Osteoarthritis Final Presentation

Osteoarthritis Final Presentation - Novel Hyaluronic Acid...

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Unformatted text preview: Novel Hyaluronic Acid Derivatives to Alleviate Osteoarthritis Osteoarthritis Chris Clark Kim Fink Objective Objective To design a polymer to be used in non-surgical injections to relieve non surgical symptoms of osteoarthritis symptoms – Increased retention time – Maintain flexibility and strength Maintain – FDA approved – Reasonable cost Overview Overview Osteoarthritis Osteoarthritis Current Treatments Current Novel Hyaluronic Acid Derivative Novel Demand Demand FDA FDA Conclusions Conclusions The Knee Joint The www.medicinenet.com/ osteoarthritis/page2.htm Articular Cartilage Articular Transmits load from one surface to another another 2-3 mm thick Components Components – Water (70%) – Collagen (10-20%) – Proteoglycans (5-10%) – Chondrocytes (~5%) Synovial Fluid Synovial Fills gap between joints Fills – Approx. 50 µm thick Approx. During walking can be 0.8-1.5 µm During 1.5 – Volume ~1 ml Enclosed in synovial membrane Major components Major – Water – Proteoglycans – Hyaluronic Acid (HA) Synovial Fluid Synovial Properties Properties – Viscosity ~ 300-10,000 cP 10,000 cP – Coefficient of friction ~ 0.02 Compare to 0.03 for ice-on-ice Compare Main contributor to these properties Main Hyaluronic Acid Hyaluronic Hyaluronic Acid (HA) Hyaluronic Structure Structure – Linear repeating disaccharide D-glucuronic acid and N-acetyl-D-glucosamine acid – Number of units = 500 - 25,000 Number http://www.glycoforum.gr.jp/science/hyaluronan/HA01/HA01E.html HA in Synovial Fluid HA Average molecular weight for healthy knee Average 105 – 107 Daltons Concentration for healthy adult Concentration 3.4 mg/ml Non-Newtonian shear thinning Non Viscosity – variable – – – Increases with increasing molecular weight High at low shear rate Low at high shear rate The Disease The Osteoarthritis – General Facts Over 23 million Americans affected Over Most common in people 65+ Most Anyone susceptible Anyone – Impact injuries – Obesity – Prolonged elevated activity $1.5 billion/year industry in US $1.5 Osteoarthritis Osteoarthritis Most common in load-bearing joints Most – Knees, hip, lower back, neck Possibly due to decreased lubrication and load bearing properties of cartilage and synovial fluid and Leads to degeneration of cartilage and eventually bone-on-bone contact eventually Normal vs. Osteoarthritic Osteoarthritic Knee www.medem.com Symptoms Symptoms Mild to severe pain pain Limited range of motion motion Approx. 25% of patients unable perform daily functions functions http://adam.about.com/encyclopedia/19506.htm Current Treatments Current Physical therapy Physical – exercise techniques Oral medication Oral – Tylenol, Ibuprofen, Celebrex Tylenol, Celebrex – Effective for moderate pain Total Knee Replacement Total Hyaluronic acid (HA) injections Hyaluronic Current Treatments – Total Knee Replacement Advantages: Advantages: – Last 15-25 years Disadvantages: Disadvantages: – Time away from work Desk work (3-6 weeks) Desk Labor intensive work (several months) Labor – Requires extensive physical therapy – Risk of infection – Cost ~ $15,000 Total Knee Replacement Total www.raphaelmosseri.com/ mi_genou_uk.html Current Treatments – Hyaluronic Acid Injections Intra-articular injections of HA Intra articular derivatives derivatives – Series of injections, must be repeated Series after 6 months – Aims to increase the viscoelasticity of the Aims viscoelasticity of synovial fluid synovial Available HA Injections – Available HYALGAN® HYALGAN – Similar in structure and properties to natural Similar hyaluronic acid hyaluronic – Mixed results Hylan G-F 20 (SYNVISC®) Hylan – Crosslinked HA – Viscosity and elasticity near that of healthy 18-27 27 year old adult year – Last up to 6 months – $620 for 3-week treatment Problems Problems Current HA injections appear to degrade over time in the body degrade It has been proposed by some that the mechanism by which this degradation is occurring is through bond breaking (example of mechanism shown on next slide) (example Problem – Degradation Karthe Ponnuraj and Mark J. Jedrzejas, “Mechanism of hyaluronan binding and degradation: structure of Streptococcus pneumoniae hyaluronate lyase in complex with hyaluronic acid disaccharide at 1.7 Å resolution”, J. Mol. Biol. (2000) 299, 885-895 Solution – First Consideration CF3 modified HA CF – Increase the dipole to increase viscosity – Reduce degradation rate – Enzyme used to initiate reaction – Low cost of reagents – Problem: Reports of toxicity Our Solution Our HYAL-VYNE® HYAL-VYNE® HYAL High molecular weight hyaluronic acid derivative derivative ~106 Da HA modified with 2-vinyl HA New crosslinker introduced crosslinker Forms a viscoelastic hydrogel viscoelastic Modified HA Modified Hyaluronic acid polymer modified with 2Hyaluronic vinyl (R = -CH=CH2) vinyl – Polymerized using Ovine Testicular HAase (OTH) Polymerized HAase Crosslinker Crosslinker Ammonium Peroxydisulfate Ammonium – Chemical Formula = (NH4)2S2O8 – Molecular Weight = 228.18 g/mol Molecular – Cost = $3.61/500g Crosslinker Crosslinker Advantages Advantages – Sulfate has been proven to reduce Sulfate degradation rates degradation – Ability to stabilize a structure against Ability denaturation denaturation – Non-toxic Crosslinker Crosslinker http://www.llnl.gov/ipac/technology/profile/environment/GelledDecontaminant/UCRL_AR_143212.pdf Crosslinking Crosslinking Provides greater stability Increases size of structure for higherIncreases molecular weight Effects the solutions properties such as Effects – strength – viscosity Hydrogels Hydrogels 3D network of crosslinked hydrophilic crosslinked hydrophilic polymer chains polymer Absorb water Absorb – Able to retain shape upon loading and Able unloading unloading – Able to absorb more than 20% of their Able own weight own HYAL-VYNE® HYAL HYAL-VYNE® HYAL Required concentrations (mol/ml) (mol/ml) – HA = 2.8*10-4 – Crosslinker = 5.5*10-5 Reaction controlled by time time HYAL-VYNE ® HYAL VYNE Viscosity ~ 16 Pa—s Pa Molecular weight ~ 3 million Daltons Molecular Crosslinks per polymer chain ~ 24 Crosslinks Monomers per polymer chain ~ 44 Monomers Total number of monomers ~ 6700 Total Total number of crosslinks ~ 1000 crosslinks Lubrication Theory Lubrication Elastohydrodynamic Lubrication (EHL) Elastohydrodynamic – Applied in cases of low geometric conformity Applied subject to elastic deformation subject – Applies to most biological systems – Synovial fluid falls into Elastic-Isoviscous Regime Synovial Elastic – Use theory to calculate minimum film thickness Use of new gel to compare to normal synovial fluid synovial Minimum Film Thickness Minimum According to the Dowson-Higginson equation, the According Higginson minimum film thickness for EHL is minimum hmin = 1.6 0.7 α 0.6 µ 0 u E '0.03 R 0.43 ~ w0.13 Where µ0 = viscosity at atmospheric pressure Where ũ = effective speed E’ = reduced Young’s modulus R = effective radius effective w = load load α = material constant material Minimum Film Thickness Minimum Parameters: Parameters: – ũ = U0/2 = (0.03+0.03)/2 = 0.03 m/s /2 m/s – R = 0.20 m 0.20 – w = 2.6 MPa 2.6 MPa – α = 9.9 x 10-9 – E’ = 66.5 kPa 66.5 kPa HYAL-VYNE® Synovial Fluid Viscosity, µ0 Viscosity, 16 Pa—s 16 Pa 15.3 Pa—s 15.3 Pa Minimum film Minimum thickness, hmin 1.54 µm 1.54 1.50 µm 1.50 Demand Demand Demand Equations Demand p1d 1 + p2d 2 ≤Y p1d 1β = α p 2 d d 1 +d 2 2 d d α 1 β 2 ≤D Parameters Product demands, d1 and d2 = ??? ??? New treatment cost, p1 = $2400/injection Current treatment cost, p2 = $1300/year Total market demand, D = 7 million Total spent on treatment, Y = $1.5 billion/ year α amount costumers know about new treatment relative to others amount β measure of how much better new treatment is compared to competitors competitors Happiness Function Happiness Attributes Wi Design Design Variables Variables Frequency of Treatments 0.75 Pain of Injection Cost Min Max yi Crosslink Density -10.00% 10.00% 10.00% 0.125 Molecular Weight -20.00% 20.00% 20.00% 0.125 Injection Volume -5.00% 5.00% -5.00% Viscosity -10.00% 10.00% -10.00% Old Treatment Happiness = 40% Old New Treatment Happiness = 62% New Demand Demand competition' s happiness new treatment happiness 40% β= = 0.645 62% β= Year (0) = .645 Year Changes over time due to improvements in competitor products competitor Assume α gradually increases until new product is gradually equally known equally Demand Demand Year Alpha, α Alpha, Beta, β Beta, 0 0 0.645 1 0.15 0.715 2 0.4 0.785 3 0.89 0.855 4 0.99 0.925 5 1 0.995 6 1 1.065 7 1 1.135 8 1 1.205 9 1 1.275 10 1 1.345 Demand Demand Total demand changes each year Total – – – Year 1 = 370,000 people Year 2 = 621,000 people Year 3 = 625,000 people (max) By Year 6 it is expected that a better treatment will be created due to the increasing competition increasing FDA Approval Process FDA FDA Approval - Outline Classification Classification Type of Premarket Approval Premarket Necessary Experiments Necessary Possible Scenarios for success/failure Possible Time and Money requirements Time Product Classification Product Drug or Device? Drug – Drug: used for diagnosis or treatment of Drug: disease or to affect the structure or function of the body function – Device: used for diagnosis or treatment Device: of disease or to affect the structure or function of the body, but does not depend on metabolic process to achieve primary purpose achieve Product Classification Product HYAL-VYNE Medical Device Device Classification Device Class I: General Controls Class – Least stringent; minimal risk Class II: Special Controls Class – More regulations than Class I; no life-threatening threatening health risks health Class III: Premarket Approval Premarket – Most strict control; often intended to prevent or Most treat disease or sustain human life; require extensive review before marketing extensive Premarket Approval (PMA) Premarket Traditional PMA Traditional – All non-clinical and clinical tests completed, then clinical PMA submitted to FDA all at once PMA – If denied, possibly have to start completely over Modular PMA Modular – Non-clinical and clinical tests divided into clinical modules, information from one module reviewed by FDA at a time by – Allows for easier reassessment in case of denial Modular PMA Modular First a PMA shell must be submitted First – No predetermined format, customized for No particular device particular – Outlines experiments to be conducted in Outlines each module each – Gives approximate time of completion PMA Shell PMA HYAL-VYNE Module Number Contents Time to Complete Nonclinical Laboratory Studies: Physical and Chemical Property Tests Degradation Tests Toxicity Tests 3 Years Nonclinical Laboratory Studies: Animal Testing Sterilization and Packaging Injection Procedure 3 Years Clinical Studies: Human Patient Testing Physician Instructions Patient Instructions 5 Years • 1 • • • 2 • • • 3 • • FDA Approval Process Modeling Modeling First-Stage Decisions First First-Stage Decision Variables First – “Here-and-Now” decisions that must be made decisions prior to beginning a project prior Number of Employees Number – PhDs and lab technicians that will manage and PhDs conduct experiments conduct Number of Experiments Number – Number of repeated experiments that will be Number performed to submit to the FDA to prove consistency of results consistency First Stage Variables First-Stage Decisions: Number of Employees and Number of Experiments Determine Number of Workers Determine Number of workers 1 PhD, 10 Lab Techs 1 PhD 10 Lab Technicians $326,000 1 PhD, 5 Lab Techs 1 PhD 5 Lab Technicians $196,000 1 PhD, 2 Lab Techs 1 PhD 2 Lab Technicians $118,000 Determine Number of Experiments Determine Number of Experiments Determine Number of Experiments Determine Number of Experiments 100 Experiments $170,000 100 Days 85 Experiments $150,000 90 Days 50 Experiments $100,000 65 Days 100 Experiments $170,000 105 Days 100 100 Experiments $170,000 150 Days 85 Experiments $150,000 95 Days 85 Begin FDA Approval Begin Pre-FDA Experimentation 50 Experiments $100,000 70 Days 50 85 Experiments $150,000 140 Days 50 Experiments $100,000 120 Days FDA Risk FDA Name Min NPV Max NPV 10 workers 85 experiments -396.31 805.83 5 workers 85 experiments -554.35 815.63 2 workers 85 experiments -415.27 901.93 Distribution for 10 workers 85 experiments/M1060 1.000 M ean=206.0359 0.800 0.600 0.400 0.200 0.000 -0.4 -0.4 -0.2 0 0.2 0.4 0.6 0.8 V alues in Thousands 5% -.2121 90% 5% .5818 1 Modules Modules We have assigned probabilities (0-100%) We 100%) for each anticipated result after a particuar particuar module is submission to the FDA There are three probabilities listed for each scenario, which correspond to the number of experiments performed of In the case of disproval, we will re-evaluate In evaluate our procedures and resubmit the module our Module 1 Module Non-Clinical Testing Non – Compression/tension ratings – Viscosity – Crosslinking density – Product purity – Degradation rates – Toxicity Module 1: Non-clinical chemical and physical properties, degradation, and toxicity tests Module 2 Module Non-Clinical Animal Testing Non – Biocompatability/Immunogenicity – Biodegradation – Infection – Injection procedure (large animals only) – Range of mobility (large animals only) Module 3 Module Clinical Trials (Human patient testing) Clinical – Range of motion – Reduction in pain – Lasting effects – Effectiveness over placebo Conclusions Conclusions Conclusions Conclusions The novel hydrogel HYAL-VYNE® will be hydrogel will hyaluronic acid modified with 2-vinyl hyaluronic vinyl and crosslinked with ammonium crosslinked with peroxydisulfate peroxydisulfate (NH4)2S2O8 increases (NH – Stability – Retention – Load support Conclusions Conclusions Expected demand of 325,000 and will reach 625,000 per year Expected project life of 5 years Expected Total product cost ~ $210 million Total Cost per injection ~ $688 Cost Expected FDA approval process cost will be ~ $2 million, and will take ~ 9 years $2 Further Studies – Scale-up With the determined demand, it would required that: required – The plant capacity for HYAL-VYNE® be be approximately 1000 Liters/yr approximately – The cost of the treatment to be The competitive should be ~ $1500 per year or $2400 per injection or Special Thanks Special Research contacts Research – CBME Miguel J. 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