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Beyond Xpert: fast-followers and NAAT pipeline
David Boyle
Program for Appropriate Technology for Health (PATH)
July 8th, 2013 Advanced TB DX Research McGill University Montreal
The Emerging TB Dx technology Landscapes
Slide 2
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
Current TB Dx pipeline from the WHO
The Fast Followers…What we want to see
Slide 4
• Choice
• More robust tech
• Cheaper
• Perf. good or better
• Tools to meet varied
market needs
COMPETITION!
The Fast Followers…What we currently see
Slide 5
Xpert MTB/RIF endorsed in 2010
2013 Manual NAAT still pending
Further STAG review, 2014
2013 MTBDRsl ‘endorsed’
Fast Followers = Emerging TB Dx technologies
Point of care (or point of treatment?)
Slide 6
Source: World Health Organization. Diagnostics for tuberculosis: Global demand and market potential (2006).
The UNITAID 2013 Pipeline
Slide 7
1. Screened NIH funding to developers
2. Reached out to over 190 companies or research groups
3. We asked them to complete a basic questionnaire
4. All NAAT platforms were considered for TB Dx and MDR/XDR, not just ones described for use in peripheral settings
Questionnaire Components
Slide 8
1. Intended Use 2. Price 3. Performance 4. Operational Characteristics 5. Regulatory Approval And Manufacturing
Information
Technologies Identified and Assessed
Slide 9
Commercial 17
Setting Lab TB Dx MDR/XDR Integrated Partially integrated
Reference 14 8 6/4 0 14
Peripheral 5 5 2/0 1 4
Development 10
Setting Lab TB Dx MDR/XDR Integrated Partially integrated
Reference 5 5 4 1 4
Peripheral 5 5 3 4 1
NAAT at the Upper Laboratory Levels
Slide 10
Larger laboratories often get ignored:
High throughput and/or high complexity tests can be performed
TB Dx and MDR/XDR screening is needed
Improved Dx and analysis
Sample prep automated
Cost effective at scale
Existing platforms used in USA and beyond
Existing High Throughput TB Dx Tools
Slide 11
Amplified Mycobacterium Tuberculosis Direct (AMTD) assay Hologic Genprobe (USA), US FDA approved since 1995, semi-automated, batch processing TMA amplification. 50 tests/5.5. hrs. ProbeTec ET Direct TB, Becton Dickinson (USA), 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.
Platform Agnostic Technologies.
Slide 12
Many laboratories have real time PCR capability BUT many TB assays described as technology dependent.
CapitalBio Corp. (China) and Seegene (Korea) have developed CE-IVD marked TB assays that are less platform specific.
Mycobacteria Real-time PCR, 36 tests /4 hours
Seegene Anyplex II™ MTB/MDR/XDR
Dual priming oligo (DPO), Tagging Oligonucleotide Cleavage Extension (TOCE) and Real Amplicon Detection (READ)
Seegene Products
Slide 13
Anyplex II™ MTB/MDR/XDR Detection Key features
1. Simultaneous Screening of MTB infection and drug resistance 2. Direct and positive based detection of drugR mutations 27 MDR and 13 XDR 3. Real time PCR sensitivity and specificity (DPO/TOCE)
Anyplex II™ MTB/NTM/MDR-TB Detection Key features
1. Simultaneous determination of MTB and NTM 2. For MTB, add an additional 40 minutes for MDR 3. Direct and positive based detection of drugR mutations 21 MDR 4. Real time PCR sensitivity and specificity (DPO/READ)
Comparatively rapid (90 tests/6 hours)
NAAT based tools for MDR/XDR TB
Slide 14
Source: Barnard et al., 2009 AJRCC
Line Probe Assays: Hybridization assays for MTB, MDR and XDR
Hain Lifescience (Germany) GenoType® MDRTBplus v1.0 (v2.0) (MTB/RIF/INH)
GenoType® MDRTBsl (KAN/CAP/FQ/ETH/STR) Automated sample prep and hybridization
Nipro (Japan) NTM/MDR-TB INH PZA FQ Manual sample prep and hybridization
Innogenetics (Belgium) INNO-LiPA Rif.TB - discontinued
Microarrays for MDR/XDR
Slide 15
Screening of wider numbers of genetic markers
Several platforms exist with TB Dx/MDR tests
Partially integrated
Akonni, AutoGenomics, CapitalBio and Veredus
48 tests per 6.5 hrs.
10-15 tests per 8 hrs.
$80k - 240K…
Xpert MTB/RIF Refresher
Slide 16
2 min 15 min 1 min <2 hrs. Adapted from Scott, 2010
Buffer chambers
PCR tube
Syringe barrel
Cartridge base
Cap
Cartridge body
Gasket
Valve body
Nested PCR/real time PCR
6 color detection
5 color probe determination
TB (rpoB)
RifR (rpoB)
Automated result scoring
Reaction waste stored in cartridge
HIV VL in development
New MDR assay in development
Source: Niemz and Boyle, 2012
Not all Microscopy Clinics are Equal…
Slide 17
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 tools are available to meet all peripheral setting?
The First Wave of Emerging Technologies for LRS
Slide 18
Four technologies are currently in late stage development and/or evaluation
Most developed privately via Dx start ups:
1. *Epistem – Genedrive M.tb iD
2. FIND/Eiken – Loopamp MTBC
3. *Molbio - Truelab™ M.tb
4. *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
Epistem Genedrive M.tb iD
Slide 19
Epistem – Manchester, UK based company
Rapid detection of MTB and RifR via a novel approaches to sample
prep, and real time PCR
Novel paper based
Extraction device
3 reaction amplification
Cartridge
Lyophilized reagents
High quality plastics
Single unit
Battery powered device
Novel engineering reduces power needs
Real time PCR with high res melt curve analysis
Epistem Genedrive M.tb iD
Slide 20
Process flow
Add sputum to lysis cartridge
Dry for 10 minutes
Punch out 3 paper discs
Add to 3 reaction
chambers with
20 mL water
Insert cartridge into
device, press start
button
10 min 1 min 45 min
No peer reviewed data (yet)
CE-IVD marked
Distributors in place (Xcelris and BD)
Manufacturer of Genedrive in place
FIND/Eiken – Loopamp MTBC
Slide 21
PDP between FIND and Eiken Chemical Corp (Japan).
Loop mediated amplification (LAMP) assay for TB
Isothermal amplification , simplified yet rapid and sensitive test
Source: UNITAID TB Dx pipeline semi annual report 2012
Simple, minimally instrumented sample preparation, batch capable
Slide 22
FIND/Eiken – Loopamp MTBC
Simple, minimally instrumented sample preparation, batch capable, 6 samples ~ 1 hr.
Slide 23
FIND/Eiken – Loopamp MTBC
Current status:
1. Technology performance described: Mitarai et al. 2011
2. Dossier of test data presented to Expert review group 20th April, 2012 a) 11 evaluation studies (rural or simple urban microscopy centers)
performed in 3 countries
b) “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 10 ‘independent’ studies are underway
4. Further publications and release of the Expert review report are anticipated in 2013
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
Suite of kits, tools and equipment (all battery powered and wireless)
Molbio - Truelab™ M.tb
Molbio - Truelab™ M.tb
Slide 25
Unique aspects to core technology
Disposable chip based PCR reactor
‘Hot block’ on chip
Lyophilized reagents
Unique reaction sealing upon heating
Single module instrument
Android 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 update
Ustar - NATeasy TB
Slide 27
Ustar Biotechnologies – Hangzhou, China.
Rapid detection of MTB via cross isothermal priming amplification (CPA)
No dedicated instrumentation
CE-IVD marked kit requiring hot block, pipettor and centrifuge
Syringe based extraction tool in evaluation
Slide 28
Ustar - NATeasy TB
Unique aspects to core technology
Glassified CPA reagents
Disposable and sealed immunochromatographic strip
No instrumentation of significant cost
CFDA submission underway
A Basic Comparison of Emerging Tests to Xpert
Slide 29
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 2009
Genedrive PCR N Y Y 1 Y MC 2013
Loopamp LAMP N Y N 1 N MC 2012
Truelab PCR N Y Y 1 N MC 2013
EasyNAT CPA N N Y 2 N MC 2009
* While all assays are intended for use in the periphery,
these technologies claim to be less infrastructure dependent
than the Xpert
None of these emerging assays are fully integrated
None of these assays are WHO endorsed
The Next Wave(s)
Slide 30
Fully Integrated platforms for NAAT with TB Dx assay potential
All are competitors to the GeneXpert
Abbott (m2000)*, Alere q*, BD (BD MAX), Biocartis Apollo*, Biofire Dx (Idaho Technologies), Enigma ML*, iCubate+*, iQuum (LIAT), Nanosphere* (Verigene), NWGHF, Wave 80*
+ iCubate market a RUO TB product
* These groups have TB products in development
Slide 31
Emerging Integrated Platforms for Use in LRS Wave 80 (USA) EOSCAPE
EOSCAPE Processor
Slide 32
Core Components and Instrumentation
Slide 33
NWGHF Integrated TB Device
Slide 34
Funded via Quidel
Custom designed collection cup
MTB cells lysed at 95 ˚C
Exogenous control
Single module instrument
On board control controller
Battery powered
Product marketed to LRS
Upload all test and QM data
Data storage
Summary
Slide 35
• The first wave of emerging technologies will meet only their targeted markets (e.g. India, China, Indian subcontinent)
• Only the Loopamp tool has been evaluated elsewhere
• Reagent costs are competitive with Cepheid
• Increased costs for user training and continual evaluation (QA and QC)
There are new waves of technology being developed
• Greater degrees of integration
• Wider range of targets
• Improved sample collection
• Designed for LRS markets
THANK YOU!
Slide 36
1. UNITAID
2. The technology developers
3. Madhu