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

Global TB Drug Pipeline: The Need and the RealityZhenkun Ma, Ph.D. Workshop on Advanced Design and Development of Potential Drugs against Tuberculosis August 3-5, 2009 Die Wilgers South Africaw

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The Landscape of TB Diseases A Simplistic ViewTotal Active TB (2007)Incidence 9.27 MillionWHO Report 2009 Global Tuberculosis Control : Epidemiology, Strategy, Financing

TB/HIV (2007)Incidence 1.37 Million 79% in Africa Region

Active TBMtb Infected (~2 billion) Mtb/HIV Co-infected (~14 million) HIV Infected (~42 million)

M(X)DR Mtb Infected

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 populationsw www.tballiance.org

Current TB Therapy and Unmet NeedsForms of DiseaseDrug-Susceptible DS-TB Drug-Resistant M(X)DR-TB TB/HIV Co-Infection Latent TB Infection

Current Therapy4 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 NeedsShorter, simpler therapy Totally oral, shorter and safer therapy No or low DDI, coadministration with ARVs Shorter, safer therapy

* Rifampin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E)

Development of shorter, simpler therapy against various forms of TB will have the greatest impactw www.tballiance.org

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 controlw www.tballiance.org

Global TB Drug R&D PipelineDiscovery Preclinical Development Clinical Development

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

Nitroimidazole MGI Riminophenazine Multifunctional Dipiperidine Homopiperazine TL1 Inhibitor AZ Compd

TBK-613 CPZEN-45 SQ641 SQ73 SQ609 DC-159a

SQ109 PNU-100480 Linezolid

TMC207 OPC-67683 PA-824 Rifapetine

Gatifloxacin Moxifloxacin

* Information based on 2008 survey by Stop TB Partnership Working Group on New Drugs

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TB Drug in Development

Existing drugs repurposed for TB New drugs developed for TB

Meropenem/ Clavulanate TBK-613 AZD-4563 CPZEN-45 BTZ-043

Linezolid

Rifapetine

Gatifloxacin Moxifloxacin

SQ109 PNU-100480

TMC207 OPC-67683 PA-824

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MoA of TB Drugs in DevelopmentDNA Gyrase Gatifloxacin Moxifloxacin TBK-613

Multiple Targets PA-824 OPC-67683Bioreduction Reactive Species DNA

Cell-Wall Synthesis SQ-109 MeropenemClavulanate* CPZEN-45* BTZ-043

RNA Polymerase RifapentinemRNA

+ ADP H AT P

Peptide

ATP Synthase TMC-207

Ribosome Linezolid PNU-100480 AZD-4563

* Not orally active

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FluoroquinolonesDNA gyrase inhibitors interfere with DNA replication, transcription and repair Know 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 inhibitors Cornerstone in 1st line therapy responsible for shortening therapy to 6 months High 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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OxazolidinonesRibosome inhibitors inhibiting protein synthesis by binding to 70S initiation complex Introduced 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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DiarylquinolinesATP synthase inhibitor novel MoA Highly active against both replicating and non-replicating bacteria Narrow-spectrum

Br N

HO O Me

1

2

Me N Me

TMC-207 (Tibotec-TB Alliance) Phase II trial for MDR-TB Trials for DS-TB planned

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Nitroimidazoles

Bioreduction novel MoA Highly active against both replicating and non-replicating bacteria Narrow-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

CPZEN-45 (Lilly Partnership) Semisynthetic Preclinical InjectableF3C O O NO2 S N N

CH3 O

Meropenem/Clavulanate (Albert Einstein College of Medicine/NIH) -Lactam class Preclinical Injectable

BTZ-043 (NM4TB Consortium) Benzothiazinone class Inhibit decaprenylphosporyl-D-ribose 2-epimerase (DprE) Preclinical

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Is the Global Pipeline Strong Enough?

Discovery

Preclinical

Clinical

Cumulative Success Rate # Projects for 1 Registration Global TB Drug Portfolio

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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Considerations for Resource UtilizationScientific/technical feasibility

Highest Priority

Ability to address unmet needs

Time to registration

Focus on high priority projects that balance impact, feasibility and time to registrationw www.tballiance.org

Current TB Alliance PortfolioTB ALLIANCE PROGRAMSMoxifloxacin PA-824 TMC-207 Quinolone TBK-613 Nitroimidazoles Mycobact. Gyrase Inhibitors Riminophenazines InhA InhibitorsDiarylquinolines

DISCOVERYLead Identification Lead Optimization Preclinical

CLINICAL DEVELOPMENTPhase 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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Is A 2-Month or Even Shorter Therapy Possible?1952 Isoniazid(H) 1955 Cycloserine

Discovery of TB Drugs1961 Ethambutol(E) 1992 Gatifloxacin 2000 PA-824 2005 TMC-207 2006 OPC-67683

1943 1957 1954 Streptomycin(S) Pyrazinamide(Z) Kanamycin 1948 PAS

1960 1963 Ethionamide Capreomycin 1963 Rifampicin(R)

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

1970s Addition of R: S/H/R/E 9-12 months of therapy

Development of Regimens

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Some Thoughtsthink 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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