TB Drug Co-Development Roundtable: TMC207 (bedaquiline) CPTR meeting Oct 04, 2012 Chrispin Kambili, M.D. To edit footers: "insert tab>header and footer" and apply to all 0 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) 5 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?