC2001 TMC207 MIC 7H11 99%

2 3 99%

MIC 0.008 0.015 0.06 g/mL

2.7.3.6- -1

2.5.4.1.4.2 BR

C208 Stage 1 Stage 2 BR DST

87% BR

C209 XDR-TB pre-XDR-TB XDR-TB 18.0%

pre-XDR-TB 21.5% BR

61.1% 85.0%

2.7.3.3.1.4(1) TBC2001 7H11

BR DST 3 3

2 1

7H9 4

2.5

28

2 3 DST

3 1 2 20701003

20702001 MDR-TB

7H9 DST pre-XDR-TB

2.7.3.6- -2

2.5.4.1.5 Background Regimen BR

C208 Stage 2 ITT BR

62.5% TMC207 BR

C208 Stage 2 TMC207 59.5% 54.3%

BR BR 1

21.3% 2 10.0% 3 8.1%

C209 ITT BR

89.3% 52.4% 76.0%

71.7% 49.8% 51.5%

+

C208 Stage 2 7.5% 0% 0.6% C209

46.4% 12.9% 9.9%

20/30

IIb mITT BR ITT

TBC2001 6

BR 4 66.7%

2 33.3% 1

16.7% 2.7.3.6- -4

2.5.4.2

2.5.4.2.1

2.5.4.2.1.1 C208 Stage1

C208 Stage 1

Stage 1 TMC207 BR 8

TMC207

BR N-

M2 TMC207 BR

2.5

29

Stage 1 BR

BR

TMC207 400 mg q.d. 2 TMC207

200 mg t.i.w. 6

BR

18 24 12

Week 8

2.7.3.1.3.1(1)

2.5.4.2.1.2 C208 Stage2

C208 Stage 2

Stage 2 TMC207 BR 24

TMC207

BR M2

Stage 2 BR

BR TMC207 400 mg

q.d. 2 TMC207 200 mg t.i.w. 22

Stage 1 BR

Stage 2

XDR-TB Rollover

2.7.6.12.2.1 24 TMC207 Rollover

TMC207 BR 24 Rollover

XDR-TB DST

24 Rollover TMC207

24 TMC207 Rollover BR Rollover

TMC207 96

Week 24 Week 72

2.7.3.1.3.1(2)

2.5.4.2.1.3 C209

C209 TMC207 BR 24

TMC207 BR

M2

Tuberculosis Symptoms Profile TSP

TMC207 TSP

2.5

30

BR

BR TMC207 400 mg

q.d. 2 200 mg t.i.w. 22 BR

18 24 12

Week 24

2.7.3.1.3.1(3)

2.5.4.2.1.4 TBC2001

TBC2001 MDR-TB

TMC207 BR

BR

TMC207 400 mg q.d. 2

200 mg t.i.w. 22 Week 24

2 TMC207

200 mg t.i.w 24

BR

1 2

BR

Week 20 24

BR BR 78 102 BR

24

4 Week 24

1 6

Week 24

2017 9 TBC2001

2

2.5.4.2.2

IIb C208 C209 TBC2001

TBC2001 MGIT

IIb M. tuberculosis

CFU C209 MGIT

TBC2001 MGIT

2.5

31

TMC207

MIC AFB

C208 Stage 1 International expert consensus group 1

C208 Stage 1 X X

C208 Stage 2 TSP C209

TBC2001

2.5.4.2.2.1 MGIT

IIb TBC2001

MGIT

2

(1)

25 C208 Stage 1

2 2

2 2

1

25

TBC2001 MGIT

MGIT MGIT

(2)

2

IIb 3

TBC2001 missing=failure

· missing=failure

· end-censored missing=failure 3 missing=failure

2.5

32

C208 Stage 1 Week 8 Stage 2

C209 Week 24

· no overruling

C208

Stage 2 C209

IIb Kaplan-Meier

50%

Cox TMC207

95%CI

C208 Stage 1 Week 8

C208 Stage 1

8 2

2

(3)

IIb

missing=failure no overruling

missing=failure

· responder

· non-responder

no overruling

· responder

· non-responder

Week 24 C208 Stage 2

Week 36 48 60 72

missing=failure TMC207

no overruling responder

2.5

33

C208 Stage 2

TMC207 responder 95%CI

IIb missing=failure non-responder

·

·

·

·

missing=failure non-responder

TBC2001 Week 24 Week 24

(4)

IIb TBC2001

restriction fragment length polymorphism RFLP mycobacterial interspersed repetitive

units - variable number tandem repeats MIRU-VNTR TBC2001 MIRU-VNTR

2.5.4.2.2.2 AFB

IIb TBC2001 MGIT TBC2001

3 AFB 5

no AFB seen scanty +1 +2 +3

0 0.5 1 2 3 3

AFB MGIT 25

2 AFB AFB 2

2.5

34

AFB

AFB 2 AFB AFB

2

C208 Stage 2 C209 AFB AFB

AFB MGIT TBC2001 AFB

2.5.4.2.2.3 CFU

C208 Stage 1 Stage 2 16 overnight

7H11 1 mL CFU log10 CFU

TBC2001

overnight

CFU C209 CFU

2.5.4.2.2.4

(1) Tuberculosis Symptoms Profile (TSP)

C209 TBC2001 TSP

C209 Week 24 TSP

MDR-TB

TMC207 12

cough fever chills sweating feeling unwell mucus in throat and/or lungs

coughing up blood shortness of breath weight loss chest pain fatigue/weakness decreased

appetite 6 not present=0 not a problem=1 a little bit of

a problem=2 somewhat of a problem=3 quite a bit of a problem=4 a severe problem=5

0 60

(2) X

IIb TBC2001 X

X

C208

Stage 2 X 6

(3)

C208 Stage 2 C209 5%

2.5

35

2.5.4.2.3 DST

IIb TBC2001 TMC207 DST

7H11 7H9 C209 7H9 TBC2001

DST

2

BR

BR

IIb TMC207

TMC207 TMC207 DST

7H11 7H9 IIb 7H9

TBC2001 MIC TMC207 MIC

4 TMC207

TMC207 4

TMC207

MIC IIb 50%

90% MIC50 MIC90

MIC50 MIC90 DST

M. tuberculosis IIb C208 C209

MIC

TMC207 MIC <0.5 g/mL C208 C209

TMC207 MIC >0.48 g/mL C208Stage 1 41 1

5.3.5.4.25 C208 Stage 2 109 0 C209 167 1 C208

Stage 2 C209 TMC207 MIC 0.5 g/mL

TMC207 MIC >0.5 g/mL

7H11

0.5 g/mL

MIC MIC >0.25 g/mL C209

1 C208 Stage 2 C209

TMC207 MIC 0.25 g/mL

MIC >0.25 g/mL 7H9

0.25 g/mL

2.7.2.4.2.10

2.5

36

2.5.4.3

2.5.4.3.1 IIb C208 C209

2.5.4.3.1.1 C208 Stage 1

C208 Stage 1 2.7.3.2.1.1(2)

(1)

C208 Stage 1 8 MGIT

Week 8 MGIT

missing=failure TMC207 51 2.7.3.2-2

Cox

TMC207 p=0.0034

95%CI 11.77 2.26 61.23

Week 24

missing=failure TMC207 70 126

p=0.0022

(2)

Week 8 missing=failure 8.7%

TMC207 47.6% Week 24 TMC207 81.0%

65.2% Week 104 TMC207 52.4% 47.8%

missing=failure

missing=failure non-responder

Week 24

8.7% TMC207

28.6% TMC207 2 9.5% 4 17.4%

CFU 8 log10 CFU

log10 CFU TMC207

2.7.3.6- -2

2.5.4.3.1.2 C208 Stage2

2.7.3.2.1.2(2)

(1)

C208 Stage 2 MGIT

Week 24 missing=failure

125 TMC207 83

2.5

37

2.7.3.2-4 end-censored missing=failure

127 TMC207 84

2.7.3.2-5 Cox

missing=failure p<0.0001 end-censored missing=failure p=0.0003


TMC207 73 125 TMC207

10 TMC207 1 Day 72

Week 72

missing=failure 168 TMC207

86 p=0.0290

(2)


TMC207 78.8% 57.6% no overruling TMC207

missing=failure Week 24

p=0.008


TMC207 62.1% 43.9%

missing=failure

p=0.035 TMC207

TMC207 Week 24 responder responder

TMC207 78.8% 65.8% no overruling

TMC207

AFB TMC207 AFB

TMC207 84 115 MGIT

TMC207 73 125 Cox

AFB

p=0.0383 Week 24 AFB missing=failure

TMC207 78.8% 62.1% MGIT

CFU Week 8 log10 CFU

2.7.3.6- -2 CFU C208 Stage 1

Stage 2 2 Week 24

CFU Week 8 MGIT

X Week 24

TMC207 41.8% 39.2% Week 24

2.5

38

TMC207 52.7% 52.9% Week 24

TMC207 5.5% 7.8%

2.7.3.6- -18 TMC207 Week 24

3 responder 1

Week 24 5% responder

TMC207 52.1% 47.2% non-responder TMC207 0%

37.5% 5% responder

TMC207 41.7% 52.8% non-responder TMC207 100%

50.0% 5%

non-responder 12.5% responder 0% TMC207 non-responder

0% responder 6.3% 2.7.3.6- -20

X

2.5.4.3.1.3 C209

2.7.3.2.1.3(2)

(1)

C209 MGIT


end-censored missing=failure

57 2.7.3.2-10 2.7.3.2-11

(2)



27.8% 7.3%

10.2% 1.5%

3.4%

AFB missing=failure 58 MGIT

57 Week 24 AFB

missin=failure 70.2% MGIT

TSP

cough

feeling unwell mucus in throat and/or lungs chest pain fatigue/weakness Week 24

TSP responder non-responder

responder cough TSP

responder non-responder

2.5

39

X Week 24

36.8% 61.5%

1.7% 2.7.3.6- -18

Week 24 3 responder 2

Week 24 5% responder

53.8% non-responder 54.2% 5%

responder 38.6% non-responder 29.2%

5% non-responder 16.7% responder 7.6%

2.7.3.6- -20

TSP cough

2.5.4.3.2 II TBC2001

2.7.3.2.2.2

FAS 4 MGIT

14 15 MGIT 2.7.3.2-9 2.7.3.2-10 FAS 4

MGIT Week 2

2.7.3.6- -6 2.7.3.6- -7

AFB 4 AFB AFB

14 113 2.7.3.6- -8

CFU Day -1 4 1

3 CFU 1 199 TMC207

2.7.3.6- -9

TMC207 MGIT 16.1

37.8 TMC207

2.7.3.6- -10

6 TSP Day -1

0 2.7.3.6-

-11

X 2 cm

2 2 cm 4

2.7.3.6- -12

2.5.4.3.3 IIa C202

2.7.3.2.3.1

2.5

40

C202 TMC207 7 DS-TB

DS-TB 3

25 mg 100 mg 400 mg TMC207 7

600 mg q.d. 300 mg q.d. 7

3 TMC207

7

TMC207

3

DS-TB 120 75

TMC207 25 mg 15 100 mg 16 400 mg 14

15 15 8 TMC207

25 mg 1 100 mg 2 1 4

7

ITT

60%

34.0 18 61 57%

TMC207 25 mg 100 mg 7

log10 CFU TMC207

400 mg log10 CFU Day 3 5 6 7

Day 1

Day 7 log10 CFU

TMC207 25 mg -0.04 p>0.05 TMC207 100 mg -0.26 p>0.05 TMC207 400 mg

-0.77 p<0.05 -1.70 p<0.05 -1.88 p<0.05

Day 1 TMC207 400 mg

C202 1 log10 CFU

5.3.5.2.1 TMC207-C202 Sec4.3.2

2.5.4.3.4

TMC207 24 Week 24

IIb C208 Stage 1 C208 Stage 2 C209 TBC2001

- C208 C209 TBC2001

- BR C208 Stage 2 C209 TBC2001

24 C208 Stage 1 8 BR 16

2.5

41

C208 Stage 1 Week 24

BR

- BR C208

C209

NTP TBC2001

-2014 4 25

- C209 TBC2001 XDR-TB C208

XDR-TB

- C208 Stage 1 C208 Stage 2 C209

TBC2001

- C208

C209 TBC2001

- IIb TMC207 C208

Stage 1 21 C208 Stage 2 66 C209 205 mITT

TBC2001 4 FAS

2017 9 TBC2001 6 Week 24

Week 24 IIb

2.5.4.3.4.4


MDR-TB C209

MDR-TB

C208 Stage 1 Stage 2 C209

2.5.4.1

2.5.4.3.4.1

C208 Stage 1 Stage 2 C209 mITT MGIT

2.5.4.3-1 TBC2001

MGIT MGIT

TMC207 24 C208 Stage 2 C209

missing=failure C208 Stage 2 TMC207 C209

73 57 TMC207 8 C208 Stage 1 TMC207 70

C208 Stage 1 Stage 2 C209

C208 C209 94% TMC207

MDR-TB

2.5

42

C208 Stage 1 Stage 2 TMC207

TMC207

8 Cox

missing=failure C208 Stage 1 p=0.0022 Stage 2 p<0.0001

end-censored missing=failure

Cox

C208 Stage 1

p=0.0307 Stage 2 p=0.0003

C209 57 missing=failure end-

censored missing=failure

TBC2001 MGIT FAS4

14 15 2 2.7.3.2-9

2.5.4.3-1 MGIT

C208 Stage 1 Stage 2 C209 mITT

Analysis Method C208 Stage 1 C208 Stage 2 C209

TMC207/BR N = 21

Placebo/BRN = 23

TMC207/BR N = 66

Placebo/BR N = 66

TMC207/BR N = 205

Primary missing = failure analysis 70 days 126 days 73 days 125 days 57 days End-censored missing = failure 78 days 129 days 84 days 127 days 57 days No overruling for discontinuation NA NA 72 days 99 days 57 days N = number of subjects; NA = not analyzed

2.5.4.3.4.2

C208 Stage 1 Stage 2 C209 2.5.4.3-2

Week 24 missing=failure C208

Stage 1 65.2% Stage 2 57.6% TMC207 Stage 1 81.0% Stage 2 78.8%

C209 Week 24 79.5% C208 TMC207

no overruling

TBC2001 MGIT FAS

2.5.4.3-2 Week 24

C208 Stage 1 Stage 2 C209 mITT

Microbiological Status at Week 24, n (%)

C208 Stage 1 C208 Stage 2 C209 TMC207/BR

N = 21 Placebo/BR

N = 23 TMC207/BR

N = 66 Placebo/BR

N = 66 TMC207/BR

N = 205 24-week responder

(missing = failure) 17 (81.0) 15 (65.2) 52 (78.8) 38 (57.6) 163 (79.5)

24-week responder (no overruling) 19 (90.5) 16 (69.6) 53 (80.3) 43 (65.2) 167 (81.5) N = number of evaluable subjects; n = number of subjects with that result.

2.5

43

2.5.4.3.4.3

TBC2001

IIb C208 Stage 2 C209

DST BR

BMI HIV

C208 Stage 2 C209 mITT MGIT

Week 24 missing=failure 2.5.4.3-3

2.5

44

2.5.4.3-3 MGIT Week 24

C208 Stage 2 C209 missing=failure mITT

Parameter

C208 Stage 2 C209 TMC207/BR Placebo/BR TMC207/BR

N

24-week responder (missing = failure)

n (%) N

24-week responder (missing = failure)

n (%) N

24-week responder (missing =failure)

n (%) Lung Cavitation

No cavitation 12 12 (100) 10 8 (80.0) 70 62 (88.6) Cavitation in one lung only 42 30 (71.4) 41 21 (51.2) 109 82 (75.2) Cavitation in both lungs 12 10 (83.3) 15 9 (60.0) 26 19 (73.1)

Pooled Center Asia (for C209: other than China)

8 8 (100) 4 4 (100) 31 26 (83.9)

China - NA - NA 50 41 (82.0) Eastern Europe 6 3 (50.0) 7 3 (42.9) 41 34 (82.9) South Africa (- 1) 14 11 (78.6) 17 7 (41.2) - NA South Africa (- 2) 13 9 (69.2) 13 11 (84.6) - NA South Africa (- other) 10 7 (70.0) 12 6 (50.0) 70 51 (72.9) South America 15 14 (93.3) 13 7 (53.8) 13 11 (84.6)

Extent of Resistance of M. tuberculosis Strain at Baseline MDRH&R-TB 39 32 (82.1) 45 28 (62.2) 93 81 (87.1) pre-XDR-TB 15 11 (73.3) 12 4 (33.3) 44 34 (77.3) XDR-TB - NA - NA 36 20 (55.6)

PZA Susceptibility at Baselinea Resistant 38 28 (73.7) 33 16 (48.5) 135 102 (75.6) Susceptible 18 16 (88.9) 25 16 (64.0) 37 32 (86.5)

HIV Status at Baseline Negative 61 48 (78.7) 52 27 (51.9) 188 152 (80.9) Positive 5 4 (80.0) 14 11 (78.6) 10 6 (60.0)

Number of Drugs Active in vitro in Baseline BR (agar proportion method, only validated critical concentrationsa)

0 - - - - 14 9 (64.3) 1 - - 3 2 (66.7) 28 18 (64.3) 2 13 8 (61.5) 8 3 (37.5) 36 27 (75.0) 3 20 17 (85.0) 22 14 (63.6) 58 51 (87.9) 4 17 15 (88.2) 13 4 (30.8) 21 17 (81.0) 5 4 3 (75.0) 10 8 (80.0) 8 7 (87.5)

Baseline BMI category < 18 kg/m2 24 18 (75.0) 29 17 (58.6) 50 42 (84.0)

18 - < 20 kg/m2 10 8 (80.0) 13 8 (61.5) 59 44 (74.6) 20 - < 25 kg/m2 28 22 (78.6) 18 10 (55.6) 76 62 (81.6) 25 kg/m2 4 4 (100) 6 3 (50.0) 20 15 (75.0)

Baseline Albumin Grade Grade 0 38 31 (81.6) 24 14 (58.3) 167 137 (82.0) Grade 1 11 9 (81.8) 14 10 (71.4) 15 12 (80.0) Grade 2 14 11 (78.6) 27 13 (48.1) 22 14 (63.6) Grade 3 3 1 (33.3) 1 1 (100) 1 0 (0)

N = number of subjects in subgroup; n = number of subjects with culture conversion; NA = not applicable a As DST was not performed for all anti-TB drugs, some drugs are not accounted for. DST (validated critical concentrations) was done for INH, RMP, EMB, SM, PZA, ETH, OFL, KAN, and CAP.

C208 Stage 2 C209

2 cm

2 cm

2.5

45

C208 Stage 2 TMC207 93.3%

73.0% C209 72.9%

82.0% 84.6% C208 Stage 1

6 TMC207 81.0%

C208 Stage 2 C209

C208 Stage 2

Week 24

53.8% 57.1%

C209 Week 24

C208 Stage 2

C208 Stage 2 TMC207 MDRH&R-TB pre-XDR-TB

MDRH&R-TB 83 pre-XDR-TB 70

TMC207 MDRH&R-TB 125 pre-XDR-

TB Week 24 50% C208

Stage 2 MDRH&R-TB 62.2% pre-XDR-TB 33.3%

TMC207 MDRH&R-TB pre-XDR-TB MDRH&R-TB 82.1% pre-

XDR-TB 73.3%

C209

C208 Stage 2 MDRH&R-TB 87.1% pre-

XDR-TB 77.3% XDR-TB 55.6%

C208 Stage 2 C209

DST BR

C208 Stage 2 C209 BR

3 2

BMI

BMI

2.5

46

C208 Stage 2 C209 Grade 2

Grade 1

C208 Stage 2 TMC207

Grade 3

HIV HIV

C208 Stage 2 TMC207 5 C209 10

C208 Stage 2 C209 Week 24

C209

75.6% 86.0% 61.5%

60.0% C208 Stage 2 TMC207 80.0%

54.1% 2.7.3.3.3(1)2)

2.5.4.3.4.4

(1) C208 Stage 1

responder missing=failure TMC207 11 52.4%

10 43.5% no overruling responder

TMC207 81.0% 17/21 52.2% 12/23

2.7.3.5.1.1(1)

(2) C208 Stage 2

responder missing=failure TMC207 41 62.1%

29 43.9% Week 24 responder TMC207 52 11 21.2%

38 13 34.2% non-responder TMC207

11 4 7 13

8 5 Week 24 non-responder TMC207

14 28 responder TMC207 0

4 14.3% 2.7.3.6- -11


responder TMC207 78.8% 52/66 62.1% 41/66

2.5

47

International expert consensus group 1

31.8% TMC207 57.6% p=0.003

2.7.3.2.1.2(2)

(3) C209

responder missing=failure 148 72.2% Week 24

responder 163 non-responder 24 14.7%

5 19 Week 24 non-

responder 42 responder 9 21.4%


responder 83.9% 172/205

International expert consensus group 1 61.0%

2.7.3.3.2.2(6)

(4) TBC2001

FAS 4 Week 2

TMC207 2

Week 2 2.7.3.5.2

(5)

C208 Stage 1 4

17.4% Stage 2 10 15.2% TMC207 Stage 1 2 9.5% Stage 2

6 9.1% C209 8 3.9%

C208 Stage 1 4 TMC207 2

Week 24 BR Week 28 104 TMC207 2

1 2.5 BR Week 84

MDRH&R-TB 3 TMC207 1 2 pre-XDR-TB 3

TMC207 1 2 MDRH&R-TB

2 1 1

C208 Stage 2 10 TMC207 6 Week 24

Week 32 120 responder Week 24 non-responder

12 2.7.3.5.1.1(2) Week 24 non-responder 4

4 Week 24 Week 14 22 2 1

Week 24 1 Week 24 Week 28

Week 36 1 TMC207 non-responder 16 14 9

TMC207 5 2 1

2.5

48

MDRH&R-TB 15 TMC207 6 9

MDR-TB 1

C209 8 Week 24 Week 36 120 responder

Week 24 non-responder 5 2.7.3.5.1.1(3)

Week 24 non-responder 3 3 Week 24

Week 16 2 Week 24 Week 60 Week 120 1

8 5 3

1 2.5 BR Week 36

MDRH&R-TB 3 pre-XDR-TB 5

IIb C208 Stage 1 1

C208 Stage 2 2 C209 17

2.7.2.4.2.7(8)

TBC2001

2.5.4.3.4.5 DST

DST 2.5.4.1.4

(1) BR

1)

C208 Stage 1 DST 10

TMC207 1 TMC207 1 5

BR

1

BR 9 4

4 2 BR

TMC207 1

1 BR

1 BR

5 2 responder

C208 Stage 2 DST 31

TMC207 12 TMC207 2 16

BR 1

BR TMC207 2 responder 1 no

overruling 2 MDRH&R-TB pre-

XDR-TB

16 7 responder 9 non-responder non-responder 9 5

MDRH&R-TB pre-XDR-TB

2.5

49

pre-XDR-TB 1 XDR-TB 3 non-

responder

C209 DST 26

17 BR 1

7 responder 10 non-responder no overruling

non-responder 10 4 XDR-TB 5 pre-XDR-TB 1

MDRH&R-TB pre-XDR-TB 5 3

XDR-TB MDRH&R-TB 1

C208 Stage 2 C209

BR

1

TBC2001 FAS

BR

(2) TMC207

1) MIC MGIT

IIb no overruling

TMC207 MIC

Week 24 TMC207 MIC

2.7.3.6- -24

C208 Stage 2 C209

TMC207 MIC 0.12 μg/mL

2.7.3.6- -25

2) MIC

IIb TMC207

TMC207 TMC207 MIC

4 IIb

TMC207 MIC MIC

7H11

TMC207 MIC C208 Stage 1 1 C208

Stage 2 11 C209 24 TMC207 MIC

4 C208 Stage 1 1 C208

Stage 2 2 C209 17 C208 Stage 2 2 pre-

XDR-TB C209 17 10 XDR-TB 4 pre-XDR-

TB 3 MDRH&R-TB

TMC207

2.5

50

TBC2001 FAS 4

TMC207 MIC

3) TMC207 BR

IIb TMC207 BR

· TMC207 MIC BR

· TMC207 MIC 4 BR

TMC207 BR

C209 BR

+ thiacetazone DST

TMC207 MIC

TMC207 MIC 4

TMC207 MIC

TMC207

2.7.2.4.2.7(4)

2.5.4.4

2.5.4.4.1

IIb TMC207

TMC207

600 ng/mL AUC24h 14.4 g h/mL

I R207910-CDE-102 CDE-102 TMC207-C104

C104

· M2

· M2 AUC24h 100 g

h/mL

· 600 ng/mL AUC24h 14.4 g

h/mL

5

TMC207 400 mg q.d. 2 6

1. TMC207 200 mg t.i.w.

2. TMC207 300 mg t.i.w.

3. TMC207 400 mg t.i.w.

2.5

51

4. TMC207 400 mg 2

5. TMC207 200 mg q.d.

C208 Stage 1 TMC207 400 mg q.d.

2 TMC207 200 mg t.i.w. 48 6

8 AUC24h 23 g h/mL

8 AUC24h 40 g h/mL

TMC207 400 mg q.d. 2 M2

20% M2 AUC24h 100 g h/mL

I CDE-102 C104 TMC207-C109

TMC207 400 mg q.d. 2 IIa

C202 TMC207 25 mg 100 mg 400 mg q.d. 7

400 mg log10 CFU Day 3

5 6 7

C208 Stage 1 TMC207 400 mg q.d. 2

200 mg t.i.w. 6 MDR-TB TMC207 BR 8

MGIT Cox

TMC207

p=0.0034 8 TMC207 26.1%

4.2% TMC207 TMC207

BR 8

C208 Stage 2 C209 TMC207 200 mg t.i.w. C208 Stage 1

6 22 TMC207 400 mg q.d. 2

200 mg t.i.w. 22 24 MDR-TB BR

C208 Stage 2 MGIT

Cox TMC207

missing=failure p<0.0001 end-censored

missing=failure p=0.0003 C208 Stage 2

TMC207 83 125 C208 Stage 2 C209

TMC207 BR 24 TMC207

C208 C209 TMC207 24

TMC207 400 mg q.d. 2 22 TMC207 200 mg t.i.w.

WHO6

2.5

52

2.5.4.4.2

TBC2001 TMC207 IIb

TMC207 400 mg q.d. 2 200 mg t.i.w. 48

22 TMC207 24 BR

TMC207 24

#P3192 TBC2001 24

24 TMC207

MDR-TB 20

TBC2001 6 Week 24

TMC207

MGIT 4

TMC207

Week 2 4

14 15 1

TMC207 21

TMC207 BR 24

TMC207 5 TMC207

MDR-TB TMC207

TMC207

PK 6 MDR-TB

2.7.2.5

2 1 1 400 mg

3 1 200 mg 3 48

2.5.4.5

TMC207 TMC207

400 mg q.d. 2 200 mg t.i.w. 48 22

TBC2001 2.5.4.4.2 24

24 TMC207

24

2.5

53

FAS 4 24

3 3 1

TMC207 24 TMC207

MDR-TB MDR-TB TMC207

TMC207

2.5.4.6

MDR-TB IIb BR

TMC207 24

II C208 Stage 2

24 TMC207


TMC207 TMC207 73 125

missing = failure p<0.0001 end-censored

missing=failure TMC207

p=0.0003

Week 24 TMC207 78.8% 57.6%

missing=failure

p=0.008

C208 Stage 2 TMC207

TMC207


TMC207 p=0.0022 Week 24

TMC207 C208 Stage 1 Stage 2

TMC207 BR

C209 C208 Stage 2 C209

Week 24 57 missing=failure

C209

C209 Week 24

C208 Stage 1 Stage 2 TMC207

79.5%


missing=failure TMC207 62.1% 43.9%

missing=failure

p=0.035 TMC207

1 TMC207 C209

missing=failure 72.2%

2.5

54

MDR-TB TBC2001 FAS 4

14 15

MDR-TB TMC207

2.5

55

1 Laserson KF, et al. Speaking the same language: treatment outcome definitions for multidrug-

resistant tuberculosis. Int J Tuberc Lung Dis. 2005;9(6):640-5.

2 Holtz TH, et al. Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors

and relationship to treatment outcome. Ann Intern Med. 2006;144(9):650-9.

3

4 . - 2014 . . 2014;89(7):683-

90.

5 . . 2 . : ; 2012.

6 World Health Organization. The Use of Bedaquiline in the Treatment of Multidrug-Resistant

Tuberculosis: Interim Policy Guidance. Geneva: World Health Organization; 2013.

2.5

56

2.5.5 15 I 11

IIa 1 IIb 2 II 1 TMC207

2.5.5-1

MDR-TB IIb

II TBC2001 3 IIb 2

C208 C209 C208 C208 Stage 1 Stgae 2

C208 C209

2.7.4.1.1.3(2)1) IIb

2.5.5-1

*1

IIb

C208 Stage 1 5.3.5.1.1 MDR-TB

*2,*3 Week 104

T*4 23P*5 24

C208 Stage 2 5.3.5.1.1 MDR-TB

*2,*3 Week 72

Week 120

T*4 79P*5 81

C209 5.3.5.2.2 MDR-TB

*3 Week 24

Week 120

233

II

TBC2001 5.3.5.2.3 5.3.5.2.4

MDR-TB

4 /Week 24

*6

6 /Week 24

6

I TBC1003

5.3.4.1.1 88

*1 *2 C208 Stage 1 Stage 2 *3 C208 C209 *4 T TMC207 *5 P *6 TBC2001

2.5.5.1

2.5.5.1.1

2.5.5.1.1.1 IIb

C208 Stage 1 Stage 2 C209 440 MDR-TB

105 335 TMC207

335 C208 Stage 1 23 C208 Stage 2 79 C209

233 2.7.4.1.2.1(1)/ 2.7.4.1-10

C208 TMC207

TMC207 35.9 35.3

TMC207 102 68.6% 70/102 41.2% 42/102

2.5

57

8.8% 9/102 7.8% 8/102 42.2% 43/102

C208 C209 TMC207 35.0

TMC207 335 65.7% 220/335 34.9%

117/335 29.6% 99/335 20.3% 68/335 15.2%

51/335 2.7.4.1.3.1(1)/ 2.7.4.1-21

C208 DST MDRH&R-TB pre-XDR-

TB TMC207 67.9% 55/81 22.2% 18/81

71.3% 62/87 18.4% 16/87 XDR-TB

TMC207 4.9% 4/81 5.7% 5/87 C208

XDR-TB

DS-TB TMC207 4.9% 4/81

4.6% 4/87 TMC207 1

2

2 cm TMC207 60.8% 62/102

51.4% 54/105 TMC207 HIV

TMC207 11.0% 11/100 18.1% 19/105 TMC207

TMC207

C208 C209 TMC207 MDRH&R-TB 57.4% 148/258

pre-XDR-TB 24.0% 62/258 XDR-TB 15.9% 41/258

C209 XDR-TB 3 BR

2 cm

54.6% 183/335 HIV 6.7% 22/328 2.7.4.1.3.1(1)/

2.7.4.1-22

IIb

2.7.4.1.3.1 IIb

BR 2.7.4.1.4.1(1) 2.7.4.1.4.2(1)

2.5.5.1.1.2 II

TBC2001 6 TMC207 6

3 45.5 25

73 2.7.3.2.2.1/ 2.7.3.2-7 MDR-TB

pre-XDR-TB XDR-TB 2 cm

2 33.3%

2.7.3.2.2.1/ 2.7.3.2-8

2.5

58

TBC2001

2.7.3.2.2.1

BR 2.7.4.1.4.1(2) 2.7.4.1.4.2(2)

2.5.5.1.2

2.5.5.1.2.1 IIb

C208 Stage 1 ITT 2.7.4.1-3

51.1% TMC207 56.5% 45.8%

48.9% 43.5% 54.2%

17.4% 16.7% 13.0% 16.7%

2.7.4.1.2.1(2)1)

C208 Stage 2 ITT 61.9%

TMC207 63.3% 60.5% 37.5%

36.7% 38.3% 11.4% 7.4%

3.8% 8.6% 7.6% 8.6%

2.7.4.1.2.1(3)1)


TMC207

C209 ITT 76.8%

23.2% MDR-TB

7.3% 17/233 5.2% 12/233 2.7.4.1.2.1(4)1)

C208 TMC207

24.9 23.9

22 TMC207 60.8% 62/102

61.0% 64/105

TMC207 29 28 28

27

C208 C209 TMC207 25.0

C208 TMC207 24.9

C208 C209 24.0 C208

23.9 C208 C209 22

81.8% 274/335 C208

2.7.4.1.2.1(1)3)

TMC207

2.7.2.3.1.3(2) 1

2.5.5.1.2.2 II

TBC2001 TMC207 24 TMC207

2.5

59

24 TMC207

2.7.3.1.1.2(4)

40.0

25.0 50.0 48.5 33.0 81.0 2.7.4.1.2.2(2)

Week 24 5

2.7.3.2.2.1/ 2.7.3.2-6

2.5.5.2

TMC207

National Institute of Allergy and Infectious Diseases Division of

Microbiology and Infectious Diseases DMID Adult Toxicity Table DMID

4 Grade 1 Grade 2 Grade 3

Grade 4

C208 Stage 1 Stage 2 C209 TBC2001

BR 5

BR

BR

ICH MedDRA

SOC PT MedDRA/J

2.7.4.1.1.2 2.7.4.1.1.3(4)

C208 Stage 1 Stage 2 C209 BR

TMC207 96

24 6 TBC2001

126

24 TBC2001

2.5.5.3

2.5.5.3.1

IIb

2.5

60

C208 TMC207 96.1% 98/102

95.2% 100/105 TMC207 1

1.0% TMC207 6.9% 7/102

1.9% 2/105 TMC207 Grade 3

TMC207

C208 C209 TMC207 91.0%

305/335 6.3% 21/335 C208

Stage 2 TMC207 1 C209 TMC207 2 3

2.7.4.2.1.1(1)1)/ 2.7.4.2-1

IIb TMC207 C209 C208

Stage 2 C208

Stage 2 97.5% 77/79 C209 88.8% 207/233 C208

MDR-TB C209

87.1%

C209 85.8%

4

2.7.4.2.1.3 C209

5

C208 TMC207 35% SOC

TMC207 57.8% 59/102 56.2% 59/105

40.2% 41/102 37.1% 39/105 36.3%

37/102 22.9% 24/105 35.3% 36/102 32.4%

34/105 5.0%

TMC207 20% TMC207 35.3% 36/102

25.7% 27/105 29.4% 30/102 20.0% 21/105

23.5% 24/102 11.4% 12/105 22.5% 23/102

27.6% 29/105 20.6% 21/102 22.9% 24/105

TMC207 5.0%

35.3% 25.7% 29.4% 20.0% 23.5% 11.4%

TMC207 5.0%

22.5% 27.6%

C208 C209

C208 2.7.4.2.1.2(1)1)/ 2.7.4.2-3

C208 Stage 2 C209 Week 0

4 Week 5 2.7.4.2.1.3(1)

TBC2001 83.3% 5/6 TMC207

BR 50.0% 3/6 83.3% 5/6

2.5

61

Grade 3 4 1 1

2.7.4.2.1.1(2)

2 66.7% 4/6

50.0% 3/6 33.3% 2/6

1

2.7.4.2.1.2.(2)

2.5.5.3.1.1

IIb Grade 1

2 2.7.4.8- -26 C208 TMC207 Grade 3

27.5% 28/102 22.9% 24/105

TMC207 Grade 3

TMC207 10.8% 11/102 13.3% 14/105

Grade 3 3% Grade 4

TMC207 7.8% 8/102 3.8% 4/105

TMC207 Grade 4 3.9% 4/102

Grade 4 1

Grade 4 2.5.5.5.1.1

C208 C209 TMC207 Grade 3

C208 C208 C209

TMC207 Grade 3 6.6% 22/335 Grade 4

1.8% 6/335 1 C208

Grade 3 BR

TBC2001 Grade 3 2

Grade 3 Grade 4 1

TMC207 BR

TMC207 BR

2.5.5.3.2.2

2.5.5.3.1.2

C208

TMC207 67.6% 69/102 64.8% 68/105

TMC207 20.6% 21/102 14.7%

15/102 12.7% 13/102 2.7.4.8- -34 PART A

C208 C209 TMC207

43.0% 144/335 TMC207

C208 2.7.4.8- -34 PART B

2.5

62

TBC2001

50.0% 3/6

Grade 1

BR IIb 2.7.4.2.1.5(1) TBC2001

2.7.4.2.1.5(2)

2.5.5.3.2

2.5.5.3.2.1

IIb 440

33 7.5%

C208 Stage 1 47 1 TMC207

BR C208 Stage 1

3 TMC207 1

2 XDR-TB XDR-

TB

267

C208 Stage 2 160 7 TMC207 79 6

81 1

TMC207 3 1 1

TMC207 3 TMC207

C208

Stage 2 6

TMC207 4 2 TMC207 1

5

262 TMC207

C208 Stage 2 TMC207

TMC207 10 1

9

344 1 TMC207 120

TMC207 5

1 TMC207

5 BR

HIV TMC207

2.5

63

C209 233 12

10 3 2

C209

4

2.7.4.2.1.6(1)

2.7.6.12.1(3)1) C208 Stage 1 2.7.6.12.2.4(1) C208 Stage 2 2.7.6.14.3(1)

C209

2.7.4.2.1.6(1) 2.7.4.8- -100 C208 Stage 1

2.7.4.8- -101 C208 Stage 2 2.7.6.14.3(1) C209

TBC2001

2.5.5.3.2.2

C208 Stage 1

TMC207 4.3% 1/23 4.2% 1/24 BR TMC207

13.0% 3/23 8.3% 2/24

TMC207

2.7.4.8- -45

C208 Stage 2 TMC207

22.8% 18/79 18.5% 15/81 2

TMC207 2 0

2 1 2 3 2 1 0 4

1 TMC207

1 2 2.7.4.2-

7

TMC207 10.8% 7/65

2.3% 1/43 2.7.4.2-8

C209 20.2% 47/233

6.4% 15/233

3 2.6% 6/233

2.1% 5/233 1.7% 4/233 1.3% 3/233

QT 1

SOC PT

1.3% 3/233 BR

2.4% 4/165

2 1 2.7.4.8-

-47

2.5

64

IIb 1

2.5.5.4 C209 QT

QT SMQ 2.5.5.4.4 2.7.6.14.3(1)2)

TBC2001 1

TMC207 BR

21

TMC207 BR TBC2001

2.7.6.15.3(2)2)

2.5.5.3.2.3

TMC207 BR

2.7.4.2.1.8

C208 Stage 1

C208 Stage 2 TMC207 5.1%

4/79 6.2% 5/81 2

TMC207 3

2 TMC207 3

2 B 2.7.4.8- -50

C209 2.6% 6/233

QT

1 2.7.4.8- -52

TBC2001 TMC207

2.5.5.4

TMC207

2.7.4.1.1.3(4)5)

· Hepatic disorders SMQ

· Acute pancreatitis SMQ

· Severe cutaneous adverse reactions SMQ

· QT Torsade de pointes/QT prolongation SMQ

· Rhabdomyolysis/myopathy SMQ

SMQ SMQ SMQ

SMQ Drug-related hepatic disorders-comprehensive search SMQ

SMQ

2.5

65

SMQ SMQ SMQ

SMQ SMQ

IIb MedDRA ver.14.0 SMQ II MedDRA

ver.19.0 SMQ

C208

TMC207 15.7% 9.5% TMC207

SMQ TMC207 8.8% 1.9%

C208 C209

TMC207 17.3% SMQ 11.0%

2.7.4.8- -55

TBC2001 4 9 2.7.4.8- -56 )

2.5.5.4.1 Hepatic Disorders SMQ

C208 SMQ TMC207

8.8% 9/102 1.9% 2/105 TMC207

TMC207 SMQ 2.9%

3/102 5.9% 6/102 Grade 3 2.9%

3/102

TMC207 SMQ

TMC207 3.9% 0% AST 2.9% 0%

C208 C209 SMQ TMC207 11.0%

37/335 TMC207 SMQ

0.9% 3/335 Grade 3

3.3% 11/335

IIb

Hy's Law 2.5.5.5.1.4

TBC2001 SMQ 4

Grade 3 4 1 BR

BR

4 1 Grade 2

BR BR

2

Grade 1

TBC2001

2.5

66

2.5.5.4.2 Acute pancreatitis SMQ

IIb SMQ TMC207

3.0%

C208 SMQ TMC207

2.0% 2/102 1.0% 1/105 TMC207

2

1 TMC207

2.0% 2/102

1

Grade 3

TMC207 1

C208 C209 SMQ

TMC207 1.5% 5/335 4

1

0.9% 3/335 Grade 3

0.3% 1/335

IIb

TBC2001 SMQ

2.5.5.4.3 Severe cutaneous adverse reactions SMQ

IIb SMQ

SMQ

C208 TMC207 2.0%

2/102 2.9% 3/105 C208 C209

TMC207 3.0% 10/335 Grade 1

C208 C208

C209 TMC207 0.6% 2/335

TBC2001 SMQ 2

1 Grade 1 BR

BR

BR

2.5.5.4.4 QT Torsade de pointes/QT prolongation SMQ

C208 QT SMQ TMC207

3.9% 4/102 3.8% 4/105 TMC207

QT 3 1 QT 4

2.5

67

Grade 1 TMC207 2.0%

2/102 3.8% 4/105

C208 C209 QT SMQ TMC207

3.0% 10/335 QT 9 1

2.1% 7/335

C209 1 Grade 3 QT

TMC207 8 Day 8 Grade 3 QT

TMC207 BR

TMC207 BR

Day 11 QT

Day 28 2.7.6.14.3(1)2) 2.5.5.5.3

TBC2001 QT SMQ 1 3

Grade 1 QT BR

TMC207 QT

TMC207 MDR-TB

2.5.5.4.5 Rhabdomyolysis/Myopathy SMQ

IIb TBC2001 SMQ

2.5.5.5

IIb TBC2001

2.5.5.5.1

2.5.5.5.1.1 DMID

C208 Stage 1

25% AST

TMC207 90.5% 95.7% AST

33.3% 17.4% 28.6% 17.4% TMC207

23.8% 8.7% -

GGT 14.3% 0%

TMC207

2.5

68

Grade 1 2 Grade 3 4

40.9% TMC207 52.6%

C208 Stage 1 BR

2.7.4.3.1.2(1)1)

C208 Stage 2

25% TMC207 91.0% 86.4% AST

62.8% 49.4% 41.0% 44.5% ALT 37.2% 17.3%

34.6% 34.5% 25.7% 32.1% 26.9%

28.4% 26.8% 17.2% 23.1% 25.9%

AST ALT TMC207

Grade 1 2 Grade 3 4

37.0% TMC207 38.5% Grade 3 4

5%

TMC207 14.1% 6.2% AST 11.5% 4.9% GGT

9.0% 3.7% ALT 7.7% 2.5% 6.4% 6.2%

5.1% 6.2% 5.1% 1.2%

C208 Stage 2

2.7.4.3.1.2(2)1)

C209 25%

31.9% AST 26.2% Grade 3 4

5% 9.6%

25% AST

ALT Grade 3 4

5% 12.6% AST 8.7% GGT 5.2%

2.7.4.3.1.2(3)1)

TBC2001 2 AST

50.0% ALT 33.3% Grade 3

ALT Grade 3 2 Grade 3 Grade 4 1

2.7.4.8- -72

2.5.5.5.1.2 DMID

C208 Stage 1 25%

CPK TMC207 52.4%

39.1% 47.6% 30.4% 28.6%

34.8% 19.0%

4.3% LDH 14.3% 0%

TMC207 BR

I TMC207 34.8% 25.0%

2.5

69

31.8% 18.2% 13.6% 0%

TMC207

TMC207 2.7.4.3.1.2(1)2)

C208 Stage 2 25%

I TMC207 47.4% 44.4%

37.2% 44.4% 35.9% 34.6% % 33.3%

35.8% 32.1% 30.9%

26.9% 30.9% 15.4% 25.9% 24.4% 30.9%

I 28.2% 28.4% II 19.2% 28.4% LDH 26.9%

16.0% % 24.4% 27.2% % 25.6% 18.5%

TMC207

5% LDH %

2.7.4.3.1.2(2)2)

C208 CPK LDH

TMC207 C208 Stage 2 LDH

2 LDH

C208

CPK Division of Acquired Immunodeficiency Syndrome DAIDS

TMC207 9.9% 9.6%

Grade 1 C208

CPK

C208

C209 10% CPK

25.8% II 19.7% % 18.3%

17.9% 16.6% I 15.3%

15.3% 13.1% % 12.2%

11.4% % 10.0%

25% CPK 35.7% 27.8%

27.0% 26.1% I 25.7%

II 25.3% 2.7.4.3.1.2(3)2) TBC2001

66.7%

33.3%

2.7.4.8- -73

2.5.5.5.1.3 I II

/

2.4.4.8.3.3

2.5

70

2.4.4.8.3.4 IIb

I II

IIb

IIb TBC2001

I II

TMC207

2.5.5.5.1.4 Hy’s Law

IIb Hy's Law2 3 IIb Hy’s Law

C208 Stage 2 C209 1

C208 Stage 2 Hy's Law 1 TMC207 pre-XDR-TB 43

TMC207

BR

Week 98

Week 24 Week 84 Hy's Law

BR

4 5 TMC207 16

TMC207 BR

C209 Hy's Law 1 Grade 3 3

Grade 3 1 Grade 4 2 Grade 4 1

TMC207

BR

BR 4 BR

2.5.5.5.1.5

C208 2 TMC207 1

1.0% 1 1.0% TMC207

TMC207 1 Stage 2 30 BR

Day 90 TMC207

Day 92 Grade 1

2.5

71

TMC207 BR

C208 C209 TBC2001

2.5.5.5.2

C208 Stage 1 2

BR 5

2.7.4.4.1.1(1)

C208 Stage 2

10% TMC207 29.5% 35.8%

16.7% 24.7% 17.9% 18.5%

12.8% 16.0% TMC207 4

5.1% 2 2.5% Grade 3

TMC207 1 126 mmHg

Grade 3 Grade 2

2.7.4.4.1.1(2)

C209 5%

16.0% 15.2% 6.9%

Grade 3 5 2.2%

3 1.3% 2.7.4.4.1.1(3)

TMC207

TBC2001 2

50.0% 33.3%

Week 2

Grade 3 1 TMC207

2.5.5.5.3

TMC207 thorough QT TBC1003

MDR-TB IIb TBC2001

2.5.5.5.3.1 QTc TMC207 TBC1003

TBC1003 TMC207 800 mg

QT/QTc

thorough QT/QTc

2.5

72

400 mg 2.7.4.2.1.10(1)2)

TMC207 QTc

88 Group 1 3 Group Group 1

A 44 Group 2 3 B 22

Group 2 Group 3 Group 1 A Day 1 TMC207 800 mg Day 2

Group 2 3 B Day 1

TMC207 Day 2 400 mg

Group 2 1

QTcF TMC207

5.19 ms 90%CI 1.46 8.92 ms ICH E14 6

10 ms ICH E4

TMC207

500 ms QTc 60 ms QTc

TMC207 M2 QTcF

2.7.2.2.3(1)

2.5.5.5.3.2 IIb

(1)

C208 Stage 1 QTcF

TMC207 TMC207 17.6 ms

11.8 ms

BR QTcF

TMC207 22.5 ms

QRS PR

C208 Stage 2 TMC207 QTcF

17.9 ms QTcF

14.1 ms

PR QRS PR

C209 QTcF 10 ms

TMC207 PR

QRS PR

C208 TMC207 QTcF

5

Cmax QTcF

C208 C209 C208

2.5

73

Week 2 Week 3 M2 QTcF

(2)

C208 Stage 1 QTcF 500 ms QTcF

480 500 ms 60 ms TMC207 2 8.7%

8 QTcF 30 60 ms

TMC207

BR

BR 4 TMC207 2

TMC207 2 1 TMC207 16

2.7.6.12.1(3) QT 1 TMC207 52

Grade 1 2 1

Week 60 Grade 1 1 Week 84 Grade 2

TMC207

C208 Stage 2 QTcF TMC207 1 500 ms

60 ms TMC207 10 13.0% 2 2.5%

60 ms TMC207 4

2 QTcF 450 ms

1 QTcB PT QT VERBATIM TERM

PROLONGED QTCB C208 Stage 2

TMC207

C209 QTcF 450 500 ms 36

15.5% 480 500 ms 5 2.2% 480 500 ms 1

60 ms QTcF 500 ms 2 9.0%

1 Week 36 514 ms 1 Week 24 516 ms Week 36 529 ms

C209 TMC207

QT 1 2.5.5.4.4

QT QT Torsade de pointes/QT prolongation

SMQ 2.5.5.4.4

(3) I

CPK I

2.4.4.8.3.2

C208 I

TMC207 TMC207 30.7% 35.6%

2.5

74

BR4 7 I

TMC2078 I

I CPK-MB

TMC207 TMC207

IIb I 2

(4) QT

in vitro IKr9 C209 QTcF

C209 QTcF Week 24

177 12.28 ms

17 31.94 ms

C208 Stage 2

TMC207 MDR-TB

2.5.5.5.3.3 TBC2001

50 bpm QTcF

2 4 QTcF 4 2 >450

480 ms 1 >480 500 ms 1 514 497 505 ms QTcF

TMC207 QT

QTcF 30 60 ms 4 QTcF 60 ms

2.5.5.6

IIb

2.5.5.3.2.1

TBC2001

2.5

75

2.5.5.7

2.5.5.7.1 I

TMC207 I 8 5 132

3 57 I 8

I 2

TMC207 HIV-1

C117 C112

QT/QTc TBC1003 thorough QT/QTc I

I 2.7.4.1.1.3(2)2)

I TMC207 1 189 TMC207

BR

TMC207 60.3% 114/189 TMC207 400 mg

55.6% 25/45

I

TMC207 3 1.6% Grade 2 1

Grade 1 Grade 3 1 Grade 3 1 2

TMC207 400 mg

TMC207 18.0% TMC207 400 mg

15.6% 11.1%

I Grade 1 Grade 2

Grade 3

TMC207 3 Grade 3

SMQ

1 Grade 2 80 U/L 13 53 U/L 1 Grade 1

69 U/L 11 54 U/L

C104 TMC207

I 3 TMC207

8 8 C112 HIV-1 16 C117

44 TBC1003 TMC207

3

C117 HIV-1 1 2 Grade 3

Grade 3 TMC207 400 mg 200 mg 2

TMC207

HIV-1

TBC1003 2 1 TMC207

Grade 3 1 Grade 1

TMC207

2.5

76

TMC207

C112

1 TMC207 Grade 3

Grade 2 2 Grade 2 1 Grade 3 1

2 TMC207

CPK Grade 1

TMC207

thorough QT I

I

TMC207 500 ms

QTcF QT C109

TMC207

QTc TMC207 800 mg

TBC1003 ICH E14 6 QTcF

I I 3

800 mg 400 mg q.d. 15

TMC207

2.5.5.7.2 IIa C202

C202 DS-TB

C202

IIb

75 TMC207 25 mg 15 TMC207 100 mg 16

TMC207 400 mg 14 15 15

89.3% 67/75 7

5.3.5.2.1 TMC207

TMC207 25 mg 13.3% 2/15 TMC207 100 mg 37.5%

6/16 TMC207 400 mg 64.3% 9/14 46.7% 7/15

20.0% 3/15 TMC207

TMC207 100 mg 1 TMC207 400 mg 3

+ 2

TMC207 400 mg 2

1 Grade 4 1 Grade 3

2.7.4.2.1.10(2)1) TMC207

2.5

77

Grade 4

Grade 3 TMC207 400 mg 1

C202 Day -1 Day 7

5 TMC207 400 mg Day 7 QTcF

10 ms TMC207 25 mg 100 mg QTcF

Day 7 TMC207 400 mg QTcF

TMC207 400 mg 20.6 ms 10.7 ms

8.4 ms 5 24.5 ms 13.1 ms 15.8 ms

500 ms QTcF

TMC207 400 mg QTcF

TMC207 25 mg 100 mg 400 mg 7

3

2.5.5.8

TMC207 18 MDR-TB

BR 2 400 mg q.d. 22

200 mg t.i.w. 24 WHO

24 TMC207

MDR-TB TBC2001

5 50.0

BR

1 /Grade 1

IUATLD, Inc MDR-TB

III STREAM Stage 2 MDR-TB

BR TMC207 40

2.5.5.9

2.5.5.9.1

IIb TBC2001

C208

HIV BMI

C208 C209

2.5

78

TMC207 Grade 3 >45 <65

45 45 22.2% >45 <65 40.0%

16.7%

36.7% TMC207 >45 <65 20.8%

50.0% TMC207

TMC207 Grade 3

12.5% 34.3%

9.4% 28.6% TMC207

Grade 3 TMC207

23.1% 28.3% 19.1%

6.8% 34.3% 5.9%

QTcF 30 ms

HIV QTcF

30 ms HIV

BR QTcF

30 60 ms MDRH&R-TB pre-XDR-TB XDR-TB

BMI <18 18 <20 20 <25 25 2 cm 2 cm

2 cm

2.7.4.5.1

2.5.5.9.2

2.5.5.9.2.1

TMC207 MDR-TB

Child-Pugh

7 9 I C112

TMC207 400 mg M2

2.5

79

16 8

8

1 Grade 3 2

2.5.5.7.1

19%

TMC207 TMC207

TMC207

2.7.2.2.2.4(1)

2.5.5.9.2.2

C208 C209 TMC207 CLCR

289 42 4

C208

CLCR

TMC207 0.01%

CLCR

2.7.2.3.1.7(8)

TMC207

TMC207

TMC207

2.5.5.9.2.3 HIV

IIb HIV-1 C117

C117 ARV HIV-1 16 TMC207

400 mg

1 2 Grade 3 TMC207

HIV-1

2.7.4.5.1.4(2)

C208 C209 TMC207 306 HIV 22

HIV HIV

2.7.4.5.1.4(1)

HIV

SOC HIV HIV

2.5

80

HIV 19.6%

HIV 31.8% 2.7.4.8- -86

Grade 3

HIV HIV

ALT HIV

HIV Grade 3 4

HIV

Grade 3 4 HIV HIV

HIV QTcF

30 60 ms HIV

HIV

2.5.5.9.3

TMC207

TMC207

IIb

13 TMC207 7 6

1 TMC207 3 TMC207 1 2 1

TMC207 2.7.4.5.4 TMC207

TMC207

TMC207

TMC207

2.4.4.8.6

TMC207

45 mg/kg TMC207 M2

Cmax 2.4.4.8.6

TMC207

TMC207

TMC207

TBC2001

2.5.5.9.4

TMC207

TBC2001 1

TMC207 400 mg q.d.

2 400 mg t.i.w.

2.5

81

2 200 mg t.i.w.

200 mg t.i.w.

QT/QTc TBC1003 TMC207 800 mg

44

TMC207

TMC207 TMC207

QT

TMC207

DOTS

TMC207 2 3

3 3

2.5.5.10 Adverse Drug Reaction ADR

Adverse Drug Reaction ADR JRD IIb C208 C209

IIb TMC207

24 TMC207 M2

132 112 48

ADR 2.7.4.6.1 2.7.4.8- -102 IIb

ADR 2.7.4.6

C208 10.0% ADR TMC207

35.3% 29.4% 23.5% 20.6% 12.7%

TMC207 5.0% ADR

TMC207 23.5% 11.4% 35.3% 25.7%

29.4% 20.0% 6.9% 1.0%

TMC207 5.0% ADR 5.9% 11.4%

C208 ADR

TMC207 10% ADR C208 C209 C208

C208

12.7% C208 C209 6.9% C208

C209 ADR 2 QT 1

0.3%

C208 TMC207 Grade 3 ADR

2 1 C208 C209

2.5

82

TMC207 3 Grade 3 ADR 8

4

C208 TMC207 3 2.9%

ADR C208 C209 C208

TMC207 3 QT

TMC207 1 ADR

C208 ADR 1.0%

1/105 TMC207 6.9% 7/102

AST TMC207 3.9% 4/102 2.9% 3/102

ADR ALT

TMC207 2.0% 2/102 1.0% 1/105

2.5.5.10.1 ADR

C208 C209 TMC207

43.0% 144/335 ADR 49.6% 166/335

ADR 5%

9.3% ADR 18.2% 6.9%

12.2% 6.3% 17.0% ADR 5%

5% 4.8% 13.1%

0.9% 8.7% 3.3% 6.9% 2.4% 7.2%

ADR

2.5.5.11

TMC207 2012 12 28 JRD

2016 9 5

Periodic Benefit Risk Evaluation Report/Periodic Safety Update Report

PBRER/PSUR 2016 3 6 2016 9 5

2.5.5.12

IIb TBC2001 TMC207

QT IIb

ADR 2.5.5.10

2.5

83

IIb

TMC207 C208 TMC207 3.9% 0%

2.5.5.4.1 TMC207 TMC207 AST

Week 24 2.7.4.8- -2 TMC207

TBC2001

AST 3 50.0% ALT 2 33.3% ALT

1 Grade 3

2.5.5.5.1.1

TMC207 TMC207

QTcF TMC207

IIb TBC2001 QT C209 1

QT

2.5.5.4.4

CPK I TMC207

2.4.4.8.3.2 CPK-MB I

TMC207 TMC207

2.5.5.5.3.2(3) TMC207 QT

TBC2001 1 3 QT Grade 1

BR

TMC207 QT TMC207

MDR-TB

TBC2001 1

TMC207 BR

21

TMC207 BR 2.5.5.3.2.2

IIb 2.5.5.3.2.1 C208

Stage 2 TMC207 12.7% 10/79 3.7%

3/81 C209 6.9% 16/233

MDR-TB 10% 8% 21%10

IIb C208 Stage 2 C209

C208 Stage 2 Week 72 C209 Week 24

2.5

84

MDR-TB TBC2001

IIb

MDR-TB TMC207 BR 24

400 mg q.d. 2 200 mg t.i.w. 48

22

MDR-TB

2.5

85

1 Micro Labs Limited. SmPC pyrazinamide.Version 1.0. Karnataka: Micro Labs Limited [Updated

2012 May, Revised 2010 March]. Available at:

https://extranet.who.int/prequal/sites/default/files/documents/TB172part4v1.pdf

2 Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf.

2006;15(4):241-3.

3 Food and Drug Administration. Guidance for industry: drug-induced liver injury: premarketing

clinical evaluation. 2009.

4 Arbex MA, et al. Antituberculosis drugs: drug interactions, adverse effects, and use in special

situations. Part 1: first-line drugs. J Bras Pneumol. 2010;36(5):626-40.

5 Arbex MA, et al. Antituberculosis drugs: drug interactions, adverse effects, and use in special

situations. Part 2: second line drugs. J Bras Pneumol. 2010;36(5):641-56.

6 Food and Drug Administration, HHS. International conference on harmonisation; guidance on E14

clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-

antiarrhythmic drugs; availability. Notice. Fed Regist. 2005;70(202):61134-5.

7 Physicians Total Care, Inc. Ethambutol hydrochloride (Myambutol). Available at:

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=3d523d8a-a5b8-44eb-8575-

e36f186602a3

8 Liu A, et al. Sudden cardiac death and tuberculosis - how much do we know? Tuberculosis (Edinb).

2012;92(4):307-13.

9 Effects of Clofazimine and TBI-166 on cloned hERG Potassium Channels Expressed in

Mammalian Cells. Global Alliance of TB Drug Development, Final Report, ChanTest Study

Number: 100209.HBU, 2010.

10 Ahuja SD, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient

outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med.

2012;9(8):e1001300.

2.5

86

2.5.6

2.5.6.1

C208 Stage 2 MDR-TB TMC207 BR 24

400 mg q.d. 2 200 mg t.i.w. 48

22

missing=failure

p<0.0001 missing=failure p=0.008

C208 Stage 2 Week 24 TMC207 73

125 TMC207 78.8% 57.6%

2.5.4.6 BR

TMC207 C208 Stage 2 TMC207 2/12

16/31 2.5.4.3.4.5(1)1) C208 Stage 2

TMC207

C209 Week 24 MGIT 57

Week 24 79.5% missing=failure

C208 Stage 2

IIb missing=failure

C208 Stage 2 TMC207 62.1% 43.9%

p=0.035 C209 missing=failure

72.2% 2.5.4.6

C209 XDR-TB XDR-TB 62.2%

23/37 XDR-TB

29 44%1 2 3

International expert consensus group 4 C208

Stage 2 TMC207 C209 57.6% 61.0% C208

Stage 2 31.8% 2.5.4.3.4.4

C208 Stage 2 TMC207 12.7% 10/79

3.7% 3/81 C209 6.9%

16/233 MDR-TB 10%

8% 21% 5 2.5.5.12

MDR-TB TBC2001 FAS 4

14 15

2.5.4.4.2

TMC207

MDR-TB 6

2.5

87

2.5.6.2

TMC207 TMC207

QT

IIb ADR 2.5.5.10

IIb

TMC207 C208 TMC207 3.9% 0%

TMC207 TMC207 AST

Week 24 2.7.4.8- -2 TMC207

TBC2001

AST 3 50.0% ALT 2 33.3% ALT

1 Grade 3

2.7.4.8- -72

TMC207 TMC207

IIb QTcF TMC207

C208 30 60 ms

TMC207 52.5% 32.7% 60 ms TMC207

10.1% 4.0% QT

C209 1 QT TMC207

CPK-MB I TMC207

TMC207 2.5.5.5.3.2 TBC2001

1 3 QT Grade 1 BR

2.5.5.5.3.3 TMC207 QT

TMC207 MDR-TB

TMC207

QTcF

500 ms QTcF TMC207

BR TMC207 TMC207

HIV 65

18

HIV 22 IIb

HIV TMC207

TMC207 3 BR DOTS

DST TMC207 DST

4 BR

2.5

88

TMC207 24 TMC207

TMC207 BR

TMC207

· 400 mg 1 1 2

· Day 14 400 mg 14 3

· Day 14 400 mg 14 400 mg

1 1 14 3

TMC207 CYP3A4 CYP3A4

CYP3A4

2.7.2.2.1.4

TMC207 CYP3A4 15

CYP3A4

2.5.6.3

IIb C208 C209 MDR-TB BR

TMC207 24

II

TBC2001 FAS 4

MDR-TB IIb

IIb International expert consensus group

C208 Stage 2 TMC207 C209 57.6% 61.0%

C208 Stage 2 31.8%

TMC207 BR

QT

C208 Stage 2 C209

MDR-TB

1 TMC207

MDR-TB

TMC207 WHO 2013

2.5

89

MDR-TB

TMC207

Responsible Access

Program

2.5

90

1 Kim DH, et al. Treatment outcomes and survival based on drug resistance patterns in multidrug-

resistant tuberculosis. Am J Respir Crit Care Med. 2010;182(1):113-9.

2 Jacobson KR, et al. Treatment outcomes among patients with extensively drug-resistant

tuberculosis: systematic review and meta-analysis. Clin Infect Dis. 2010;51(1):6-14.

3 Liu CH, et al. Characteristics and treatment outcomes of patients with MDR and XDR tuberculosis

in a TB referral hospital in Beijing: a 13-year experience. PLoS One. 2011;6(4):e19399.

4 Laserson KF, et al. Speaking the same language: treatment outcome definitions for multidrug-

resistant tuberculosis. Int J Tuberc Lung Dis. 2005;9(6):640-5.

5 Ahuja SD, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient

outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;

9(8):e1001300.

6 Centers for Disease Control and Prevention (CDC). Emergence of Mycobacterium tuberculosis

with extensive resistance to second-line drugs--worldwide, 2000-2004. MMWR Morb Mortal

Wkly Rep. 2006;55(11):301-5.

2.5

91

2.5.7 2.5

2.5.1

2.5.2

2.5.3

2.5.4

2.5.5

2.5.6

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