TB Drug Co-Development Roundtable:
TMC207 (bedaquiline)
CPTR meeting Oct 04, 2012
Chrispin Kambili, M.D.
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Why MDR?
• Current SOC in DS TB:
– 95% effective
MDR TB is a time bomb.*
– Inexpensive (USD 36/regimen)
• TMC 207 interaction w/rifampicin
* Margaret Chan, WHO Director General, Beijing, 2009
• MDR-TB: greater medical need
– Current SOC only ~60% effective
– Requires 5-6 second line drugs to create a regimen which is more expensive,
less effective, and associated with more side effects.
– Long treatment duration (typically 18-24 months)
– Huge fiscal burden to public health systems
Bedaquiline Development Plan
2004 2005 2006 2007 2008 2009
Non
Clinical
2011
2012
2013
2014
2015
Non-Clinical
Phase I
11 trials
C202
75 pts
Phase II
2010
C208 Stage 1
MDR-TB pts
C208 Stage 2,
MDR-TB pts
C209, 233 MDR,
pre-XDR, XDR-TB pts
Phase III
C210, ~600 MDR ,
pre-XDR-TB pts
2016
Intro: Clinical Development Status PhIIb
•
•
Key Phase I PK findings
McNeeley D, et al. IUATLD 2006. oral
Van Heeswijk et al., ICAAC 2007, A-780
Van Heeswijk, et al., IUATLD 2007, PS-71358-11
Van Heeswijk et al, IAS 2010, WEPE0097
Van Heeswijk et al, IAS 2011, MOPE172
Rustomjee et al., AAC 2008, 52, 2832
Diacon et al., NEJM 2009, 360, 2397
McNeeley et al, IUATLD, 2010 Session N.00189
•
Linear PK
•
Positive food effect (2-fold increase in exposure)
•
Administration of rifampin lowers TMC207 levels 50% (CYP3A4)
•
Administration of LPV/r modestly increased TMC207 exposure (22%).
•
Administration of NVP does not affect TMC207 exposure
•
Long terminal elimination half-life (steady state levels not achieved by day 14)
Key Phase II findings
•
TMC207-C202: Proof of Principle demonstrated in a one-week EBA trial
•
TMC207-C208 Stage I: TMC207 added to a 5-drug BR increased culture conversion by
~40% at 8 weeks in MDRTB
–
TMC207-C208 Stage II: in a placebo controlled trial, TMC207 added to a 5-drug BR
resulted in faster culture conversion (12 wks vs 18 wks; p = 0.003) and higher
proportion of sputum culture conversions (79% vs 58%; p=0.008) at 24 weeks .
Objectives for Development of
New MDR-TB Therapy
More
Effective
Treatment
Improved
Safety /
Tolerability
Shortening
Treatment
Duration
Simplified
Regimens
4
Dec 2012: TMC207-C210: Phase III superiority design: A
new short course regimen in MDR-TB
BR = K(4m)PrHLECZ (6m) + LECZ (3m)
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We hope to…
Photo courtesy of James Nachtwey
• Change an antiquated, cumbersome,
treatment paradigm
• Contribute to the realization of global
ambitions to eradicate TB by 2050
• Forge a sustainable model(s) to
develop medicines that address
neglected diseases
• Save the lives of nearly 150,000
people who die each year from MDRTB around the world
Current status
•June 29, 2012: Janssen submitted a New Drug Application
(NDA) to the U.S. Food and Drug Administration (FDA)
seeking accelerated approval for bedaquiline (TMC207), as
part of combination therapy for pulmonary multi-drug
resistant tuberculosis (MDR-TB).
– This is the first NDA to seek an indication for MDR-TB.
– Priority review has been granted
•August 31, 2012: Janssen announced submission of a
Marketing Authorisation Application to the European
Medicines Agency (EMA) seeking conditional approval for
bedaquiline (TMC207), to be used as part of combination
therapy for pulmonary, multi-drug resistant tuberculosis
(MDR-TB) in adults.
FDA Advisory Committee:
FDA Advisory committee meeting to discuss TMC207 (bedaquiline)
scheduled for Nov 28, 2012
Thank you!
Questions?