R&D/Manufacturing of Biomaterials and Medical Devices (with Jim’s Help)

Avco Medical Products (1971 - 1978)Thoratec / Mercor (1978 - 1988)

Polymer Technology Group (1989 - 2010)ExThera Medical Corporation (2010 - Now)

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Processing/Conversion Clean Room Device Assembly

Lab & Pilot Batch Synthesis <1-100 L Production Synthesis 10-1000 gal.

Characterization and QC

Biomedical Polymers: The Ideal

A Practical Biosurface Polymer Chemistry

“…organic functional groups designed and introduced onto

man-made surfaces to control the biological

interactions…yielding tailor-made surfaces.” *

How can this be done?

1. With coatings & topical treatments

2. Through understanding and application

of Surface Activity and Self Assembly of

soft blocks and end groups →

‘SMAs, SMEs and SAMEs’

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(Polyurethane) Block Copolymers with ‘SAME’:

‘A Biomaterials Toolkit’

SAME [ ] SAME*Polymer Backbonen

]]

n

Surface Properties

= Hard Block

= Soft Segment # 1= Soft Segment # 2

= SAME # 1= SAME # 2

Bulk Properties

*Note: ~1018 end groups/gram of linear polymer @ 100K Da.

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End Groups Can Modify Important Surface Properties

• Biostability

• Lubricity / Low Sliding Friction

• Thrombo-resistance

• Anchoring Bioactive Molecules

• Protein Adsorption

• Abrasion Resistance (Roller Pump)

• Antimicrobial Activity

• Permeability of Dense Membranes

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r

Liquid Reactants In

Continuous Reactor for Bulk Synthesis of Thermoplastic

(Co)Polymer Pellets: For Injection Molding and Extrusion

Pelletized

Product

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Biomedical Polymers Developed and Commercialized

• Bionate® polycarbonate-urethane by continuous synthesis

• Bionate®II polycarbonate-urethane with SAME surface modification

• CarboSil® silicone-polycarbonate-urethane copolymer

• Elasthane™ polyether-urethane (Pellethane-2363 replacement)

• PurSil® silicone-polyether-urethane copolymer

• PurSil® AL aliphatic silicone-polyether-urethane copolymer

• BioSpan®/ Cardioflex™ segmented polyether-urethane-urea

• Thoralon™ surface-modified segmented polyether-urethane

• Angioflex™ / Avcothane™-610 high-purity polyetherurthane

• Avcothane™-51 / Cardiothane™ silicone-polyurethane hybrid (scale up)

All PTG Polymers have FDA Master Files↑

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Some Blood- and Tissue-Contacting DevicesThat Use our Biomedical Polymers

• Intraaortic Balloon

– Avco/Kontron/Arrow

• Sac and Diaphragm VADs

– Thoratec, ThermoCardio, Sunshine Heart, Hershey Medical Center, others

• Vascular Access Graft

– Bard (Thoratec Vectra® )

• Pacemakers and Leads

– Medtronic

• Neuro-stimulators and Leads

– ANS/St. Jude

• C-V Catheter

– Vygon

• Continuous Glucose Sensors

– Dexcom, Medtronic

• $ilicone-Hydrogel Contact Lense$

– Vistakon: Acuvue Advance, Oasys, and TruEye

• Prosthetic Cervical Disc

– Medtronic Bryan Disc

• Prosthetic Lumbar Disc

– Axiomed Freedom Disc

• Dynamic Spinal Fixation Implant

– Zimmer Dynesys®

• Anti-Viral Drug Delivery

– Conrad TFV LNG Intravaginal Ring

Monolayers Matter! : In Vivo Platelet Thrombus on Catheters is Reduced Three Orders of Magnitude by Amphiphilic Terpolymer

‘Surface Modifying Additive’ (SMA): ‘Thoralon™’

γ

Camera

Goat

Control PU

Surface Modified PU

Experiment in progressRadiolabled platelet

uptake vs timeVentricular assist

device (VAD) explants

w/o SMA

w. SMA

≈1000-fold reduction in adherent platelets

on modified PU catheter

Thoratec PVAD & IVAD

Clots

43 Years of Biomaterials for Blood-Contacting Cardiovascular Devices

AVCO IAB 1971:

First Cardiac

Assist Device

Sunshine Heart

C-Pulse* 2010

Thoratec Vectra™ Vascular Access Graft

TCS HeartMate® LVAD

Jarvik III

TAH

Thoratec PVAD

Kantrowitz

CardioVad™

Abiomed BVSAbiocor TAH

Thoratec IVAD * No blood contact

Therapeutic Applications of Biomedical Polymers:

Curing Bloodstream Infections with Polymeric Adsorbents

Bob Ward and Keith McCrea

ExThera Medical Corporation

Berkeley, CA 94710

www.extheramedical.com

Bloodstream Infections Are Becoming More Deadly

• (Over) use of anti-infective drugs promotes resistance

• Slow pathogen ID delays treatment:

– Metastatic infections and septic shock may result

– Mortality increases 7% / hour of delayed treatment ! *

• Rapid treatment prevents progression and reduces ICU costs

• A safe, broad-spectrum, disposable device may be the answer!

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*Kumar A, Roberts D, Wood KE et al. Crit Care Med. 2006;34:1589-96

Methicillin Resistant Staphlococcus aureus (MRSA):Binds to Heparin/Heparan Sulfate

MRSA Bacteremia Incidence:– Leading cause of bacteremia in hospital

patients: 18.8%

– An emerging global pandemic

Metastatic Complications:– Infective endocarditis

– Septic arthritis and osteomyelitis

– Organ involvement (lung, liver, spleen, brain)

Mortality: Over 36% from MRSA!

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Warnings from Trusted Sources

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“Bacteria will inevitably find ways of resisting the antibiotics we develop, which is why aggressive action is needed now to keep new resistance from developing and to prevent the resistance that already exists from spreading.” (U.S. CDC)

“The problem of

antimicrobial

resistance calls for

international

cooperation, as well

as concerted efforts

at the national level.”

(ECDC)

“The WHO’s first global report on antimicrobial resistance, reveals that it is no longer a prediction for the future. Antibiotic resistance—when bacteria change and antibiotics fail—is happening right now, across the world”

Antibiotic crisis

needs united global

response 23 May 2014

“Growing resistance

among pathogens to

antibiotics and other drugs

demands a coordinated

global response on the

same scale as efforts to

address climate change,

say experts including Dr

Jeremy Farrar, Director of

the Wellcome Trust.

Without an international

commitment to tackle the

issue, the world faces a

future in which simple

infections that have been

treatable for decades

become deadly diseases,

they warn.”

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Blood Pump

One Device to Remove Pathogens, Toxins and

Pro-inflammatory Cytokines from Whole Blood

Seraph® Microbind® Affinity Blood Filter:A broad-spectrum adsorption-hemoperfusion device

Dual-lumen Central

Venous Catheter

Design Control Inputs for a Safe and Effective Sorbent Hemoperfusion Device

1. A disposable broad-spectrum biomimetic, whole-blood sorption hemoperfusion device

a. Binds bacteria, viruses, parasites, toxins and pro-inflammatory cytokines

Works on drug-susceptible and drug-resistant pathogens

2. Rapid kineticsa. Convective transport of adsorbates to binding sites

• No rate-limiting diffusion into mesopores or through membranes

→No size exclusion of (cellular) adsorbates

3. Very high binding capacity per unit weight of adsorbent

4. Highly anti-thrombogenic blood-contacting surface

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Design Control Inputs for a Safe and Effective Sorbent Hemoperfusion Device

5. Pathogens do not die and release toxins when adsorbed

6. Treats whole blood without fractionation

7. Simple design is easily scaled up for manufacturing

8. Disposable component has multi-year shelf lifea. Stored dry at room temperature

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Anand Kumar MD, University of Manitoba

From Late InterventionAntimicrobial Drug Therapy

To Early Antimicrobial Device Therapy with Seraph®

A Paradigm Shift:

RITYEVE S

RITYEVE S

Treating BSI to Prevent Sepsis & Septic Shock

Microbial load

Inflammatoryresponse

Toxic burden

TIMEt(a) t(b)

TIME

Toxic burden

Microbial load

Antimicrobial

therapy

Cellular dysfunction/tissue injury

earlier antimicrobial

therapy (Seraph ®

Shock

Threshold

Cellular dysfunction/tissue injury

Inflammatory response

Shock

Threshold

t(a) t(b)

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Biomimetic Binding in Seraph Media:Heparin ≈ Heparan Sulfate (glycosaminoglycans)

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heparan

sulfate

Cell Surface

ATIII

peptide backbone pathogen

ATIII

ATIII

ATIIIATIII

Surface of

Seraph Media

heparin

toxin

Some of the Pathogens that Bind to Heparin/Heparan Sulfate

23 © ExThera Medical 2/13

Bacteria

S. aureus Endocarditis, Meningitis, Sepsis

MRSA Flesh Eating Bacteria,Endocarditis, Meningitis, Sepsis

Borreliaburgdorferi

Lyme Disease

Strep. pyogenes

Scarlet Fever, Strep.Throat, Toxic Shock Syndrome

Strep. pneumoniae

Pneumonia, Sepsis, Meningitis, Endocarditis

Viruses

CMV Organ Failure

Dengue Hemorrhagic Fever,Dengue Shock Syndrome

Hepatitis C Liver Failure, Cancer

HIV Aids

West Nile Encephalitis, Meningitis

Parasites and Other

Babesia Malaria of the Midwest

Plasmodium spp. Malaria

T. cruzi Chagas

Prions Mad Cow Disease, vCJD

Removal of Pro-inflammatory Cytokine from Porcine Plasma by Seraph: TNF-α

• 50% Reduction @30 min.

• 80% Reduction @80 min.

• 5 liters of plasma dosed with TNF-α at 83 µg/L

• Circulated at 150 mL/min through a Seraph cartridge back to a large blood bag

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Constant 80%

reduction of inlet

concentration

Time [min.]

Drug-Resistant BacteriaGram Positive

BacteriaGram Negative

BacteriaViruses, Fungi, and

Toxins

MRSA S. aureus E. coli HSV-1, HSV-2

CRE - E. coli and K. pneumoniae

S. pneumoniae K. pneumoniae C. albicans

ESBL - K. pneumoniae E. faecalisAcinetobacter.

baumannii Endotoxin*

VRE - E. faecalis E. faecium P. aeruginosa*S. aureus

a-hemolysin

Current List of Successful In Vitro Results

Considered “URGENT THREAT” by CDC

Seraph® Microbind ®

Affinity Blood Filter

Drug resistant bacteria removed as easily as drug susceptible Lowering bacteria and toxin loads should allow antibiotic

treatments to be more effective No need to identify which bacteria is causing the infection

• Allows early treatment and better outcomes

Considered “SERIOUS THREAT” by CDC

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Expanding Seraph’s Binding Capacity to Include Endotoxin

• Endotoxemia is common during sepsis regardless of infecting organism

• Initial gram negative organism, or leaky gut

• High-grade endotoxemia increases mortality

• Endotoxins bind to (cationic) surfaces that are thrombogenic….not to heparin

• Can heparinized media in close proximity to thrombogenic surfaces prevent thrombosis ??

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(Thrombogenic) Supplemental Adsorbent Gives Seraph Ability to Safely Remove Endotoxin

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Human blood with LPS* (10 ng/mL)

circulated through Seraph columns

at 150 mL/min for 2 hr.

LPS Reduction (n=3):

Mixed Media: 98%

Heparin Only: 0%

* Lipopolysaccharide© ExThera Medical 4/13

Mixed Media

Heparin-Only

SEMs After Blood Contact

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Media Synthesis and Drying:

Automated Manufacturing of Seraph Columns:Optimized for Specific Diseases or Very Broad Spectrum Use

Heparin Media 3Media 2 (Media 4?)

Order Blend & Quantity Automated

Blending

and Filling

Filled

Seraph

Column

0.E+00

1.E+05

2.E+05

3.E+05

4.E+05

5.E+05

6.E+05

7.E+05

8.E+05

9.E+05

1.E+06

MRSA+CRE

CRE

MRSA

Independent Binding Studies - Bacteria Removed SeparatelyStarting Concentration

(CFU/ml)Ending Concentration

(CFU/ml)% Reduction CFU/g

MRSA 1.21E+05 1.02E+04 92% 3.69E+05

K. pneumoniae (CRE) 1.40E+05 7.83E+01 99.9% 4.66E+05

Total CFU/g expected if tested simultaneous without binding competition 8.36E+05

Polymicrobial Study - Bacteria Removed SimultaneouslyStarting Concentration

(CFU/ml)Ending Concentration

(CFU/ml)% Reduction CFU/g

MRSA 2.03E+05 3.52E+04 83% 5.59E+05

K. pneumoniae (CRE) 2.07E+05 1.12E+05 46% 3.17E+05

Total CFU/g (MRSA + K. pneumoniae) 8.76E+05

Polymicrobial Binding Does Not Change Capacity of Seraph Media

Conclusion: Competitive binding is negligible.

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High Binding Capacity of Seraph Filter:[ % of Total Pathogens in 5 Liters of Infected Blood ]

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Seraph® Animal Safety Study (During Dialysis)

Catheter Placement Filling While Displacing Saline

Experiment In Progress Rinsed Column at 3.5 hrs.©ExThera Medical 4/14

Conclusion

The Seraph® Microbind® Affinity Blood Filter (Seraph) uses ExThera’s proprietary biomaterials (adsorption media) to create a device that fills a large and growing clinical need

• A safe, broad-spectrum treatment of bloodstream infections caused by increasingly drug-resistant organisms

• Captures pathogens and toxins to reduce the inflammatory response and stop the progression of BSI to sepsis, severe sepsis and septic shock

• Reduces healthcare costs by avoiding expensive ICU care

• Addresses several very large markets• Therapeutic: Bloodstream Infections / Sepsis

• Prophylactic: Blood Banking

Confidential

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• 99.8% of herpes simplex virus 1

• 80% of TNF-α cytokine in one hour 5

Bacteria, Toxins, Viruses and Pro-inflammatory Cytokines

• 85% of MRSA bacteria in single pass 1,2,3

• 100% of S. aureus α-toxin in a single pass 2

• > 99.9% of E. coli, Klebsiella pneumoniae

(‘CRE Super Bugs’) 3

• 85% of Pseudomonas aeruginosa 3

• 98% of Endotoxin 4

Independently Tested

Collaborators

Centers:1 University of Gothenburg, Sweden

2 Texas A&M, USA

3 Antimicrobial Test Labs, USA

4 Ludwig Boltzmann Institute, Austria

5 University of Minnesota, USA

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Thank YouJim!

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