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Beyond Xpert: The fast-followers and the NAAT pipeline
David [email protected]
7th July 2014 Adv. TB Dx CourseMcGill UniversityMontreal
The Emerging TB Dx technology Landscapes
Annual or semi-annual reviews focusing on the status of the TB Dx pipeline
Peer reviewed articles: specific focus on technologies, performance parameters and placement
Slide 2
The Fast Follower NAATs…What we want to see
• Choice • More robust tech• Cheaper• Perf. As good or
better than current tools
• A selection of Tools that meet varied market needs
COMPETITION!Slide 4
The Fast Followers…What we currently see
Xpert MTB/RIF endorsed in 2010
2013 Manual NAAT still pendingFurther STAG review, Q4 2014/Q1 15)2015
2013 MTBDRsl2013 MDRTBplus v2.0?
Fast Followers = Emerging TB Dx technologiesSlide 5
Point of care (or point of treatment?)
Source: World Health Organization. Diagnostics for tuberculosis: Global demand and market potential (2006).
Slide 7
The UNITAID 2014 Pipeline
1. All NAAT platforms were considered for TB Dx and MDR/XDR, not just ones described for use in peripheral settings
2. Screened NIH funding to developers/academic groups
3. Reached out to over 190 companies or research groups (67 companies, 182 products)
4. We asked them to complete a basic questionnaireSlide 8
Questionnaire Components
1. Intended Use2. Primary market(s)3. Price4. Performance5. Operational Characteristics6. Regulatory Approval And Manufacturing
Information
Slide 9
NAAT Products IdentifiedCompaniesProducts
3292
Setting Lab TB Dx MDR/XDR Integrated Partially integrated
Open
Reference 18 6 3 3 10 5
Intermediate 63 18 15 9 25 29
Peripheral 11 3 1 1 6 5
CompaniesProducts
1228
Setting Lab TB Dx MDR/XDR Integrated Partially integrated
Open
Reference 1 1 0 0 1 0
Intermediate 10 7 3 7 0 3
Peripheral 17 6 6 15 3 0
Slide 10
NAAT at the Upper Laboratory Levels
Larger laboratories often get ‘ignored’:
High throughput and/or high complexity tests can be performed TB Dx and MDR/XDR screening is neededImproved Dx and analysisSample prep automatedCost effective at scale
Existing platforms used in USA and beyondSlide 11
Existing High Throughput TB Dx Tools
Genprobe (USA) Amplified Mycobacterium Tuberculosis Direct (AMTD) assay, US FDA (1995), semi-automated, batch processing TMA amplification. 50 tests/5.5. hrs.
BD (USA) ProbeTec ET Direct TB, semi-automated, SDA, 150 tests/day
Roche (Switzerland), COBAS® TaqMan® MTB, real time PCR, internal control flags, UNG to prevent test contamination, bar coding for tracking. Automated systems. 44 tests/3 hrs.
Abbott m2000, real time PCR 94 samples in 5 hrs.
Slide 12
Platform Agnostic Technologies.Many laboratories have real time PCR capability BUT many TB assays described as technology dependent
CapitalBio Corp., Qiagen, Zeesan (all China) and Seegene (Korea) have developed CE-IVD marked TB assays that are less platform specific
Mycobacteria Real-time PCR, 36 tests /4 hourscareTB-RT PCR kit, 90 tests/6 hoursSeegene Anyplex II™ MTB/MDR/XDRDual priming oligo (DPO), Tagging Oligonucleotide Cleavage Extension (TOCE) and Real Amplicon Detection (READ)
Slide 13
Seegene ProductsAnyplex II™ MTB/MDR/XDR Detection
Key features1. Simultaneous Screening of MTB infection and drug resistance2. Direct and positive based detection of drugR mutations
27 MDR and 13 XDR3. Real time PCR sensitivity and specificity (DPO/TOCE)
Anyplex II™ MTB/NTM/MDR-TB DetectionKey features1. Simultaneous determination of MTB and NTM2. For MTB, add an additional 40 minutes for MDR3. Direct and positive based detection of drugR mutations
21 MDR4. Real time PCR sensitivity and specificity (DPO/READ)
Comparatively rapid (90 tests/6 hours) and platform ‘agnostic’Slide 14
NAAT based tools for MDR/XDR TB
Source: Barnard et al., 2009 AJRCC
Line Probe Assays: Hybridization assays for MTB, MDR and XDR
AID (Germany) 3 products*Fuji Rebio (Belgium) 2 productsHain Lifescience (Germany) 5 products*Nipro (Japan) 4 productsVircell (Spain) 2 productsYD Diagnostics (R. Korea) 5 products*
*Offer hyb. stations and scanners
Slide 15
Microarrays for TB Dx/MDR/XDRScreening of wider numbers of genetic markersSeveral platforms exist with TB Dx/MDR testsPartially integratedAkonni, AutoGenomics, CapitalBio and Veredus48 tests per 6.5 hrs.10-15 tests per 8 hrs.$80k - 240K…
Slide 16
Xpert MTB/RIF Refresher
2 min 15 min 1 min <2 hrs.Adapted from Scott, 2010
Bufferchambers
PCR tube
Syringebarrel
Cartridgebase
Cap
Cartridgebody
Gasket
Valvebody
Nested PCR/real time PCR6 color detection5 color probe determination
TB (rpoB)RifR (rpoB)
Automated result scoringReaction waste stored in cartridgeHIV VL in developmentNew MDR assay in development
Source: Niemz and Boyle, 2012Slide 17
Not all Microscopy Cenrters are Equal…
Source: TB Alert Source: PATH
Although both are functional areas there’s fundamental differences:Space, staff, and infrastructure all affect ability to perform NAAT What NAATs are available to meet all peripheral settings?Slide 18
The First Wave of Emerging Technologies for LRS
Four technologies are currently in evaluationMost developed privately via Dx start ups:
1. *Epistem – Genedrive M.tb iD2. FIND/Eiken – Loopamp MTBC3. *Molbio - Truelab™ M.tb4. *Ustar - NATeasy TB
All positioned to compete with Xpert based on cost and simplified technology
* Development efforts focused on entry to private or local markets
Slide 19
Epistem Genedrive M.tb iDEpistem – Manchester, UK based companyRapid detection of MTB and RifR via a novel approaches to sampleprep, and real time PCR
Novel paper based Extraction device
3 reaction amplificationCartridgeLyophilized reagentsHigh quality plastics
Single unit Battery powered deviceNovel engineering reduces power needsReal time PCR with high res melt curve analysis
Slide 20
Epistem Genedrive M.tb iDProcess flow
Add sputum to lysis cartridgeDry for 10 minutesPunch out 3 paper discs
Add to 3 reaction chambers with 20 µL water
Insert cartridge intodevice, press startbutton
10 min 1 min 45 min
CE-IVD marked, DCGI IndiaDistributors in place for Asia (Xcelris)Manufacturers in place (US and China)Limited peer reviewed evidence
Slide 21
FIND/Eiken – Loopamp MTBC
Source: UNITAID TB Dx pipeline semi annual report 2012
1. PDP between FIND and Eiken Chemical Corp (Japan)2. ‘Open’ platform3. Loop mediated amplification (LAMP) assay for TB4. Isothermal amplification , simplified yet rapid and sensitive test5. Manual, minimally instrumented sample preparation, batch
capable
Slide 22
FIND/Eiken – Loopamp MTBCSimple, minimally instrumented sample preparation, batch capable, 6 samples ~ 1 hr
Slide 23
FIND/Eiken – Loopamp MTBCCurrent status: CE-IVD marked
1. Technology performance described: Mitarai et al. 20112. Large China eval in 20133. Dossier of test data presented to Expert review group 20th
April, 2012. 11 evaluation studies (rural or simple urban microscopy centers) performed in 4 countriesa) “while the LAMP technology has potential as a rapid TB diagnostic tool
the body of evidence presented to the Group was insufficient to make a recommendation either in favor of, or against the use of TB-LAMP as a replacement test for AFB microscopy.”
3. A further 14 ‘independent’ studies are ‘complete’ (>7,000 tests)
4. The Expert Group review in Q4 2014/Q1 2015
Slide 24
Molbio – India, a collaboration between Bigtec (Bangalore) and Tulip Group (Goa)Rapid detection of MTB and via a novel chip based real time PCR, CE-IVD marked, DCGSuite of kits, tools and equipment (all battery powered and 2 wireless enabled)
Molbio - Truelab™ M.tb
6 µL
Slide 25
Molbio - Truelab™ M.tbUnique aspects to core technologyDisposable chip based PCR reactor‘Hot block’ on chipLyophilized reagentsUnique reaction sealing upon heating
Single module instrumentAndroid controller Upload all test data Download Rx instruction GPS Data storage
Slide 26
Molbio - Truelab™ M.tb
An example of data output – TB positive
Source: UNITAID TB Dx pipeline: semi annual updateSlide 27
Ustar - NATeasy TBUstar Biotechnologies – Hangzhou, ChinaRapid detection of MTB via cross isothermal priming amplification (CPA)No dedicated instrumentationCE-IVD marked kit requiring hot block, pipettor and centrifugeCFDA approvedSyringe based extraction tool in evaluation
Slide 28
Ustar - NATeasy TB
Unique aspects to core technologyGlassified CPA reagentsDisposable and sealed immunochromatographic stripNo instrumentation of significant cost
Slide 29
A Basic Comparison of Emerging Tests to Xpert
Test Amplification Fully Integrated
Dedicated
Instrument
M/plex
(IAC)
TAT
(hrs)
MDR Intended Setting*
Market Release
MTB/RIF PCR Y Y Y 2 Y MC# 2009Genedrive PCR N Y Y 1 Y MC 2013Loopamp LAMP N Y N 1 N MC 2012Truelab PCR N Y Y 1 N MC 2013EasyNAT CPA N N Y 2 N MC 2013
* While all assays are intended for use in the periphery, these technologies claim to be less infrastructure dependentthan the Xpert# The GeneXpert was designed for use in laboratoriesNone of these emerging assays are fully integratedNone of these assays are (yet) WHO endorsed
Slide 30
The Next Wave(s)
Fully Integrated platforms for NAAT with TB Dx/DR assay potential
All are direct competitors to Xpert
Alere q, Enigma ML, Great Basin Inc., iCubate+, Insilixa, NanoBioSys Inc., NWGHF, QuantuMDx, and Wave 80
+ iCubate market a RUO TB product
Slide 31
Insilixa HYDRAFully-integrated, hand-held, and highly-multiplexed genotyping platform for POC diagnostics
Targeted performance for TB testing:
1. <1hr 4. +250 SNPs 2. Fully-integrated 5. Test cost comparable to Xpert® 3. Hand-held 6. Instrument cost < $1000
Slide from G. Skoolnik, Stanford
Slide 35
NWGHF Integrated TB Device
Funded via QuidelCustom designed collection cupMTB cells lysed at 95 ˚CExogenous controlSingle module instrumentOn board control controllerBattery poweredProduct marketed to LRS
Upload all test and QM data Data storage
Slide 36
Summary• The first wave of emerging technologies will meet their
targeted markets (e.g. India, China, Asian subcontinent)• Only the Loopamp tools has been evaluated at scale• Reagent costs are (more) competitive re Cepheid• Lower cost instrumentation• Increased costs for user training and continual evaluation
(QA and QC)
There are new waves of technology being developed• Greater degrees of integration• Broader range of targets• Increased sample volume• Specifically designed for LRS markets• Innovative technology = greater robustness, lower costSlide 37