How to boost R D for a low-cost point-of-care

How to boost R&D for a low-cost, point-of-care rapid diagnostic test and better drugs for tuberculosis Meeting with Médecins Sans Frontières Geneva, April 11, 2008 Giorgio Roscigno CEO / FIND

FIND • Vision To impact quality of life of people suffering from poverty-related diseases • Mission To develop rapid, accurate, easy to use and affordable point of care diagnostic tests to help fight diseases that disproportionally affect the poor

FIND’s Operational model • FIND is a not-for-profit (US 501 c 3) Swiss Foundation • Co-invests with partners in order to lower risk, reduces break-even time, and significantly reduces the barrier for a commercial company to invest and moves the technology along the value chain. • As a not-for-profit, FIND can leverage its investment against the affordability of the product for the FINDTarget Markets in the High Disease Burden countries and low income countries ð Public sector and private not-for-profit sectors

Moving from development to impact Impact on poor patients Collecting evidence for scaling up Developmen t Evaluation Demonstrati on Adoption into global policy

Poverty is multidimensional CONTEXT Limited infrastructures Tests must be cheap, if not free (Public/private no profit) Test should work within local conditions (Part of the demonstration phase/ knowledge sharing) POLITICAL ECONOMIC Consumption Income Assets Rights Influence Freedom GENDER Tests should ensure equity of access (Patient centered approach) HUMAN Health Education Nutrition SOCIO-CULTURAL Status Dignity WHO/OECD, 2001

Equity and societal cost effectiveness analysis of new Dx in Lesotho Scope of the study • To synthesise an approach for assessing impact of new Dx tools and modalities on equity of access to TB diagnosis Specific objectives • To develop locally appropriate tools to describe poverty profile and geographic distribution of TB patients • To assess main barriers to TB diagnosis in Lesotho • To assess health system costs of new TB diagnostics • To assess the cost effectiveness of new tools

Detection of TB still relies on microscopy ¾ Only one quarter of TB cases in the world are ever really diagnosed and reported as smear positives ¾ New technologies, especially molecular-based, have promising potential ¾ But spending on TB R&D diagnostics currently represents less than 8% of TB research funding Source: The Treatment Action Group (TAG) report on tuberculosis (TB) research and development (R&D) in 2006

Patient-centered approach based on a tiered level laboratory Fraction of FIND budget spending patients seen Reference Lab 5% Detection 75 % Regional Lab • Screening • Primary care microscopy • Resolution testing (screening negative drug resistance, e. g. , culture) • Passive case finding • Detect and treat 10 % Peripheral Lab 25 % culture • Surveillance • Reference methods • Network supervision Clinic / Health Post symptoms Resolution 25 % Surveillance 60 %

FIND / TB diagnostic pipeline Health Level Referral Hospital Projects 2008 2007 Liquid Culture STAG Access A Rapid speciation STAG Access A Rapid Molecular DST Interferon Gamma Assays 2010 2009 I Impact Demonstration STAGAccess A I Impact I Demonstration Evaluation 2012 2011 STAG Access Impact A A Microscopy Center LED Microscopes Manual NAAT Fully automated NAAT Health Post Feasibility & Develop Eval Feasibility & Eval Develop Demo STAG Acc A Imp I Demonstration STAG Acc A Imp I AB detection Feasibility & Development Evaluation Demonstration STAG Access AG detection Feasibility & Development Evaluation Demonstration STAG Access Enose Feasibility & Development Evaluation Demonstration STAG Access

Gaps in R&D (1) The slow road to microscopy diagnosis of TB ¾ The starting-point in the fight against all contagious diseases is the obligation to report, because without this most cases of the disease remain unknown. Robert Koch, 1905 ¾ A new POC TB Diagnostic tool could save up to 400, 000 lives per year. Nature

For Molecular Testing the main driver is to the POC • FROM: centralized big laboratory machines TO: self-contained simple-to-use chemistry & equipment e Hom r’s cto Do ice Off rs nte Ce lth atient Hea utp or O linics C a ion eg d R ls an ral spita Ru Ho l al ferr s Re ital p Hos

Mtb Antibody / Antigen Dx • Two key areas: Biomarkers & Technology • No well-defined molecular targets (except DNA) • Dx target identification ongoing – Various “Omics” approaches taken • Detection technology dependent on type and number of markers employed – LFI most likely technology for POC but limited by sensitivity and number of analytes

Gaps in R&D (2) TB Biomarker Research q Lack of systematic approaches to marker discovery: no consensus on TB biomarkers q Lack of reproducibility of preliminary biomarker results (e. g. , antibodies, LAM antigen) q Probable causes of failure and bias: § opportunistic approaches § poor understanding of in vivo antigen processing § lack of appropriate detection technology § inefficient sample preparation procedures § poorly documented clinical samples

Boosting R&D for a low-cost, point-of-care rapid diagnostic test: point-of-care rapid diagnostic test bridging the gaps • Biomarker discovery: – Academia • Immunology • NAAT targets • Biomarker validation: – Commercial partner • Extensive clinical trials • Prototype products • Appropriate technologies with appropriate partners

Mtb Antibody / Antigen Dx Discovery POC by combining biomarkers and technology • Academic research (UCI) leads to novel, high throughput protein expression technology • FIND technology scouting identified this outstanding opportunity to close serology target gaps • UCI spin-off founded Imm. PORT Inc. , who became a FIND partner • This PPP generated first ever whole Mtb proteome array chip to identify unknown antibody targets serving as key reagents for POC development • Partner company attracted by FIND expertise and short term cash rather than long term advanced purchasing mechanism

How to bridge and which incentives for novel biomarkers and appropriate technology Biomarkers Technology ð High risk / high cost ð Big Dx companies only in profitable segments (sequencing, arrays) ð Academia driven ð Industry focused primarily on big markets (e. g. , cancer, diabetes, . . . ) ð Bioinformatics challenges ð Validation and reproducibility are critical issues Incentives: ð Publications, IP, additional R&D funds ð Prizes ð Biotech / small-med. tech. as major drivers of innovation (short to medium term) but often prohibited by short term goals of VCs (profit) [Imm. PORT] ð High profile research institutions and military (MIT, DARPA) may provide “out of the box” solutions (medium to long term) but TB dx applications are typically not an “A” priority [Cepheid] Incentives: ð Research reagents contracts (Ab/Ag) ð “Public” Venture Capital to support smallmed companies ð Small business grants linking academia and companies ð Prizes to establish market value of technological platform ð Advanced market commitment (larger company)

IVD Industry operates a different business model from Pharma industry Far more sensitive to cash flows; IVD projects take only a few years and product sales cash flows are critical in the short term 1. Technology cycle times are only a few years; the need to get to the break-even point is greater 2. Replacement products from competitors eat into margins and profit far earlier than in Pharma 3. IP is important but linked to shorter product lifetimes; ð results in limited ROI on IP

Is there a role for novel market incentives in catalyzing IVD Development Projects? • The « Carrot » of a « Prize » ? – Academia: doubtful, since main driver is peer recognition and publications – money is always welcome – Public VC for commercial partners: most likely, since it helps project « hurdle rates » and break-even points – For large companies: doubtful, as it must be sufficiently significant to actually be an « incentive » ; i. e. $ in millions – The Advance Market Commitment: no, not a driver for IVD companies as cash flow is king and most IVD’s are not « commodity-like » possibly attractive to larger DX Co with mature technologies.