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TB Drug Co-Development Roundtable: TMC207 (bedaquiline)
Chrispin Kambili, M.D.
CPTR meeting Oct 04, 2012
1To edit footers: "insert tab>header and footer" and apply to all
Why MDR?
• Current SOC in DS TB:– 95% effective– Inexpensive (USD 36/regimen)
• TMC 207 interaction w/rifampicin
• 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
MDR TB is a time bomb.*
* Margaret Chan, WHO Director General, Beijing, 2009
Bedaquiline Development Plan
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
Non-Clinical
11 trials
C20275 pts
C208 Stage 1 MDR-TB pts
C209, 233 MDR, pre-XDR, XDR-TB pts
Phase II
Phase I
Phase III
C210, ~600 MDR , pre-XDR-TB pts
Non Clinical
C208 Stage 2, MDR-TB pts
Intro: Clinical Development Status PhIIb
• Key Phase I PK findings• 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 .
McNeeley D, et al. IUATLD 2006. oralVan 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, 2832Diacon et al., NEJM 2009, 360, 2397
McNeeley et al, IUATLD, 2010 Session N.00189
More Effective
Treatment
Improved Safety /
Tolerability
Shortening Treatment Duration
Simplified Regimens
5
Objectives for Development of New MDR-TB Therapy
Dec 2012: TMC207-C210: Phase III superiority design: A new short course regimen in MDR-TB
6BR = K(4m)PrHLECZ (6m) + LECZ (3m)
• 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 MDR-TB around the world
We hope to…
Photo courtesy of James Nachtwey
• 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.
Current status
FDA Advisory Committee:
FDA Advisory committee meeting to discuss TMC207 (bedaquiline) scheduled for Nov 28, 2012