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Zhenkun Ma, Ph.D. Workshop on Advanced Design and Development of Potential Drugs against Tuberculosis August 3-5, 2009 Die Wilgers South Africa
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TB/HIV (2007)
Incidence 1.37 Million 79% in Africa Region
Active TB
Mtb Infected (~2 billion) Mtb/HIV Co-infected (~14 million) HIV Infected (~42 million)
MDR-TB/HIV (2007)
Incidence ?
MDR-TB (2007)
Incidence 0.5 Million
We have to think about how to develop new drugs that can have impact to all these patient populations
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Current Therapy
4 drugs; 6 month therapy (2RHZE + 4RH) Few drugs (including injectables); 18 months; poorly tolerated Drug-drug interactions (DDI) with ARVs 6-9 months H
Unmet Needs
Shorter, simpler therapy Totally oral, shorter and safer therapy No or low DDI, coadministration with ARVs Shorter, safer therapy
Development of shorter, simpler therapy against various forms of TB will have the greatest impact
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Novel MoA, effective against MDR- and XDR-TB Shortens therapy against both DS and M(X)DR-TB Suitable for co-administration with ARVs Orally active, once daily or less frequent dosing Adequate safety and tolerability profiles Affordability low cost of goods
A new TB treatment, if too expensive or too cumbersome to adopt, will have limited impact to TB patients and TB control
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Malate Synthase InhA Inhibitor Protease Tryptanthrin Energy Metabolism LeuRS Inhibitor RNA Polymerase Menaquinone Topo I Summit Compd Natural Products Kinase Inhibitor Focused Screening Phenotypic Screening Actinomycete Screening Fungal Metabolite Screening Target Discovery TAACF Screening Persistence Target Synthetic Lethality
Gatifloxacin Moxifloxacin
* Information based on 2008 survey by Stop TB Partnership Working Group on New Drugs
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TB Drug in Development
Linezolid
Rifapetine
Gatifloxacin Moxifloxacin
SQ109 PNU-100480
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+ ADP H AT P
Peptide
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Fluoroquinolones
DNA gyrase inhibitors interfere with DNA replication, transcription and repair Know class broad-spectrum antimicrobials; used as 2nd line therapy for MDR-TB
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Rifamycins
RNA polymerase inhibitors Cornerstone in 1st line therapy responsible for shortening therapy to 6 months High dose rifamycins may further shortening therapy (animal data)
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Oxazolidinones
Ribosome inhibitors inhibiting protein synthesis by binding to 70S initiation complex Introduced recently for the treatment of serious hospital infections
PNU-100480 (Pfizer)
Improved efficacy in mouse model Phase I trial planned
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Diarylquinolines
ATP synthase inhibitor novel MoA Highly active against both replicating and non-replicating bacteria Narrow-spectrum
Br N
HO O Me
Me N Me
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Nitroimidazoles
Bioreduction novel MoA Highly active against both replicating and non-replicating bacteria Narrow-spectrum
OPC-67683 (Otsuka)
Phase II trials for MDR-TB
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SQ-109 (Sequella)
Ethylenediamine class Phase I trials
CH3 O
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Discovery
Preclinical
Clinical
2.0% 50 14
3.2% 31 6
5.4% 19 8
8.5% 12 6
15% 7 3
26% 4 4
58% 2 2
Significant pipeline gap; more projects and high quality projects needed
(Data from: Brown, D.; Superti-Furga, G. Drug Discovery Today 2003, 8, 1067-1077)
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Highest Priority
Time to registration
Focus on high priority projects that balance impact, feasibility and time to registration
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DISCOVERY
Lead Identification Lead Optimization Preclinical
CLINICAL DEVELOPMENT
Phase I Phase II Phase III
Bi-Functional Molecules Tryptanthrines Phenotypic Screening Protein Synthesis Inhibitors GSK Whole-Cell Screening Malate Synthase Inhibitors Menaquinone Syn Inhibitors Natural Products Protease Inhibitors EM Inhibitors RNA Polymerase Inhibitors Topoisomerase I Inhibitors NITD Portfolio
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Discovery of TB Drugs
1961 Ethambutol(E) 1992 Gatifloxacin 2000 PA-824 2005 TMC-207 2006 OPC-67683
1996 Moxifloxacin
1960s PAS replaced by E: S/H/E 18 months of therapy 1952 First regimen: S/PAS/H 24 months of therapy 1946 First randomized trial : S Monotherapy led to S resistance
2010s Potential New Regimen 2-3 months, oral therapy? 1980s S replaced by Z: H/R/Z/E 6-8 months , oral therapy
Development of Regimens
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Some Thoughts
think about how to develop new TB therapies that can benefit all patient populations develop new TB drugs in the context of regimens, not single drugs keep adoption in mind new drugs without being adopted will have limited impact find the right balance between impact, feasibility and time to patience focus on targets or lead series that can have activity against both drug resistance and persistence
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