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Evaluation of Squalestatin 1 as an Enzyme Inhibitor for Lowering Cholesterol Presented by Sam Noor-Mohammadi Daniel Feze April 28, 2008 Advanced Process.

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Presentation on theme: "Evaluation of Squalestatin 1 as an Enzyme Inhibitor for Lowering Cholesterol Presented by Sam Noor-Mohammadi Daniel Feze April 28, 2008 Advanced Process."— Presentation transcript:

1 Evaluation of Squalestatin 1 as an Enzyme Inhibitor for Lowering Cholesterol Presented by Sam Noor-Mohammadi Daniel Feze April 28, 2008 Advanced Process Design

2 Reversal of Medication Labels

3 Agenda Problem Statement Background Drug Model Production ◦FDA ◦Manufacturing Economics ◦Demand Model-Price Model Conclusions

4 Problem Statement This work evaluates the economic potential of a new enzyme inhibitor for lowering cholesterol levels in human plasma. We looked into ◦FDA Process ◦Manufacturing and Production ◦Economics and Pricing of the Drug

5 Cholesterol Produced by liver cells and acquired through diet and natural production Three major types: ◦High density lipoprotein (HDL) “good cholesterol” ◦Low density lipoprotein (LDL) “bad cholesterol” ◦Triglycerides Important in transfer of blood constituents (ex. lipids) Important in cell survival

6 Formation of Plaques Formation of Plaques in the Arteries LDL are retained by artery walls while moving the cholesterol from liver to peripheral tissue. This accumulation is responsible for the hardening of the arteries

7 Health Facts High Cholesterol Leads to Heart Disease 29% of Heart Disease Related Deaths in the U.S Each Year 17.5% of People Over 20 Years of Age are at Risk for Heart Disease and Stroke

8 Health Facts Good Serum Cholesterol Level is 199 mg/mL ◦In 2005-2006, 16% of American Adults had Levels Over 240 mg/mL ◦For Women Over 60 Years this Level was Higher than Men ◦For Women and Men 20-59 Years the Same Levels Were Observed

9 Solutions to Lowering Cholesterol 1. Low Fat Food, Exercise 2. Herbal and Nutritional Solutions 3. Statin Drugs ◦Vitoryn ◦Zocor ◦Zetia ◦Lipitor ◦Pravachol

10 Statin Drugs Ranges From 10-80 mg/day High Dosage are Given to Patients with High LDL Levels and Serum Cholesterol Levels DrugDosage (mg/day)Percent Reduced Lipitor10 to 2030%-45% Mevacor4030%-45% Pravachol4030%-45% Crestor1030%-45% Zocor20 to 4030%-45%

11 How it Works: ◦By inhibiting HMG-CoA in the Biosynthesis of Cholesterol Production ◦Main Enzyme in Producing Cholesterol How Statins Work

12 Side Effects of Statins Common Side effects in most of the cholesterol lowering drugs ◦Head pain ◦Dizziness ◦Rash ◦Throwing up ◦Some dissolve in fat and reach barriers of brain cell membrane ◦Insomnia

13 Other Problems with Statins Interfere with the Biosynthesis of Coenzyme Q 10 CoQ 10 is Vitamin like, Fat-Soluble Antioxidant High Concentrations in Vital Organs like Heart Important in Energy Production Statins lower cholesterol in plasma and also CoAQ 10 (Passi, 2003)

14 New Drug Squalestatin 1 Selective Inhibitor of Squalene Synthase ◦Key Enzyme in Cholesterol Biosynthesis

15 New Drug SQ1 will be used to lower serum cholesterol level ◦By Controlling the Flux of Cholesterol Biosynthesis Squalestatin 1

16 New Drug SQ1 Inhibits Squalene Synthase ◦Lowers the Production of Cholesterol

17 How Dosage is Determined Inhibition dependant of daily production of squalene synthase (13.4 nmoles per day) squalestatin binds to squalene synthase to form complex Number Molecules Squalestatin = Number Molecules of Squalene Synthase

18 Dosage 10 to 20 mg daily doses for 40 to 60% inhibition

19 Dosage and Percent Reduction DrugDosage(mg/day)% Reduced SQ12060% Statins4060%

20 Squalestatin Pathway Hepatic and Renal Elimination squalestatin

21 Renal Clearance Passive diffusion across glomerulus Fick’s law application P= permeability size dependant A= kidney filtration area (516 cm 2 ) C= squalestatin concentration in the plasma and kidney

22 Squalestatin 1 Clearance

23 Side Effects Side Effects: ◦Have not been tested but it can be assumed lower side effects than other cholesterol lowering drugs because of its inhibition of a different enzyme.

24 Toxicology Evaluation Higher Clearance than Atorvastatins Lower doses 10 to 20 mg Vs 20 to 40mg Higher diffusions coefficient in the kidneys (shorter half life ) 8 hours Vs 14 hours

25 Toxicology Evaluation No Ubiquinone metabolism related side effects (43 % of severe side effect) Myalgia : muscle ache and weakness = 24% Arthralgia joint pain =19% Asthenia overall body weakness

26 Production Plan FDA process Manufacturing

27 FDA Approval Process Pre –FDA: Test tubes and mammalians testing Phase I: Safety test on small number of patients Phase II: Efficacy Test on Familial Hypercholesterolemia patients Phase III: Safety and efficacy tests on subjects with special conditions  Hundreds to thousands of patients are volunteered for this phase.  Last and most determining phase

28 Pre-FDA More tests = better rate of success through FDA Too many tests= waste of time and money

29 Pre-FDA Decision Tree 1 PhD, 8 labs Technicians PRE-FDA Option A, 28 Weeks $162,000 2 PhD, 12 labs Technicians 1 PhD, 12 labs Technicians Option B, 31 Weeks $179,000 Option B, 28 Weeks $215,000 Option A, 21 Weeks $162,000 Option A, 24 Weeks $185,000 Option B, 21 Weeks $162,000

30 FDA Flow Chart ( Phase I ) 1year, 1.22millions, 70 subjects.1% 12.12% 87.78% No Antibody Stimulation Phase I Drug is Safe Adverse Side Effects Clinical Hold Up Back to R&D

31 Flow Chart (Phase II) 2 years, $5.2 millions,200 subjects 1.1% 10.5% 10% 79.4% Phase II Severe Side Effects Minor Side Effects Drug is Ineffective Drug is Safe and effective Clinical Hold Up back to R&D

32 FDA Flow Chart (Phase III) 900 patients, $61.8 millions,6 years 0.50% 10% 89.5% Phase III Unexpected Side Effect Drug is Ineffective Booster to increase Titer Drug is safe and effective Biologics License Application Pre-approval Facility inspection Advisory Committee Clinical Hold Up Drug is not SafeDrug is Safe

33 FDA Summary Cost ($) In MillionsLengthParticipants Phase I1.221 year70 Phase II5.22 years200 Phase III61.86 years900

34 FDA Summary The chances of passing are estimated at 69% The total cost is $69.3 millions for 10 years 31% Risk of failing FDA approval for a total loss of $138 millions

35 Manufacturing Process Calcium Salt Extraction

36 Squalestatin Extraction

37 Fermenter Scale Up 1. H/D ratio 2. Volumetric oxygen transfer coefficient (Kla) 3. Power consumption volume 4. Impeller tip velocity

38 Fermenter Scale-Up H/D ratio The most important factor in fermenter geometric design Advantages: 1. bubble residence time increase 2. top sparger air pressure is higher (higher O2 dissolution) 3. Volume of air required decrease with constant SLV

39 Fermentor Scale-Up Air impelled fermenter Considerable mixing energy savings. Greater Kla value Greater sparger pressure

40 Column Chromatography scale-up Pressure drop across each column (Darcy equation) L= column height, ∆P= pressure drop across the column, µ = viscosity of the mobile phase, ν= superficial velocity K= constant, p= resin particle diameter, ε = void fraction, Column size V1,Q1 = pilot plant column volume and flow rate V2,Q2 = scaled up column volume and flow rate

41 Economics Price of the Drug ◦Demand Model Production Manufacturing

42 Demand Model Assumptions Number of People Who Need a Type of Cholesterol Lowering Drug ◦8,000,000 800,000 Patients will Switch from the Highest Selling and the lowest Priced Statin Drug to this New Medication

43 Demand Model Assumptions Cond. Assume Percent Prescribed ◦10mg is prescribed 50% ◦20 mg is prescribed 25% ◦40 mg is prescribed 15% ◦80 mg is prescribed 10% Prescriptions are Renewed Every Year

44 Demand Model Equation  Awareness Function ◦Function of time, advertising and professional education  =0, No knowledge  =1, Perfect Knowledge d 1 ; Demand for the New Product ; Market Demand ◦Assumed 0.78 Y; Consumer Budget P 1 and P 2 ; New and Old Product Price

45 Demand Model  ; Consumer Satisfaction, Ratio of Old to New ◦=H 2 /H 1 ◦H; Consumer Satisfaction Function   W i yi  y; Consumer Related Property ◦ Effectiveness; % serum cholesterol reduction ◦ Side effects; Related to Plasma Concentration of Drug  W; Product Weight

46 Effectiveness Efficacy is the measure of the effectiveness of the drug in reducing the life threatening condition a patient is suffering from.

47 Effectiveness

48 Effectiveness Reduction in % Serum Cholesterol Level ◦Lower=Higher Satisfaction ◦By Measuring the Level in Blood

49 Side Effects Assumed that 50% of Prescriptions are for 10 mg/day ◦No or Very Low Side Effects Less Important than the Efficacy of the Drug ◦Based on a Doctor's Recommendation and Opinion

50 Beta Factor Beta WeightY1Y1 Y2Y2 Efficacy0.951.260.74 Side effects0.050.5 H=  (weight*y) 1.220.73  0.6

51 Alpha Factor

52 Demand Model


54 Price of the Drug Price of the New Drug ◦$1.33 or $1.70 for 10 mg/day (one tablet) ◦Demand model was solved for this range of values ◦Demand below $1.33 did not make sense

55 Business Economics Equipment Prices

56 Business Economics Raw Material Suggested Factor Quantity Per year Cost Per UnitValue ($/year) Water (Process)$/Kg70,339,560 0.53/10 00$37,280 GlycerolKg28,1360.6$16,881 Cotton Seed FlourKg2,4321$2,432 Soybean OilKg84,4072.5$211,019 ActetonitrileKg17,993,0881.39$25,010,392 Sulfuric acidKg71,9620.07$5,037 Ammonium sulfateKg450,9440.08$36,037 Resinliters236200$47,124 Calcium acetateKg172,486179$30,875,010 Phoma sp.Kg270,037219$59,138,059 Total$115,379,310

57 Production Cost Suggested Factor Amount Per YearPrice Per year Operating Labor25.58$/h $181,618 Operating Supervision0.15 $27,243 Electricity0.045$/kWh $18,696 Fuel1.26$/GJ Steam4.2$/1000kg424 Kg$2 Maintenance0.07 $4,691,327 Operating Supplies0.15 $703,699 Laboratory Charges0.15 $105,055 Utilities$5,594,778 Manufacturing Costs$121,107,449 Taxes0.02 $1,340,379 Financing0 Insurance0.01 $670,190 Rent0 Depreciation $3,015,853 Fixed Charges w/o Depreciation$5,026,422 Plant Overhead Costs0.6 $144,907,909 Administrative Costs Included Above Distribution and Marketing Included Above Research and Development Included Above General Expenses $144,907,909 Total Product Cost w/o depreciation $271,041,780

58 FCI/TCI FDA-Fixed One Time Cost $69,000,000 Fixed Capital Investment $76,018,956.73 Working Capital $1,239,458.63 Total Capital Investment $77,258,415.36

59 NPV Based on NPV value and Demand Analysis, $1.33 and $1.70 are Best prices for SQ1 NPV ($1.33) = $13,912,008,251

60 Risk Analysis The Risk of the Project Determined from NPV and Demand Graphs

61 Conclusion High Cholesterol is a Growing Epidemic in the U.S. 20 mg/day of SQ1 will Reduce the Serum Cholesterol Level by 60% ◦Higher Efficacy ◦Lower Side Effects Demand for this Price of Drug is Close to 800,000 Patients Best Price to a Corresponding High Demand and NPV of the Project is $1.33 for 10 mg/day

62 References Baxter A., Fitzgerald B.J., Huston J.L., McCarthy A.D, Motteram J. M., Ross B. C., Sapra M., Snowden M.A., Watson N.S., Williams R.J., and Wright C., Squalestatin 1, a Potent Inhibitor of Squalene Sunthase, Which Lowers Serum Cholesterol in vivo, The journal of biological chemistry, Vol. 267, No. 17, Issue of June 15, pp. 11705-11708, 1992 Harl C. Erica, Martin Melissa, Financial and Technological Risk Analysis for the Development of New Drug, May 5, 2006

63 Questions?

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