On the Drawing Board

Last week I posted an update to progress in developing and deploying better diagnostics for tuberculosis (“TB Dx:  Getting There,” 3/1/12), but didn’t adequately cover the work aimed at the “holy grail” of TB Dx.  What is needed in the under-resourced countries are point-of-care (POC) devices to diagnose the 60-plus percent of TB patients first seen at the clinics and remote stations that lack even the basic equipment used in microscope-based tests.  Ideally, the POC diagnostics also will be capable of finding TB infection 90% of time, preferably early in infection, in kids (who don’t cough up enough sputum for standard microscopic assay), and in HIV-compromised patients (who may not have enough of the tell-tale bacteria in their sputum).  I’m especially interested in what products may be on the drawing boards of companies and what is being, or can be, done to move them along.  Just to recap, the products on the market now represent two extremes:

- rapid diagnostic tests (RTDs) that are technically simple (immunochemistry detection and visual read-out), inexpensive (less than $1.00 per test), but not sensitive or specific enough for wide use (according to a 2008 evaluation of 19 products, sensitivity was less than 60% and specificity was less than 80%, WHO RTD evaluation); and

-the Gene Xpert® MTB/RIF system which is based on Cepheid Inc.’s real-time PCR for DNA amplification and therefore complicated, lab-based (not POC), expensive (about $20 per test), but sensitive and specific in finding both “typical” TB and drug-resistant types (Xpert FAQs).

Fortunately, companies seeking to develop a TB Dx can utilize on years of work by international health agencies, research in academic laboratories, and funding by governments and foundations.  Last year, the Treatment Action Group, Stop TB Partnership, Medicines Sans Frontiers, and Imperial College published an extensive report on the requirements of POC TB Dx and criteria for evaluation (Lab Free TB Dx), information helpful in designing a product.  The report also makes recommendations for next steps among “stakeholders” but, unfortunately (to me anyway), the authors did not include companies in that group.  As for summaries of the needs and progress in POC TB Dx, the Stop TB Alliance has a web page (STBA), Syved 2010 wrote a useful overview of all TB diagnostics progress (Syved 2010), and Pai and Pai 2011 (Pai and Pai 2011) described the POC landscape and the importance of integration of a TB POC Dx with diagnostics for HIV since TB is the leading cause of mortality among HIV-infected individuals (WHO HIV).  As for market information for POC TB Dx, the Foundation for Innovative New Diagnostics (FIND) and WHO published a report on “global demand and market potential” in 2006 which has a wealth of country-specific data on current practices and diagnostic regulatory practices and classification schemes (FIND/TDR TB Dx report).  However, the chapter on the business environment was not well-researched and is less helpful.  More up-to-date, Engel et al. 2012 provides a summary of a conference on the challenges and parties (companies, investors, NGOs, and government agencies) interested in TB Dx for India and a guess of the market size for primary diagnosis of $100 million annually (Engel et al 2012).  For companies reaching the field trial stage, a resource to tap is the Tuberculosis Clinical Diagnostics Research Consortium (TBCDRC) that “support[s] non-interventional studies of promising new diagnostics at our clinical sites in South Africa, Uganda, Brazil, and South Korea.”

So what’s on the POC drawing board?  Pai and Pai 2012 point out that there are two promising routes for new Dx:  improved immunological antigen detection type tests using urine, blood, or sputum samples; and field-friendly, affordable molecular tests based on the detection of nucleic acids, proteins, or other molecules in the same samples.  These latter tests may use DNA chips or disposable cartridges and detect other infectious diseases, clearly a valuable feature.  My survey found the following efforts, all in the discovery or preclinical stage (i.e., having a prototype device) and listed by analyte (marker).

1)  Various antigens

  • Primary sponsor: Infectious Disease Research Institute
  • Commercial partner:  none
  • Objective: optimize antigen combinations to increase performance in simple lateral flow assay formats
  • Stage: preclinical
  • Source:  IDRI.

2)  Beta-lactamase

  • Primary sponsor:  FIND
  • Commercial partner:  Global Biodiagnostics
  • Objective:  adapt Global’s “biophotonic” detection platform that utilizes reporter enzyme fluorescence and detection by eye or simple reader in unprocessed sputum samples
  • Stage:  discovery
  • Source:  FIND beta-lactamase (I noted this project in last week’s post but was wrong in that it is a POC effort).

3)  Novel protein markers

  • Primary sponsor:  FIND
  • Commercial partners:  Antigen Discovery Inc., mBio Diagnostics, Inc., and MicroMol GmbH
  • Objective:  use previously identified multiple antigens from mTB proteome and combine a small to medium number into a rapid serological test for active TB
  • Stage: discovery
  • Source:  FIND antibodies.

4) Mycobacterial lipoarabinomannan (LAM)

  • Primary sponsor:  FIND
  • Commercial partners:  ChemBio Diagnostic Systems, Inc., Response Biomedical Corp., ELITech Group (previously Nanogen Inc.), TbDiaDirect, DKFZ, Chimera Biotech GmbH, PriTest Inc.
  • Objective:  use LAM as test analyte for evaluating multiple platforms (colorimetric, fluorescent and chemoluminescent), has found three with pico-nanomolar limits
  • Stage:  discovery
  • Source:  FIND LAM.

5)  LAM

  • Primary sponsor:  FIND
  • Commercial partner:  Alere, Inc.
  • Objective:  assess a new lateral flow test for simple and rapid LAM detection in urine in trials (with TBCDRC).  Results using Alere’s  “Determine TB-LAM Ag” test in HIV-infected people before antiretroviral therapy in South Africa were recently according to Denkinger and Pai 2011 (Denkinger and Pai 2011)
  • Stage:  clinical
  • Source:  FIND Alere LAM.

6)  Novel protein markers

  • Primary sponsor: Forsyth Institute and Beth Israel Deaconess Medical Center and Gates Foundation (mentioned in last week’s post as a Gates grantee)
  • Commercial partner:  Quanterix
  • Objective:  validate novel low abundance protein biomarkers using the company’s Single Molecule Array technology that is based upon the isolation of individual immunocomplexes on beads using standard ELISA reagents
  • Stage:  discovery
  • Source:  Quanterix press release.

I was not able to find any POC tests in development that use nucleic acids as analytes.  I assume the technical challenges of adapting technologies like real-time PCR (polymerase chain reaction) to very-low-resource environments is the reason but am not one to underestimate the ingenuity of motivated diagnostic companies.  It is possible that companies like Cepheid, developer of the Gene Xpert system noted above, and Seegene, Inc., developer of a real-time PCR-based reagent kit for detecting TB that works on multiple readers (Seegene) are hard at work on more “field friendly” systems.  And then there are a number of table-top or lab-based systems that use exhaled air as the sample under development by researchers and companies that will also need down-sizing and –costing to be POC:

Lots of drawing going on.

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