Commercialisation of Biosensors

Anthony P F Turner Biosensors & Bioelectronics Centre

IFM-Linköping University

Biosensor Technology TFTB34, Linköping, Tuesday19 February 2013

Outline

• Commercialisation: ingredients and hurdles • Market pull • Technology push • Home blood glucose monitors • Continuous blood glucose monitoring (CBGM) • Non-invasive glucose monitoring • Future markets • Conclusions

Ingredients for Commercialisation

• Market need • Protectable technology • Clear ownership • Platform technology or • …marked improvement • Entrepreneurship of inventors or commercialisation team

Intellectual Property Protection

• PATENTS e.g. methods & apparatus • COPYRIGHTS e.g. text, pictures & software • TRADE SECRETS i.e. technical know-how • DATABASE RIGHTS • DESIGN RIGHTS

© Copyright APF Turner 2011

Regulation and Litigation • Regulatory bodies can drastically change the product landscape e.g.

FDA & the maltose problem with GDH which hit Abbott & Roche products

• The mature glucose biosensors field is currently typified by litigation by the four dominant players against each other and the medium sized companies threatening to take market share. A series of expensive suits have been filed, some being settled out of court by substantial payments and others going to high profile trials

• In 1999 in the USA, Biacore (now GE) successfully asserted its carboxymethylated dextran patent against Thermo. In 2005, Roche asserted its proprietary position in Cotrell Current amperometric biosensors against Apex/Hypoguard and the Roche patent was declared invalid; in 2008, Abbott asserted 4 of its glucose sensor patents against Roche, Bayer, Matsushita, BD and Nova; it lost all four cases! Roche then filed suit against its competitors based on its <1µl and <5 secs claims. Once again, the cases were lost, but the battles continue.

Lord Wolf, DSc Cranfield

Professional Uptake • Sometimes there has been slow uptake of novel

technologies caused by cautious or conservative attitudes amongst professionals. These attitudes may often be rooted in culture and education and can vary greatly from country to country.

• Near-patient monitoring was initially resisted heavily by clinical chemists concerned by quality control issue associated with a shift away from centralised facilities

• Effective communication to healthcare educators and the medical community in general of the benefits of novel technologies is always essential

• A highly self-educated community living with a chronic disease like diabetes mitigates against conservatism

The Climate for Investment • Bioscience & Healthcare is a fundamental sector for private equity venture funds; it is

also one of the most challenging due to complex scientific development intricacies, a politically influenced regulatory environment and the cyclical nature of clinical developments

• These sectors are a venture sector inherent with risk. Nevertheless, sectors including biotechnology, pharmaceuticals and medical devices are proving increasingly attractive to private equity investors given their potential to dislocate existing billion dollar markets

• Private equity funds focused on life sciences raised in excess of 17 billion (USD) in 2007 and 28 billion (USD) in 2008, but far less in 2009, largely as a consequence of market conditions affecting private equity fund managers’ ability to attract capital for their vehicles (Evolution LS Ltd.). Recovery is still slow.

Reimbursement • Reimbursement for new systems can be a major

challenge and a major disincentive in investing in R&D

• A new paradigm for glucose monitoring, for example, will face challenges in established reimbursement systems for lancing and measurement

• Reimbursement schemes currently vary widely from country to country, and patient access can even vary within a country

• Reimbursement prices may be forced down (eg. Germany) or new technology refused (eg. implantable defibrillators in France and Pelikan Technologies’ painless blood sampler)

Diabetes Diagnostics: A Special Case

Newman, J.D. and Turner, A.P.F. (2005). Home blood glucose biosensors: a commercial perspective. Biosensors and Bioelectronics 20, 2435-2453.

Diabetes Prevalence • Diabetes is an immense and growing public health issue:

• The fastest growing chronic disease in the World; expected to double in prevalence by 2030

• Afflicts around 2% of the world’s population & 6% of the adult population of the western world

• 170 m diabetics worldwide, 27 m diagnosed

• In the USA, 8% of all citizens and 18% of Senior Citizens afflicted

• Asia now has the bulk of cases with four of the world's five largest diabetic populations – India (33 m), China (23m), Indonesia (9m) and Japan (7m) cases

• There is no known cure

The Diabetes Health Care Space

IMS and EAC data - 2004

$0.35B

$5.6B

$12.1B

$5.2B

Insulin

Oral Anti-Diabetics

Blood Glucose Monitoring

Lancets and other paraphernalia

Source: Frost & Sullivan

Diabetes – Influential Studies - DCCT

• Intensive therapy (including frequent monitoring of glucose) can reduce the risk of complications by 60%

• Intensive therapy increases the risk of hypoglycaemia

• All diabetics should benefit in the longer term by improved monitoring and control of blood glucose

• Diabetes Control and Complications Trial. New England Journal of Medicine, 329(14),1993 http://diabetes.niddk.nih.gov/dm/pubs/control/

• American Clinical Diabetes Educators estimated that in 2009, 37% of their Type 1 patients are using CGM, compared to only 7% in 2008

• Growing acceptance and adoption of CGM is presumably fuelled by a large amount of clinical data that has been published in the past year (the NEJM published the JDRF trial October 2, 2008) underscoring the clinical utility of CGM

• If it was widely available and reimbursed (for the device and healthcare provider time), Educators would put the following patients on GCM:

Growing Acceptance of CGM

Annual AADE Survey, Close Concerns (2009)

YEAR TYPE 1 TYPE 2 2009 91% 58% 2008 69% 35% 2007 33% 0%

Biosensors: World Market Drivers

0

2000

4000

6000

8000

10000

12000

14000

1995 2000 2005 2010

Sal

es (

$ M

illio

n)

DCCT

CBGM & New Markets

A conventional enzyme electrode

16

The YSI Analyser

1500 Sport Analysers

17

Enzyme Electrode Reactions

Yellow Springs Instrument Company Inc (YSI)

Glucose Biosensor 1975

YSI, Ohio 1987

The original YSI serum-glucose biosensor for diabetes clinics 1975

Clark, LC & Lyons, C (1962). Annals New York Academy of Sciences 102, 29.

1987

2

A brief chronology of home testing for glucose

Urine testing using, for example, Clinitest Reagent Tablets (1941) followed by visually read paper test strips for urine (1956)

Visually read paper strip for blood glucose (1964)

Instrument to measure paper strip by reflectance of light (1969)

First electrochemical home blood glucose monitor (1987)

First devices to fill by capillary action: Medisense QID (1995); Bayer / KDK / Menarini (1996)

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Ames Reflectance Meter Tom Clemens work led to the Ames Reflectance Meter. Ames was a division of Miles and is now part of Bayer. Work started in 1966, four years after Clark’s description of the glucose biosensor, but development of the reflectometer was much faster. A U.S. patent (no. 3,604,815) was granted on September 14, 1971, about two years after it went on the market. The original Meter was expensive, large and heavy, (approx 1 Kg) and required a prescription. Despite this, it was a success and eventually led to the Eyetone, then to the Ames Glucometer and eventually to the great variety of other products.

21

Mediated Enzyme Electrode

Cass, A.E.G., Davis, G., Francis, G.D., Hill, H.A.O., Aston, W.J., Higgins, I.J., Plotkin, E.V., Scott, L.D.L. and Turner, A.P.F. (1984) Ferrocene-mediated enzyme electrode for amperometric determination of glucose. Analytical Chemistry 56, 667-671.

Glucose oxidase or PQQ Glucose Dehydrogenase

22

Ferrocene-Mediated Amperometric Biosensors

1981 1983

1982

23

Mediated Amperometric Glucose Sensors

MediSense ExacTech™ 1987: Ferocene

Johnson & Johnson Lifescan FastTake™ 1998: Hexacyanoferrate

Roche Diagnostics

Lifescan

Bayer Diagnostics

Abbott

Nova biomedical

Others

China

Biosensors: $13b Market

Share

Beijing Yicheng JPS-5

Roche Accu-Check Aviva Nano

Lifescan OneTouch Ultra

Bayer Contour

Abbott FreeStyle Lite

The Market leaders in Glucose Biosensor Sales

Capillary-fill Biosensors 1996 et sequa

1995

Kyoto Daiichi, Japan (& made for Menarini, Italy and Bayer circa 1996)

Unilever, UK 1987 Kyoto Daiichi, Japan

Mass Production: Screen Printing

Mass Production: Sputtering & Lamination

Key Electrode Designs Classical top-fill design

Substrate: e.g. Mylar™ Polyethylene terephthalate (PET)

Conducting tracks: Silver & Carbon ink

Ag/AgCl reference/ counter electrode

Working electrode: Carbon, mediator, enzyme, binder (e.g PEO: polyethylene oxide) & surfactant

Dielectric (insulator)

CONTACTS

SAMPLE to meter

Key Electrode Designs Capillary-fill design

Substrate: e.g. Mylar™ Polyethylene terephthalate (PET)

Conducting tracks: Silver & Carbon ink

Ag/AgCl reference/ counter electrode

Working electrode: Carbon, enzyme, binder (e.g PEO: polyethylene oxide) & surfactant

Dielectric (insulator)

CONTACTS

SAMPLE to meter Spacer Soluble mediator

Key Electrode Designs

Auto on

Sample detect Fill detect

Automation and error correction

+ = haematocrit compensation via fill rate

More Sophisticated Designs

MediSense Precision QID with laminated sequence for ”wicking”

Bayer Breeze 2 screen-printed electrodes with hexacyanoferrate: sample detect, 1µl, 5 secs, no coding

Acencisia Contour laser ablated sputtered Pd electrodes with complex electrode sequence

The Fully-printed Glucose Sensing System

Turner, A.P.F. (2013) Biosensors: sense and sensibility. Chemical Society Reviews DOI:10.1039/C3CS35528D

Short Break

Outline

• Commercialisation: ingredients and hurdles • Market pull • Technology push • Home blood glucose monitors • Continuous blood glucose monitoring (CBGM) • Non-invasive glucose monitoring • Future markets • Conclusions

Unknown cause (34) Meter malfunction (11) False High Results (11)

Diabetic Ketoacidosis (8) Maltose/non-glucose interference (13)

Use on Critically Ill Patient (6) False Low results (6) Possible Medication Interference (5) Renal patient (2) Dehydration (1) Hyperosmolar Hyperglycemia (1) Feeding tube –glucose (1) Neonatal death (1)

1992-2009: 100 deaths associated with glucose meters reported

Adverse Events - Deaths

Source: C.C. Harper (FDA)

GDH-PQQ Problems GDH-PQQ (glucose dehydrogenase pyrroloquinoline quinone) Glucose Monitoring Technology Audience: Diabetes healthcare professionals, hospital risk managers, patients [Posted 08/13/2009] FDA notified healthcare professionals of the possibility of falsely elevated blood glucose results when using GDH-PQQ glucose test strips on patients who are receiving therapeutic products containing certain non-glucose sugars. These sugars can falsely elevate glucose results, which may mask significant hypoglycemia or prompt excessive insulin administration, leading to serious injury or death.

The specificity of GDH-FAD and GDH-PQQ

The Move to Integration

Ascensia® AUTODISC® loads the meter with 10 tests at a time

Accu-Check Compact – Preloaded drum of 17 strips

Hypoguard 100 test strips In disposable meter

Pelikan integrated 50 sensor cartridge and electronic lancing system

Roche Strip-free Glucose Sensing

Accu-Chek Compact Plus / Accu-Chek Mobile (2012) • Glucose meter system with no strips to handle and integrated lancing device. • Everything together: a test strip cartridge, no coding, a detachable lancing device, and easy,

one-handed operation. • 50 Strip-free tests on a continuous tape – no single strips to handle or dispose of • 6 lancets in a drum – no single lancets to see or touch

• Bayer’s DIDGET™ blood glucose meter plugs into a Nintendo DS™ or Nintendo DS™ Lite system

• This helps encourage consistent testing with reward points that children can use to buy items and unlock new game levels

The Importance of the User Interface

Blood Glucose: “We’ve got an App For That”

Lifescan popularised the iPhone route 2009

AgaMatrix Nugget iPhone

plug-in glucose meter gained FDA 510(k) 2011, marketted by Sanofi Aventis with iBGStar app, 2012.

Key Product Features

e.g. LifeScan’s One Touch Vario incorporating technology developed by Universal Biosensors (UBI) and manufactured in Rowville, Melbourne, Australia, launched in the Netherlands in January 2010: • 0.45µl • Side-loaded sample • No Code • Results in 5 seconds • Accurate to within ±15%

Current Paradigm of Blood Glucose Monitoring

Load lancet into launcher and

reassemble launcher

Prick finger or arm

Deposit blood drop on to test strip &

insert strip

Read test strip

Dispose of materials

1-2 Minutes

Burdensome and lengthy process is impediment to high compliance

Insulin Therapy

Diabetes Mellitus

Frequent Glucose

Monitoring

Good Metabolic

Control

Normal Life

Better Health

Painful Cumbersome Stigmatising

The Current Regimen

43

Pelikan Technologies Lancing System

Iron Core

Drive Coils

Guide Tube

Lancet

Iron Core

Drive Coils

Guide Tube

Lancet

The key component of the engine is a series of solenoids, which produce a strong, uniform and very controllable magnetic field inside a tube that houses a metal piston.

44

Pelikan Lancing Device

The Pelikan Sun went on the market in Australia, Germany and the USA from late 2007, but Pelikan Technologies (Palo Alto, USA) went into voluntray liquidation in 2011 and its asets were purchased by Sanofi.

45

Electronic Actuation Cam Driven Actuation Ballistic Actuation

Evolution of Lancet Actuation

Softclix® B-D PelikanSystems

Velocity

X

Velocity

X

Velocity

X

Skin Deformation

Exit Skin

Initial Penetration

Limit of Penetration

Skin Deformation

Exit Skin

Initial Penetration

Limit of Penetration

Skin Deformation

Exit Skin

Initial Penetration

Limit of Penetration

46

Integ LifeGuide – Minimally Invasive • Acquired by Inverness Medical Oct 2000 • Draws a tiny sample of interstial fluid (about 1 μl) from the outermost layers of the skin on the forearm in 8-10 secs • The unit then analyzes it for glucose in 30 secs • “Key” (white section) is disposable • Process avoids capillaries and nerve endings therefore is bloodless and eliminates pain associated with lancing a finger

The Case for Continuous Monitoring

Biostator-GCIIS (Circa 1981) Miles Laboratories in Elkhart, glucose-controlled insulin infusion system

Shichiri et al (1982) subcutaneous enzyme electrode with peroxide-based detection

The Origins of Continuous Glucose Monitoring (CGM)

49

Via Medical Inc Ex Vivo Glucose Sensor

Measurements taken every 5 Minutes for up to 72 hours

50

Micodialysis Micodialysis fibre

Fibre threaded through forearm (Mascini et al.)

The Arrival of Continuous Glucose Monitoring (CGM)

Medtronic Dexcom Abbott Freestyle Guardian STS Navigator Meter Kit $1,339 $800 $960-1,040 Sensors/m $350 (10x3day) $240 (4x7day) $360-390 (6x5 day) FDA Aug 2005 March 2006 March 2008 (CE June 07) approval Reading 1 per 5min (2h run in) 1 per 5min (2h) 1 per min (10h run in) Frequency Reading must be checked by finger-stick method before adjusting insulin

Sensor Augmented Pump

Real-time continuous glucose monitoring and the insulin pump have been combined into the Sensor-Augmented Pump system (Medtronic Diabetes, Northridge, CA). The first system was not widely released and it used a large transmitter, which was part of the original Guardian RT continuous glucose monitoring system. When the Minilink transmitter component of the Guardian RT monitor was approved in 2007, at that point the Medtronic Sensor Augmented Pump system was launched for marketing. Pilot studies have demonstrated improvements in mean glyceamia in users of this technology.

53

Futrex Inc 1992: Non-invasive glucose monitoring using NIR

The U.S. Securities and Exchange Commission charged Futrex with fraud, claiming that the Dream Beam never worked.

Minimally-Invasive and Non-Invasive Systems

Cygnus Glucowatch Biographer

Cygnus Inc. in Redwood City, California, has gone out of business and has stopped manufacturing its

meters. It sold essentially all of its assets to Animas Corp. (which makes insulin pumps) for $10 million.

Pendragon Pendra Pendra was CE approved in May 2003 and was available on the Dutch direct-to-consumer market. A post-marketing reliability study was performed in six type 1 diabetes patients. Mean absolute difference between Pendra glucose values and values obtained through self-monitoring of blood glucose was 52% and a Clarke error grid showed 4.3% of the Pendra readings in the potentially dangerous zone E. Pendragon now bankrupt.

Non-Invasive Monitoring: The Alarming Message To Date • Pendragon Pendra fails and Cygnus

Glucowatch stalls • Now 4 major failures in non-invasive sector • Alarming messages to investors

Yet, the push continues:

• Volatile analysis in skin & breath at Cranfield

“the science fiction you were speaking about is reality and being tested these days in Israel [by Cnoga]. The device is being in the middle of clinical tests … in the CARMEL hospital … it is been tested for CE …. the Device is not FDA approved yet. “ Samuel Payne / Dov Ben Asher. 22.10.08.

Non-invasive Monitoring

COMPANY TECHNOLOGY SITE

BioTex Inc, TX, USA Near-infrared Skin

Sensys Medical (Sensys GTS), AZ, USA Near-infrared Skin

Cascade Metrix Inc, IN, USA Mid-infrared/microfluid Skin

Light Touch Medical Inc, PA, USA Raman spectroscopy Finger

Integrity applications (GlucoTrack), Israel

Photoacoustic spectroscopy Ear lobe

VeraLight Inc (Scout DS), NM, USA Fluorescence spectroscopy Skin

Lein applied diagnostics, UK Optical Eye

Glucolight Corp (Sentris -100), PA, USA Optical coherence tomography Skin

Echo Therapeutics (Symphony tCGS, MA, USA

Sonophoresis Skin

Calisto Medical (Glucoband), TX, USA Bio-Electromagnetic Resonance Wrist

AiMedics (HypoMon), Australia Electro-physiological Chest skin

Biosign technologies (UFIT TEN-20), Canada

Electro-physiological Wrist

Cnoga Inc. (SoftTouch), Israel Optical (cell colour distribution) Skin

EyeSense, Germany Bio-chemical/fluorescence Eye (ISF)

VivoMedical, CA, USA Sweat analysis Skin

A selection of the apparently most active from >95 companies identified. Bold = in clinical trials

Glucotrack: ultrasound + thermal and electromagnetic conductivity

GlucoLight

HypoMon: 4 electrodes; electrophys changes

“The science

fiction you were

speaking about is reality “

Cnoga

Generations of Glucose Monitoring C

onve

nie

nce

1965 1970 1975 1980 1985 1990 1995 2000 2005 2010

AMES First Test Strips (Wash)

Boehringer Mannheim Visual Test Strips (Wipe)

LifeScan Non-Wipe Test Strip

Boehringer Mannheim Fast (12 sec) Test Time

Bayer Small (5μl) Blood Volume

LifeScan/TheraSense/Amira

Alternate Site Testing

Roche/Bayer Multi-Strip Integration

MediSense First Electrochemical Test Strip

Minimed

Cygnus (off the market) Dexcom

TheraSense

Continuous Monitoring

1st generation

2nd generation

3rd generation?

Pelikan Technologies Fully-integrated “One-Step” Approach

Defining Events 1962 - 1990

• 1962 First description of a biosensor: an amperometric enzyme electrode for glucose (Clark & Lyons)

• 1969 Ames Reflectance Meter launched • 1973-75 First commercial biosensor: Yellow Springs Instrument’s

electrochemical laboratory glucose biosensor • 1976 Miles Biostator: first bedside artificial pancreas • 1976 La Roche Lactate Analyser LA 640 using soluble mediators • 1981 1st Medisense electrochemical glucose sensor patent filed EP 0078363 • 1984 Shanks et al., capillary-fill Patent filed EP 0170375 • 1984 Publication of mediated amperometric glucose biosensor: ferrocene

used with glucose oxidase for the detection of glucose (Cass et. al.) • 1987 Launch of the MediSense™ ExacTech™ pen-shaped ferrocene-

mediated electrochemical home blood glucose biosensor • 1989 Launch of the MediSense™ credit card calculator-shaped ExacTech™

blood glucose biosensor

Defining Events 1990 - 2012 • 1992 Accucheck Advantage™ launched by Boehringer Mannheim • 1993 DCCT published; a major clinical study begun in 1983 which proved

the value of intensive control in reducing the complications of diabetes • 1995 Precision QID™ launched by Medisense with capillary-fill by “wicking” • 1996 Widespread introduction of capillary-fill devices by Bayer (Glucometer

Elite™), the manufacturer Kyoto Daiichi Kagaku (DIC Glucocard) and Menarini Diagnostics (Glucocard Memory)

• 1996 Abbott acquired Medisense for $867 million • 1998 Launch of LifeScan FastTake™ capillary-fill blood glucose biosensor

manufactured by Inverness Medical • 1998 Merger of Roche and Boehringer Mannheim to form Roche

Diagnostics • 2001 LifeScan purchased Inverness Medical’s capillary-fill glucose testing

business for $1.3 billion • 2004 Abbott acquires TheraSense (capillary-fill coulometry) for $1.2 billion • 2005 Medtronic Guardian introduced for continuous monitoring • 2006 Dexcom STS 7-day continuous sensor • 2012 Medtronic gained approval in Europé for automatic insulin shut off

Market Sizes in Diagnostics

• Biosensors - currently worth just under US$13 billion

• In Vitro Diagnostics (IVDs) – currently worth around US$40 billion

• Theranostics (companion diagnostics) – IVDs potentially worth US$72 billion Systems combining diagnosis, therapy and monitoring e.g. a test that qualifies a patient for treatment with a particular drug. Most common e.g. the HER-2/neu assay (Human epidermal growth factor receptor) required prior to treatment with Herceptin (humanised Mab) to determine 25% of breast cancer cases where receptors overexpressed. Also presence of KRAS mutation results in no benefit from Vectibix (Mab) for colorectal cancer. Numerous diagnostic/pharma alliances now being formed.

What Can Biosensors Contribute? The integration of diagnostics and therapy offers new funding paradigms • Convenient tests for polymorphisms • Metabolic assessments prior to and during treatment • Monitoring and control of drug administration • Outcome assessment including results of vaccination • Antibiotic resistance tests (current cost to EU ~$1.5b)

• Drug discovery and pharamacokinetic research • Alternatives to animal testing • Array-based single-cell investigation

“For every single Pharma product … the biomarker research and the

development of potentially companion diagnostics is a standard part of the development process” (Severin Schwan, CEO Roche, June 2007)

Conclusions

• Mediated amperometric glucose biosensors continue to dominate the home diabetes diagnostics market

• Peroxide based amperometric glucose biosensors predominate in the decentralised and in vivo markets

• The sector is typified by companies seeking to acquire a full set of technologies and pursuing high levels of integration (multi-sensors + multi-lancing &/or insulin injection) and sophisticated data treatment, displays and transmission

• Implantable sensors are in the market and home-use automated systems coupled to insulin infusion have been announced

• Non-invasive techniques have obvious attractions, but are meeting serious (insurmountable?) technical hurdles

Conclusions

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Web Sites www.mendosa.com/diabetes.htm www.mendosa.com/faq.htm www.ysilifesciences.com/ www.minimed.com/products/guardian/ www.viamedical.com/bgm.html www.pelikantechnologies.com http://echotx.com/ www.smartholograms.com www.glucodr.com (video) www.accu-chek.com.au/au/products/metersystems/advantage.html www.bayerdiabetes.com/sections/ourproducts/meters/breeze2 www.lifescan.com/ www.abbottdiabetescare.com/index.htm www.ifm.liu.se/biosensors

www.ifm.liu.se/biosensors

5.602

2011

Turner, A.P.F. (2013). Biosensors: sense and sensibility. Chemical Society Reviews DOI:10.1039/C3CS35528D Newman, J.D. and Turner, A.P.F. (2008). Historical perspective of biosensor and biochip development. In: Handbook of Biosensors and Biochips (Eds R. Marks, D. Cullen, I. Karube, C. Lowe and H. Weetall) John Wiley & Sons. ISBN 978-0-470-01905-4 www.wiley.com/go/biosensors Newman, J.D. and Turner, A.P.F. (2005). Home blood glucose biosensors: a commercial perspective. Biosensors and Bioelectronics 20, 2435-2453.