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Connective Tissue Proteoglycan

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Rheumatology Application. Liver Disease Application. Features of ... Rheumatology Application. Synovitis is the hallmark of RA ... Rheumatology Application ... – PowerPoint PPT presentation

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Title: Connective Tissue Proteoglycan


1
Hyaluronic Acid
The future of liver disease assessment
Denice Taylor March 2003
2
Overview
  • HA Market Potential
  • Rheumatology Application
  • Liver Disease Application
  • Features of Corgenix HA Kit
  • Sales tools
  • Competition
  • Benefits
  • Sales targets

3
Annual Market Potential for HA gt 65 M
Market Potential
  • US EU ROW
  • Liver 14 14 14
  • RA/OA 4 4 1
  • Misc 3 3 1
  • Rx 3 3 1

JP
4
Hyaluronic Acid (HA) Test Kit
  • Unique Product
  • Large Potential Undeveloped Market
  • Chronic HCV 180 million patients (1999)
  • Chronic HBV 350 million patients (2000)
  • Successful in Asian Market since 1995
  • Emerging market in Germany, Turkey
  • and Scandinavia

5
HA Test Kit
  • Sponsored International Conference on Measurement
    of Fibrosis, AASLD, Boston 2002
  • Currently in 4 major HCV trials COPILOT, Aegis,
    and 2 NIH funded studies
  • Corgenix Product Line to be extended

6
Hyaluronic Acid (Hyaluronate, Hyaluronan, HA)
  • High molecular weight polysaccharide, widely
    distributed throughout body
  • Produced mainly by fibroblasts and other
    specialized connective tissue cells
  • Function
  • Structural role connective tissue matrix
    proteoglycan
  • Participates in cell-to-cell interactions
  • Fluid retention and lubrication of joints

7
Hyaluronic Acid (HA) Connective tissue
8
Hyaluronic Acid (HA) Joint Production
9
Hyaluronic Acid (HA) Liver Removal
HA is cleared from the blood by specific
receptors in liver sinusoidal endothelial cells
(SEC)
10
Possible causes of elevated HA levels
  • ? ? Increased HA production
  • - inflammation such rheumatoid
    synovium
  • ? Increased release of HA from tissues
  • - cell damage
  • ??? Decreased HA removal from plasma
  • - decreased activity of SEC due to
    fibrosis or cirrhosis

11
HA Applications
  • Clinical use
  • Rheumatology
  • Liver disease, liver transplantation
  • Commercial and research use
  • Pharmaceutical industry
  • Nutritional supplements
  • Veterinary applications
  • Research

12
Rheumatology Application
  • Synovitis is the hallmark of RA
  • Increased production of HA is seen in RA, related
    to synovial involvement and the inflammatory
    process
  • Plasma HA levels have been shown to correlate
    with disease activity in RA

13
Rheumatology Application
  • Mean plasma HA levels are 7-fold higher in RA
    patients with active disease and 2-fold higher in
    OA patients when compared to healthy controls
  • HA can be used as a marker of synovitis in RA and
    osteoarthritis (OA)
  • HA may be useful in monitoring efficacy of RA
    therapeutics including DMARDs and biologic
    response modifiers

14
HA and Rheumatic Disease - RA and OA
15
Liver Disease
  • Serum HA levels ? with chronic injury (chronic
    hepatitis) to liver
  • Chronic injury (chronic active hepatitis) causes
    histologic changes in the liver
  • Fibrosis (infiltration of fibrous tissue) early
    histologic changes
  • Treatable
  • Reversible
  • Various grades (eg. Metavir, Ishak staging
    scores)
  • Cirrhosis advanced fibrosis and scarring
  • Reversible in certain cases
  • May lead to liver failure

16
HA in Normal Liver
Sinusoidal Endothelial Cells (SEC)
HA Receptors in Fenestrae
Stellate Cells
Space of Disse
Hepatocytes
17
HA in Liver Disease - Fibrosis
Kupffer Cell
Activated Stellate Cells
Fibrous (ECM) Proteins
18
HA in Liver Fibrosis/Cirrhosis
Irreversible Damage to Hepatocytes
19
HA Correlation with Fibrosis/Cirrhosis
20
HA and Traditional Liver Markers
21
Chronic Hepatitis
  • Multiple etiologies
  • Viral Hepatitis (80-90)
  • Hepatitis C (HCV) 90 of cases chronic 30-40
    progress to cirrhosis small develop CA
  • Hepatitis B (HBV) 5-10 develop chronic
    infection
  • Chronic substance abuse (alcohol)
  • Miscellaneous
  • Autoimmune hepatitis Hemochromatosis
  • Drug-induced hepatitis Primary Biliary
    Cirrhosis
  • NASH

22
Liver Biopsy
  • The Gold Standard method to diagnosis and stage
    fibrosis
  • Advantages
  • Can accurately stage the extent of liver injury
    and fibrosis
  • Is used to confirm the diagnosis and may lead to
    additional unsuspected diagnoses
  • Provides important prognostic information

23
Liver Biopsy
  • Disadvantages
  • Sampling error est. 24 false negative
  • Costly requires hospitalization
  • Risk of complications
  • Pain
  • Infection
  • Bleeding
  • Typically performed only every 2-5 years

24
Serum Fibrosis Markers
  • Advantages
  • Reflect the overall status of the liver (no
    sampling error)
  • Non-invasive
  • Less painful, less resistance from patients
  • Less costly (can be performed on outpatients)
  • Negligible risk of complication
  • Can be performed more frequently than liver
    biopsy

25
Serum Fibrosis Markers
  • Disadvantages
  • Cannot use to diagnose liver disease
  • Less sensitive and specific when compared with
    gold standard

26
HA in Liver Disease
Cutoff
cutoff
27
Utility of HA in Chronic Liver Disease
  • Distinguishes between cirrhotic and non-cirrhotic
    liver, regardless of etiology
  • Most sensitive serum indicator of changes in
    fibrosis and cirrhosis in CLD
  • HA reflects change in fibrosis following
    ?-interferon therapy
  • A sensitive marker for progressive liver
  • damage in primary biliary cirrhosis

28
HA Positioning in CLD
  • Use liver biopsy to establish the diagnosis of
    chronic liver disease
  • Measure baseline HA level at diagnosis
  • Monitor disease status with serum HA levels every
    4-6 months
  • Use HA to measure therapeutic response

29
Transplantation
  • Liver Transplant (approx. 5000/year in US)
  • HA is a sensitive indicator of SEC injury
  • Vascular damage prominent feature of graft
    rejection
  • HA is an early marker of rejection
  • Reflects viability of donor organ

30
HA levels in Liver Transplant Patients
Adams DH, Wang L et al. Hepatic Endothelial
Cells.Transplantation 47479-482 (1988)
31
HA in Liver Disease vs Bone Marrow Transplants
Serum HA in patients with veno-occlusive disease
following bone marrow transplantation
Fried MW, et.al. Bone Marrow Transplantation
27635 (2000)
32
HA and Bone Marrow Transplants (VOD)
Serum HA vs Bilirubin in veno-occlusive disease
patients
Fried MW, et.al. Bone Marrow Transplantation
27635 (2000)
33
Hyaluronic Acid (HA) Protein Binding Assay
(microwell format)
34
Features of Corgenix HA
  • Experts in ELISA technology
  • 18 months shelf life
  • Convenient procedure, total time 2.5 hours
  • No known interference or cross-reactivity
  • Proven track record since 1995

35
HA competition
  • Other HA kits
  • Conventional Liver Function Tests (LFTs)
  • Bilirubin ALT
  • AST Alkaline Phosphatase
  • GGT Albumin
  • Prothrombin Time
  • Other fibrosis markers
  • ?-GST PIIINP
  • Type IV Collagen Laminin
  • TGF-?-1 ?-2 Macroglobulin
  • TIMP-1
  • Fibrosis Panels
  • Prometheus
  • Fibrotest

36
Other HA methods
  • Pharmacia RIA kit
  • Echelon Competitive HA ELISA
  • Wako LiBASys
  • Mitsubishi LPIA

37
Pharmacia HA Test (RIA)
38
HA vs LFTs
  • HA
  • Reflects SEC function
  • Useful in chronic liver disease
  • Correlates with histological changes in liver
  • Early, sensitive marker for toxic liver damage
  • LFTs
  • Reflects hepatocyte function
  • Useful in acute liver disease
  • Insensitive due to extensive reserve capacity of
    liver
  • Do not reflect degree
  • of fibrosis

39
HA vs ALT as serum fibrosis markers
Serum HA is a useful marker for liver fibrosis in
chronic hepatitis C virus infection. Prospective
study n 130
Wong VS, et.al. J. Viral Hepatol 5 187 (1998)
40
Serum Fibrosis Markers
  • HA shows best sensitivity and specificity for
    cirrhosis
  • One test may not be enough
  • Additional novel markers (and therapeutics) may
    be discovered through basic research in fibrosis

41
Fibrosis panels
FIBROSpect Prometheus Labs, US
42
Fibrosis panels
Fibrotest T. Poynard et al., France
43
HA Market Japan
  • Market size (2002) 7 million
  • Clinical application chronic hepatitis
  • Disease groups
  • Hepatitis C
  • Hepatitis B
  • Alcoholic liver disease

44
HA Clinical Utility in Japan
  • Baseline measure HA levels at diagnosis
  • Monitor periodically thereafter (? 4 x per yr)
  • With anti-fibrotic therapy
  • Before treatment
  • End of treatment
  • 6-12 months post treatment
  • Disease specific cutoffs
  • Fibrosis 50 ng/mL
  • Cirrhosis 130 ng/mL

45
HA marketing challenges
  • Physician Awareness of test
  • Publications by opinion leaders
  • Training workshops
  • Advertising
  • Trade shows
  • Competition
  • Positioning

46
Sales targets
  • Reference Laboratories
  • Medical Centers
  • RA clinics
  • Hepatology clinics (with liver clearance)
  • Transplant centers
  • Hospital Laboratories
  • Research Centers
  • Pharmaceutical Companies
  • Nutritional Companies

47
510(k) status
  • Liver Clinical trial protocol under review by FDA
  • Three study sites identified
  • Trials to begin spring 2003
  • 510(k) submission late 2003
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