Developing Biomarkers into Products: An Overview Bill Rodriguez, M.D. 30 January 2018 TBVI Annual Symposium Les Diablerets, Switzerland

Disclosures Draper Richards Kaplan Managing Director Foundation FIND Scientific Advisory Board World Health Organization Expert Advisory Panel on Health Science and Technology Policy

Goals of this Presentation Highlight what is required for a newly discovered biomarker to be (a) validated and (b) available “off-the-shelf” for use in vaccine (or related) studies -- Protein / proteomic markers -- Nucleic acid markers -- T cells / T cell subsets / T cell responses / small molecules What key issues should I be concerned with? Where can I get help?

Technology Development and Adoption Technology and Adoption 1973 2003 February 2015 Dx in Resource-Limited Settings Source: Getty Images

Overview of Product Development – Diagnostic Biomarkers Technology and Adoption Concept Phase 0 Development Phase 2 Validation Phase 3 Access Phase 4 Feasibility Phase 1 Project Opportunities No Go Redirect Go Project Uncertainty Project Resources Phase 0 Review Phase 1 Review Phase 2 Review Phase 3 Review Phase 4 Review DR1 DR2 DR3 DR4 Design Reviews (DR) Phase Reviews (PR) Design Input Review Design output Review Design Verification Review Design Validation Review Biomarker Candidates

Overview of Product Development – Diagnostic Biomarkers Technology and Adoption Concept Phase 0 Development Phase 2 Validation Phase 3 Access Phase 4 Feasibility Phase 1 Project Opportunities No Go Redirect Go Project Uncertainty Project Resources Phase 0 Review Phase 1 Review Phase 2 Review Phase 3 Review Phase 4 Review DR1 DR2 DR3 DR4 Design Reviews (DR) Phase Reviews (PR) Design Input Review Design output Review Design Verification Review Design Validation Review “Hey. This just might work!” “Could this work?” “It works.” Biomarker Candidates February 2015 Dx in Resource-Limited Settings

Overview of Product Development – Diagnostic Biomarkers Technology and Adoption $2M - $20M Concept Phase 0 Development Phase 2 Validation Phase 3 Access Phase 4 Feasibility Phase 1 Project Opportunities No Go Redirect Go Project Uncertainty Project Resources Phase 0 Review Phase 1 Review Phase 2 Review Phase 3 Review Phase 4 Review DR1 DR2 DR3 DR4 Design Reviews (DR) Phase Reviews (PR) Design Input Review Design output Review Design Verification Review Design Validation Review Biomarker Candidates February 2015 Dx in Resource-Limited Settings

Overview of Product Development – Diagnostic Biomarkers Technology and Adoption What happens at the end of the Feasibility phase is: The reason so few TB biomarkers have been successfully developed to date; The difference between a $2M and a $20M Development program; Largely determined by the quality, case definition, and size of the Feasibility sample set tested; and Ultimately, a scientific question, not a product development question. $2M - $20M Concept Phase 0 Development Phase 2 Validation Phase 3 Access Phase 4 Feasibility Phase 1 Project Opportunities No Go Redirect Go Project Uncertainty Project Resources Phase 0 Review Phase 1 Review Phase 2 Review Phase 3 Review Phase 4 Review DR1 DR2 DR3 DR4 Design Reviews (DR) Phase Reviews (PR) Design Input Review Design output Review Design Verification Review Design Validation Review Biomarker Candidates February 2015 Dx in Resource-Limited Settings

Product Development Detail – Diagnostic Biomarkers Technology and Adoption February 2015 Dx in Resource-Limited Settings

Example 1: (*New and Improved*) LAM Technology and Adoption LAM: Lipoarabinomannan Previous LAM-based tests with antibodies that are low sensitivity and/or cross-react with oral bacteria Modified from Treumann and Homans: http://www.astbury.leeds.ac.uk/Report/2000/Homans.micro.3.html

Example 1: (*New and Improved*) LAM Technology and Adoption LAM: Lipoarabinomannan Previous LAM-based tests with antibodies that are low sensitivity and/or cross-react with oral bacteria Alere Determine™ TB LAM Ag test Immunochromatography Polyclonal antibodies Use urine only (due to cross activity with oral bacteria) Low sensitivity (higher sensitivity in TB-HIV co-infected patients) Modified from Treumann and Homans: http://www.astbury.leeds.ac.uk/Report/2000/Homans.micro.3.html

Example 1: (*New and Improved*) LAM Technology and Adoption LAM: Lipoarabinomannan Previous LAM-based tests with antibodies that are low sensitivity and/or cross-react with oral bacteria To validate a *New and improved* LAM in Feasibility Phase Establish and validate a new sample processing protocol Lab-based characterization of sensitivity and specificity using clinical samples of known provenance 2 clinical studies LAM (ELISA format) vs. PCR (n=50 - 100) Direct from sputum (n=~300) in TB suspects, ill controls, healthy controls Cross-contamination with oral flora Limit of detection across target demographic groups 2 analytical studies

Project structure & status TB Biomarkers as Diagnostics – Protein signature Example 2: Proteomic signature Project structure & status Track 1: To transfer newly identified (host) markers to a Luminex assay Validate the assay and determine the diagnostic performance in a large sample set Establish final biomarker signature Track 2: To identify 1-2 suitable "near patient testing" platforms and evaluate them with final markers Source: FIND

Explosion in near-patient molecular platforms Multiple platforms are available for molecular and protein diagnostic testing Explosion in near-patient molecular platforms Epistem Great Basin Veredus PositiveID Stat-Diagnostica BioFire Alere q Molbio PositiveID STATDiagnostica Great Basin Cepheid BioCartis IdahoTechnologies BioFire Alere Veredus Epistem iCubate Osmetech QuantumDx Rheonix QuantumDx Spartan Fluidigm Qiagen Micronics Curetis Roche Enigma Gentura Atlas Genetics Molbio 14

Example 3: Cepheid GeneXpert

Example 3: Cepheid GeneXpert Project post-feasibility ran from 2006-2011 FIND Support: Development/Validation: ~$10M NIAID support: Cartridge/Mfg: ~$4M Key Collaborators: David Alland, UMDNJ Catherina Boehme, FIND Mark Perkins, FIND 16

Diagnostic Biomarker Development - Failure Points Overly optimistic transition to product development before sufficient Feasibility data are collected; limited and biased assessment of biomarker data based on small-n exploratory studies poorly characterized or incomplete sample sets; lack of performance data measured on a field-deployable platform; lack of well-designed validation and confirmation studies; and lack of standards and frameworks for biomarker validation, such as geographic validation requirements, or evaluation of cross-contamination with non-tuberculous mycobacteria (NTMs).

Commercialization is Challenging Commercialization is Challenging in Markets for Diseases of Poverty Commercialization is Challenging Many companies have diagnostic technologies in late-stage development or in limited commercial use for nucleic acid, IgG/IgM, and antigen detection, and have a stated willingness to develop a high-priority test - More than 70 companies submitted product development plans for a near-patient Ebola diagnostic test during the course of the epidemic - 3 years later, only 6 companies have Ebola tests that received Emergency Use Authorization (EUA) from US FDA or the equivalent designation from WHO Diagnostic Pre- Qualification (plus tests from US CDC and DoD) - No diagnostic products have received regulatory clearance for Ebola through FDA or WHO PQ non-emergency mechanisms 18

Project structure & status FIND TB Biomarker Program TB Biomarkers as Diagnostics – Protein signature Project structure & status Source: FIND

Key Issues to Consider Are your feasibility data telling you what you think they are? Do you use standardized, validated protocols (esp. sample processing) to measure your biomarker? Do you know what commercial testing platform(s) you want t use in the field, and is it the same one as you are using in your laboratory during feasibility testing? Have you evaluated performance in multiple populations, including: - confirmed TB cases of low- and high-burden? - ill controls - healthy subjects Are there any IP issues?

Goals of this Presentation Highlight what is required for a newly discovered biomarker to be (a) validated and (b) available “off-the-shelf” for use in vaccine trials -- Protein / proteomic markers -- Nucleic acid markers -- T cell responses / small molecules What key issues should I be concerned with? 3. Where can I get help? Goals of this Presentation Feasibility data Standardized protocols Platform selection Clinical validation against reference testing in well-characterized populations Analytic validation