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Page 1: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

w www.tballiance.org

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

Page 2: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 3: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 4: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 5: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 6: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 7: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 8: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 9: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 10: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 11: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 12: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 13: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 14: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 15: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 16: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 17: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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

Page 18: Global TB Drug Pipeline- The Need and the Reality- From the TB Alliance

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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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