xdr symposium fourie new diagnostics drugs

8/6/2019 XDR Symposium Fourie New Diagnostics Drugs

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New diagnostics and drugs

for TB

Bernard Fourie PhDMedicine in Need (MEND)[email protected]


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Symptoms X-ray Smear Culture SolidCulture Liquid

DSTMolecular Probes

D e v e

l o p e

d C

o u n

t r i e s

Developing Countries

Changing Trends in TB DiagnosticsChanging Trends in TB Diagnostics

Growing Shift

Courtesy: S Sidiqui (Becton-Dickson)


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Bacteriology

Realization that culture is the only definitive diagnosisCulture is necessary for ID and ASTGoing to remain as a Gold Standard for a long timeRapid Turnaround Time is critical

More focus on liquid media



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CDC GuidelinesAFB Smear Results within 24 hours --------Culture Results report ave. 2 Weeks -------- Yes*Complete culture/Identification 3 Weeks -----Yes*Complete Culture/ID/DST in 4 weeks -------- Yes*QC, Method, Media and Reagents ------------ Yes*

*Role of BACTEC in meeting the guidelines



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FINDs Diagnostic Pipeline


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2006

ReferenceReferenceLabLab

PeripheralPeripheralLabLab

FIND Product Deliverables 2006FIND Product Deliverables 2006

--20132013

ClinicClinic

Health postHealth post

2007 2008 2009 2010 2011 2012 2013

% A

c c e s s

af t er

5 y e ar s95%

70%

10-40%

L i q u i d c

u l t u r e

M T B & D

S T

P h a g e b

a s e d

r e s i s t a n

c e t e s t

A u t o m a

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N A A T

L E D F l u

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M i c r o s

c o p y

P O C N A A

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b a s e d

L A T F l o

w

S p e c i a t

i o n

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U r i n a r y

N A A T

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B

s t r i p t e

s t


7/27

FIND/TDR Trial in Peru*

Comparison of FASTPlaque-Response test,INNO Lipa test, and direct LJ DSTGold standard: indirect DST on LJ mediumCosting sub-studyEnrolled newly diagnosed and retreatmentpatients with SS+ PTBAdditional 400 SS+ for FP sub-study

Discrepant analysis for all RIF-R tests byrepeat DST and rpo sequencing*IMT Cayetano Heredia, Inst Nat Salud, Disa Lima Norte


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FAST Plaque-Response

Specimen processing(NALC-NaOH)

Sputum collection o/n incubation rifampicin

F A S T Plaque- Response

assay procedure

Interpretation of results


9/27

FIND/TDR Trial in PeruPreliminary Results

Performance Characteristics for RIF-R *

Test Sens Spec PPV NPVINNO 93% 99% 93% 99%FP-1 95% 96% 79% 99%

FP-2 ** 94% 100% 100% 99%D-LJ 95% 99% 95% 99%

*Subject to change pending results of discrepant analysis**Based on results 135 tests with complete results


10/27

FIND/TDR Trial in PeruPreliminary Results

Performance Characteristics for MDR TB *

Test Sens Spec PPV NPVINNO 94% 97% 84% 99%FP-1 94% 95% 70% 99%

D-LJ 97% 98% 85% 100%

*Subject to change pending results of discrepant analysis


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Species Identification

Rapid identification needed for culture-based systems, especially broth cultureCurrent technologies, e.g., DNA probes,PCR, HPLC expensiveFIND working with TAUNS/BD to evaluateperformance of Capilia TB test in MGIT casefinding demonstration projects


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Capilia TB Assay

Immunochromatic assay based on detection of MPB64, present in M. tb complex but not MOTT orsome BCG strainsConsists of nitrocellulose membrane with anti-MPB64mouse antibodies conjugated with colloidal goldWith antigen-antibody reaction, see red-purple bandwithin 15 minutesEvaluated for 172 mycobacterial isolates (119 M.tbcomplex): 92% sensitivity, 100% specificity*

3 false negatives with MPB64 gene mutation

*D. Hilleman, et al. IJTLD 2005;9:1409-11


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Molecular Methods

Good performance characteristicsRapidSensitive (approaching culture)Specific

Expensive and requires sophisticatedtechnologyFIND working with partners with coretechnology and platform suitable fordeveloping country use


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LAMP

Closed systemIsothermalRapidMultiprimer

Visible readout


15/27

MTB / Rif-resistance test

Workflow sputum simple 1-step external sample prep. procedure time-to-result < 2 h throughput: > 16 tests / day / module no need for biosafety cabinet integrated controls true random access

Performance specific for MTB sensitivity better than smear, similar to culture detection of rif-resistance via rpoB gene

Product and system design test cartridges for GeneXpert System several GeneXpert modules can be combined

in 1 workstation swap replacement of detection unit ~1 day technician training for non-mycobacteriologists

cartridge

GeneXpert Systemmodule

MTB


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FIND Evaluation Studies of Interferon-gamma release assay (IGRA)

IGRAs have been shown to be as sensitiveand more specific than the TST fordiagnosis of latent TB infection (LTBI)Limited data suggest that IGRAs performwell in HIV-infected personsFIND supporting two studies nested inCREATE projects to help define role of IRGAs in diagnosing LTBI in HIV+ persons:

THRio: 3000 patients in HIV/AIDS care clinicsZAMSTAR: 10,000 HIV+/- adult TB contacts


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Interferon- based tests

Whole Blood Assay T Cell Test

QuantiFERON-TB GoldCellestis T Spot TB AssayOxford Immunotech

Whole blood exposed to

ESAT-6 and CFP-10 TB antigensInterferon- g Production Quantified

WBCs separated, Exposed to

ESAT-6 and CFP-10 antigens,Interferon-g producing cells counted


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The Interferon- Assays

Pros

Differentiates TBinfection from BCGSuitable for repeat. No

booster phenomenon Objective results, invitro procedureResults available in 24hoursNo patients second

visitSpecificity (~99%)Sensitivity (90s%)

Cons

Does not differentiatebetween latent TB andactive diseaseMultiple assays stepsBlood drawing, transport,test within 12-hoursTechnique dependentEquipment requirements(Spec. or reader,

incubator, centrifuge,pipetter)Refrigerated reagentsHigh cost

Useful in low prevalence settings and high-burden HIV


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Global TB Drug Portfolio: Sep 2005

Discovery Preclinical Clinical Testing

Dihydrolipoamide AcyltransferaseInhibitorsCornell University, NIAID

InhA InhibitorsGlaxoSmithKline, TB Alliance

Isocitrate Lyase Inhibitors (ICL)

GlaxoSmithKline, TB Alliance

MacrolidesTB Alliance, University of Illinois at Chicago

Methyltransferase Inhibitor sAnacor Pharmaceuticals

Translocase I Inhibito rs

Sequella Inc., Sankyo

Synthase Inhibitor FAS20013FASgen Inc.

MoxifloxacinBayer Pharmaceuticals, CDC TBTC, JohnsHopkins University, NIAID TBRU, TB Alliance

Diarylquinoline TMC207Johnson & Johnson

Nitroimidazo-oxazole OPC-67683

Otsuka

Natural Product s ExplorationBIOTEC, California State University, ITR, NIAID,TAACF, University of Auckland

Dipiperidines (SQ-609)Sequella Inc.

Diamine SQ-109Sequella Inc.

GatifloxacinOFLOTUB Consortium, Lupin, NIAID TBRU,Tuberculosis Research Centre, WHO TDR

Cell Wall Inhibitor sColorado State University, NIAID

Novel Antibiotic ClassGlaxoSmithKline, TB Alliance

Picolinamide ImidazolesNIAID, TAACF )

Pleuromutilins

GlaxoSmithKline, TB Alliance

QuinolonesKRICT/ Yonsei University, NIAID,TAACF, TB Alliance

Screening and Target IdentificationAstraZeneca

Thiolactomycin AnalogsNIAID, NIH

Nitroimidazole AnalogsNIAID, Novartis Institute for Tropical Diseases,TB Alliance

NitrofuranylamidesNIAID, University of Tennessee

Pyrrole LL-3858Lupin Limited

Nitroimidazole PA-824Chiron Corporation, TB Alliance

Non-Fluorinated QuinoloneTaiGen

CarboxylatesTB Alliance, Wellesley College

Nitroimidazo-oxazole Back-upOtsuka

STOP TB New Drugs Working Group


20/27

Clinical Development Pipeline

Lupin Ltd.Phase ILL-3858

TB AlliancePhase IPA-824

Otsuka Pharmaceutical Co., Ltd.Early Bactericidal ActivityOPC-67683

Johnson & Johnson (Tibotec)Early Bactericidal ActivityTMC 207

Bayer; TB Alliance; CDC ;University College of London;Johns Hopkins UniversityPhase II / IIImoxifloxacin

EC / OFLOTUB Consortium;IRD * ; WHO TDR ; Lupin Ltd.Phase IIIgatifloxacin

Sponsor / CoordinatorDevelopment StageCompound

* Institut de Recherche pour le Developement World Health Organization, Tropical Disease Research Centers for Disease Control and Prevention


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Pipeline Compounds

2005 2006 2007 2008 2009 2010 2011 2012

Mox i f lox ac in I I I I I NDAGat i f lox ac in I I I I I NDAJ & J I /I I I I I NDA

Ot suk a I I /I I I I /I I I NDALupin I I /I I I I /I I I NDAPA-824 I I I I /I I I NDASequel la I I I I /I I I NDA

Identify and develop best combination regimen(s)

2013


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Short-/Medium-term prospectsMore potent fluoroquinolones

MoxifloxacinGatifloxcinLevofloxacin

CapreomycinInjectable(Inhaled dry-powder formulation in advanced development)

PASTabletsGranular with acid-resistant outer coating

Clofazimine

Capsules(Liposomal)(Other members of class high potency against MDR)


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Ratio C max on MIC 90 of the mainfluoroquinolones

Drug (mg) C max (g/ml)

MIC90 Cmax /MIC90

Ciprofloxacin 500 1-2 1.0 1-2Ofloxacin 400 4 2.0 2Levofloxacin 500 5-7 1.0 5-7Sparfloxacin 200 1.1 0.5 2Moxifloxacin 400 4-5 0.5 8-10

Ref. : Hooper etRef. : Hooper et WolfsonWolfson AAC 1985 ; 28 : 716 AAC 1985 ; 28 : 716 --721 ; Hooper721 ; Hooper ClinClin. Inf. Dis. 2000 ; 30 : 243. Inf. Dis. 2000 ; 30 : 243 --254 ;254 ; LubaschLubasch et al., AAC 2000 ; 44 : 2600et al., AAC 2000 ; 44 : 2600 --26032603

23


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Moxifloxacin in treatment of MDRTB*

Activity of the OFX-containing third-line regimenagainst M. tuberculosis was rather weak in vivo,whereas when OFX was replaced by MXF, 9months of treatment with a modified third-lineregimen (MXF/AMK/ETH/PZA) displayed

bactericidal activity comparable to that of 6months of treatment with the standard regimen inmice

*Veziris N et al. Antimicrob Agents Chemother. 2003 Oct;47(10):3117-22


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Gatifloxacin, moxifloxacin or ofloxacin replacing

ethambutol in conventional HRZE regimen Conversion of sputum during 1 st two months*

Log rank test

2 (3)=10.69

p= 0.0136

*Preliminary data presented at IUATLD Conference, Paris 2005Oflotub Consortium Study supported by EC and WHO/TDR


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Survival of HIV-associated MDRTB NYC Treatment(Turret, NEJM 1995)

xdr symposium fourie new diagnostics drugs

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