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Global TB Drug Pipeline: The Need and the Reality
Zhenkun Ma, Ph.D.
Workshop on Advanced Design and Development of Potential Drugs against Tuberculosis
August 3-5, 2009Die WilgersSouth Africa
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The Landscape of TB Diseases – A Simplistic View
Mtb Infected(~2 billion)
Mtb/HIVCo-infected(~14 million)
Active TB
Total Active TB (2007)Incidence 9.27 Million TB/HIV (2007)
Incidence 1.37 Million79% in Africa Region
MDR-TB (2007)Incidence 0.5 Million
MDR-TB/HIV (2007)Incidence ?
► We have to think about how to develop new drugs that can have impact to all these patient populations
WHO Report 2009Global Tuberculosis Control : Epidemiology, Strategy,
Financing
HIV Infected(~42 million)
M(X)DR Mtb Infected
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Current TB Therapy and Unmet Needs
* Rifampin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E)
Forms of Disease Current Therapy Unmet Needs
Drug-SusceptibleDS-TB
4 drugs; ≥6 month therapy (2RHZE + 4RH) Shorter, simpler therapy
Drug-ResistantM(X)DR-TB
Few drugs (including injectables); ≥18 months;poorly tolerated
Totally oral, shorter and safer therapy
TB/HIVCo-Infection
Drug-drug interactions (DDI) with ARVs
No or low DDI, co-administration with ARVs
Latent TBInfection 6-9 months H Shorter, safer therapy
► Development of shorter, simpler therapy against various forms of TB will have the greatest impact
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What We Need from a New TB Treatment?
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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Global TB Drug R&D Pipeline
GatifloxacinMoxifloxacin
TMC207OPC-67683PA-824Rifapetine
SQ109PNU-100480Linezolid
TBK-613CPZEN-45SQ641SQ73SQ609DC-159a
Preclinical DevelopmentDiscovery Clinical Development
NitroimidazoleMGIRiminophenazineMultifunctionalDipiperidineHomopiperazineTL1 InhibitorAZ Compd
InhA InhibitorTryptanthrinLeuRS InhibitorMenaquinoneSummit CompdKinase Inhibitor
Malate SynthaseProteaseEnergy MetabolismRNA PolymeraseTopo INatural ProductsFocused ScreeningPhenotypic ScreeningActinomycete ScreeningFungal Metabolite ScreeningTarget DiscoveryTAACF ScreeningPersistence TargetSynthetic Lethality
* Information based on 2008 survey by Stop TB Partnership Working Group on New Drugs
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TB Drug in Development
GatifloxacinMoxifloxacin
RifapetineLinezolidExisting drugsrepurposed for TB
TMC207OPC-67683PA-824
SQ109PNU-100480
New drugsdeveloped for TB
Meropenem/Clavulanate
TBK-613AZD-4563CPZEN-45BTZ-043
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MoA of TB Drugs in Development
* Not orally active
DNA
mRNA
ReactiveSpecies
Peptide
H+ADP ATP
Bio-reduction
Multiple TargetsPA-824OPC-67683
DNA GyraseGatifloxacinMoxifloxacinTBK-613
RNA PolymeraseRifapentine
Ribosome LinezolidPNU-100480AZD-4563
ATP SynthaseTMC-207
Cell-WallSynthesis
SQ-109Meropenem-
Clavulanate*CPZEN-45*BTZ-043
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Fluoroquinolones
DNA gyrase inhibitors – interfere with DNA replication, transcription and repairKnow class broad-spectrum antimicrobials; used as 2nd line therapy for MDR-TB
Gatifloxacin (OFLOTUB Consotium)• Phase III trials for DS• Replacing ethambutol from standard
regimen• Study potential for shortening therapy
to 4 months
Moxifloxacin (REMox/Bayer-TB Alliance)• Phase III trials for DS• Replacing ethambutol or isoniazid from
standard regimen• Study potential for shortening therapy to 4
months
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RifamycinsRNA polymerase inhibitorsCornerstone in 1st line therapy – responsible for shortening therapy to 6 monthsHigh dose rifamycins may further shortening therapy (animal data)
Rifapentine (Various groups)• Phase I/II trials • Daily or high-dose rifapentine-containing regimens• Study potential for shortening therapy
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Oxazolidinones
Ribosome inhibitors – inhibiting protein synthesis by binding to 70S initiation complexIntroduced recently for the treatment of serious hospital infections
Linezolid (TBTC Study 30)• Phase I/II trials planned• Daily low dose for MDR-TB
PNU-100480 (Pfizer)• Improved efficacy in mouse model• Phase I trial planned
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Diarylquinolines
ATP synthase inhibitor – novel MoAHighly active against both replicating and non-replicating bacteriaNarrow-spectrum
TMC-207 (Tibotec-TB Alliance)• Phase II trial for MDR-TB• Trials for DS-TB planned
N
Br
OMe
NMe
Me
HO1
2
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Nitroimidazoles
Bioreduction – novel MoAHighly active against both replicating and non-replicating bacteriaNarrow-spectrum
PA-824 (TB Alliance)• Highly efficacious in EBA trials• Phase II trials on going
OPC-67683 (Otsuka)• Phase II trials for MDR-TB
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Cell-Wall Synthesis Inhibitors
SQ-109 (Sequella)• Ethylenediamine class• Phase I trials
Meropenem/Clavulanate(Albert Einstein College of Medicine/NIH)• β-Lactam class• Preclinical• Injectable
BTZ-043 (NM4TB Consortium)• Benzothiazinone class• Inhibit decaprenylphosporyl-β-
D-ribose 2’-epimerase (DprE)• Preclinical
CPZEN-45 (Lilly Partnership)• Semisynthetic• Preclinical• Injectable
N
SNO2
F3CO
NO
O
CH3
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Is the Global Pipeline Strong Enough?
# Projects for1 Registration 24712193150
CumulativeSuccess Rate 58%26%15%8.5%5.4%3.2%2.0%
Global TBDrug Portfolio
24368614
(Data from: Brown, D.; Superti-Furga, G. Drug Discovery Today 2003, 8, 1067-1077)
Discovery Preclinical Clinical
►Significant pipeline gap; more projects and high quality projects needed
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Considerations for Resource Utilization
Ability to address unmet
needs
Scientific/technical feasibility
Time to registration
► Focus on high priority projects that balance impact, feasibilityand time to registration
Highest Priority
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Current TB Alliance Portfolio
Lead Identification
Lead Optimization Preclinical Phase I Phase II Phase III
DISCOVERYDISCOVERY CLINICALCLINICAL DEVELOPMENTDEVELOPMENT
GSK Whole-Cell Screening
Bi-Functional Molecules
Protein Synthesis Inhibitors
InhA Inhibitors
Mycobact. Gyrase InhibitorsNitroimidazoles
Quinolone TBK-613
Riminophenazines
PA-824Moxifloxacin
TB ALLIANCE TB ALLIANCE PROGRAMSPROGRAMS
Phenotypic Screening
Protease Inhibitors
Topoisomerase I Inhibitors
Tryptanthrines
RNA Polymerase InhibitorsEM Inhibitors
NITD Portfolio
Natural ProductsMenaquinone Syn InhibitorsMalate Synthase Inhibitors
TMC-207
Diarylquinolines
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Is A 2-Month or Even Shorter Therapy Possible?Discovery of TB Drugs
Development of Regimens
1948PAS
1946 – First randomized trial : SMonotherapy led to S resistance
1943 Streptomycin(S)
1952 Isoniazid(H)
1963Capreomycin
1954Pyrazinamide(Z)
1961Ethambutol(E)
1952 – First regimen: S/PAS/H24 months of therapy
1960s – PAS replaced by E: S/H/E18 months of therapy
1970s – Addition of R: S/H/R/E9-12 months of therapy
1980s – S replaced by Z: H/R/Z/E6-8 months , oral therapy
1955Cycloserine
1957Kanamycin
1960Ethionamide
1963Rifampicin(R)
2010s – Potential New Regimen2-3 months, oral therapy?
1992Gatifloxacin
1996Moxifloxacin
2000PA-824
2005TMC-207
2006OPC-67683
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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”