Daniel Everitt, MD; Erica Egizi MPHGlobal Alliance for TB Drug Development, New YorkHelen Winter, PhDUniversity of Otago, New Zealand

2012 International AIDS ConferenceWashington, DC 23 July 2012

Pharmacokinetic Interaction Between the Investigational Anti-Tuberculosis Agent TMC207 and Rifampicin or Rifapentine

2

Develop new, better treatments for TB

Coordinate and act as catalyst for global TB drug activities

Ensure that new regimens are Affordable, Adopted for use, and made widely Available

(AAA strategy)

TB Alliance Mission

3Tackling TB Through Technology

Discovery and Development Process

The Context:Approach to TB Drug/Regimen Development

Drug Candidate

Pool

Phase II Phase III Single CompoundPreclinical Development

Phase I EBACompound 1

Compound 4

Compound 3

Compound 5

Compound 2

Regimen Identification in Mice

Regimen B

Identification of New DrugCandidates

Selection of Potential New Regimens

Regimen C

Regimen A

4

• Bedaquiline – a diarylquinoline– An MTB ATP synthase inhibitor – unique MOA against TB– Bactericidal against dormant and actively dividing bacteria

• MIC range 0.030 – 0.120 ug/mL– Active against Drug Sensitive and Resistant strains

• Joint development between the TB Alliance and Janssen Pharmaceutical Companies of Johnson & Johnson

• Janssen has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for the use of the TMC207 as an oral treatment, to be used as part of combination therapy for pulmonary, MDR-TB in adults. – June, 2012

Microbiology and DevelopmentBedaquiline – TMC207

5

• Efficacy– Early Bactericidal Activity (EBA)

demonstrated over 2 weeks in patients

– Phase 2 studies have demonstrated significantly greater reduction in the time to culture conversion for TMC207 versus placebo when added to an standardized background TB regimen• 80% culture conversion rate at 24

weeks when TMC207 is added to an individualized background regimen

• Well tolerated by healthy subjects and patients with pulmonary TB

• PK with tri-phasic elimination– Effective T1/2 of 24 hours; long

terminal elimination half-life

• Food Effect – approximate 2-fold increase in exposure

• Metabolism– Primarily oxidative metabolism to

M2 metabolite by CYP3A$– No in vitro induction or inhibition of

metabolism by bedaquiline

Bedaquiline – Clinical Characteristics

6

• Nevirapine– Steady state NVP did not significantly influence bedaquiline exposure

• Lopinavir/ritonavir– Exposure of bedaquiline increased by 22% and M2 exposure decreased by

41%

• Efavirenz (See: Dooley KE, et al. J Acquir Immune Defic Syndr 2012; 59:455-60)– Exposure of bedaquiline decreased by 18% with 14 days of daily efavirenz in

healthy volunteers– Bedaquiline exposure decrease may be greater with repeat dosing

• Ketoconazole – potent inhibitor of CYP3A4– Exposure of bedaquiline increased by 22%; no difference in M2

• Rifampin – potent inducer of CYP3A4– Exposure of bedaquiline decreased by 52% after 7 days rifampicin– Exposure of M2 decreased by 25%

BedaquilinePrevious Drug Interaction Studies

7

Interaction Study Bedaquiline and Rifampicin or Rifapentine

Rifapentine 600 mg qd days 20-41

+ TMC207 SD day 29

TMC207SD 400 mg

day 1

Rifampicin 600 mg qd days 20-41

+ TMC207 SD day 29

TMC207SD 400 mg

day 1

4 weeks

Period 2

Group 1N = 16

Group 2N = 16

Period 1

4 weeks

Rifapentine a rifamycin

In vitro and in vivo studies suggested induction potential of CYP 3A4 may be less than rifampin

8

N=32 subjects enrolled --29 completed

No Serious Adverse Events

1 subject with skin reaction withdrew (rifapentine group)

All AEs mild-moderate

Interaction Study – Key Study ResultsBedaquiline and Rifampicin or Rifapentine

9

N=32 subjects enrolled --29 completed

No Serious Adverse Events

1 subject with skin reaction withdrew (rifapentine group)

All AEs mild-moderate

Interaction Study – Key Study ResultsBedaquiline and Rifampicin or Rifapentine

Administration of 400 mg of TMC207 Alone (Group 1, Period 1)Administration of 400 mg of TMC207 with Rifapentine (Group 1, Period 2)Administration of 400 mg of TMC207 Alone (Group 2, Period 1)Administration of 400 mg of TMC207 with Rifampicin (Group 2, Period 2)

(Semi-Log Scale)

Source: Tables 14.2.1.1 Through 14.2.1.4

Plas

ma

TMC2

07 C

once

ntra

tion

(ng/

mL)

10

100

1000

10000

Hours from Dosing

0 48 96 144 192 240 288 336 384

Bedaquiline Alone

With Rifapentine

With Rifampicin

Mean bedaquiline concentrations

10

 Geometric LS Means of

Bedaquiline  Confidence

IntervalsTreatment Group Parameter With Inducer Alone

% Mean Ratio

90% Confidence

Rifapentine Group 1

Cmax (ng/mL)

2077 3339 62.2 (53.4, 72.5)

  AUC(0-t) (ng*hr/mL)

27612 64531 42.8 (37.8, 48.5)

Rifampicin Group 2

Cmax (ng/mL)

2240 3718 60.2 (52.0, 69.8)

  AUC(0-t) (ng*hr/mL)

25314 61209 41.4 (37.7, 45.4)

Summary of Key Plasma PK Parameters

11

 Geometric LS Means of

Bedaquiline  Confidence

IntervalsTreatment Group Parameter With Inducer Alone

% Mean Ratio

90% Confidence

Rifapentine Group 1

Cmax (ng/mL)

2077 3339 62.2 (53.4, 72.5)

  AUC(0-t) (ng*hr/mL)

27612 64531 42.8 (37.8, 48.5)

Rifampicin Group 2

Cmax (ng/mL)

2240 3718 60.2 (52.0, 69.8)

  AUC(0-t) (ng*hr/mL)

25314 61209 41.4 (37.7, 45.4)

Summary of Key Plasma PK Parameters

• Effects of both inducers on PK of M2 were similar• Cmax higher by 82-97%; AUC lower by 37 – 45%

12

Upcoming Study with bedaquiline in Regimens: NC-003

• A two week EBA study to evaluate bactericidal activity in patients with newly diagnosed pulmonary TB

• H-R-Z-E (Rifafour®) compared to various combinations of:– Bedaquiline– PA-824– Clofazimine– Pyrazinamide

• Study to start in S. Africa September, 2012

13

• Unique MOA and marked bactericidal effect on both drug sensitive and drug resistant TB infection

• Metabolized by hepatic CYP3A4 enzymes (but does note induce or inhibit these enzymes)– Both Rifampicin and Rifapentine are strong “inducers” and markedly increase

the clearance of bedaquiline• TB regimens with bedaquiline to treat HIV coinfected patients should avoid use of

rifampicin and rifapentine

• Expected to have minimal interactions of clinical importance with most anti-retroviral therapy– Not expected to affect the exposure/efficacy of ART– Care should be taken in use with ritonavir combinations until further

experience, with PK in patients, is documented

Bedaquiline – Summary of Interaction with Rifamycins and Use in Patients with TB and HIV

Thank you!