Evaluation of Squalestatine 1 as an Enzyme Inhibitor for Lowering Cholesterol By Samaneh Noor-Mohammadi Daniel-Frank Feze University Of Oklahoma College of Engineering School of Chemical, Biological and Materials Engineering Spring 2008 1 Table of Contents Abstract .......................................................................................................................................... 6 Introduction and Background ..................................................................................................... 7 Cholesterol ................................................................................................................................................ 7 Methods for Reducing Cholesterol Level .............................................................................................. 9 The Drug Model .......................................................................................................................... 11 Problem with Statin Drugs ...................................................................................................................... 11 Squalestatin 1 .......................................................................................................................................... 12 Drug Model ............................................................................................................................................. 14 Dosage ..................................................................................................................................................... 14 Pharmacokinetics .................................................................................................................................... 15 Manufacturing Squalestatin 1 ................................................................................................... 16 Process overview .................................................................................................................................... 16 Scale up ................................................................................................................................................... 18 Fermenters .......................................................................................................................................... 18 Phase I-Pre-FDA ..................................................................................................................................... 20 Cost and Duration ............................................................................................................................... 21 Pre–FDA summary ............................................................................................................................. 23 FDA ........................................................................................................................................................ 23 Phase I ................................................................................................................................................ 23 Phase II ............................................................................................................................................... 24 Phase III .............................................................................................................................................. 24 FDA Costs ............................................................................................................................................... 25 Toxicity and Efficacy Estimation ........................................................................................................... 25 2 Price Analysis .............................................................................................................................. 29 Price Model ............................................................................................................................................. 30 Alpha factor ............................................................................................................................................ 33 Beta Factor .............................................................................................................................................. 34 Effectiveness ........................................................................................................................................ 35 Demand Model Results ........................................................................................................................... 36 Business Economics .................................................................................................................... 41 NPV Analysis.......................................................................................................................................... 45 Risk Analysis .......................................................................................................................................... 48 Conclusions .................................................................................................................................. 50 References: .................................................................................................................................. 51 3 Table References Table 1: Comparison between Different Statin Drugs in the Market ......................................................... 10 Table 2: Different Sets of Experiments ....................................................................................................... 22 Table 3: Beta Calculation ............................................................................................................................ 34 Table 4: Product Cost Price List for $1.33 per Unit Scenario .................................................................... 42 Table 5: Feed Product Cost for $1.33 per Unit Scenario ............................................................................ 43 Table 6: FCI and TCI Estimations for Scenarios 1, 2 and 3, 4 ................................................................... 44 Figure References Figure 1: Endogenous Cholesterol Synthesis ................................................................................................ 8 Figure 2: Plaque Formation in Arteries ......................................................................................................... 9 Figure 3: (Right) Mevinolin Structure, (Left) A. Terreus .................................................................................................................................................................... 10 Figure 4: Squalestatin Formula; www.chem.ox.ac.uk/researchguide/dmhodgson.html ............................. 12 Figure 5: Squalestatin 1 Manufacturing Plant Layout .............................................................................. 126 Figure 6: Sample Air Impelled Fermenter .................................................................................................. 19 Figure 7: Pre-FDA Decision Tree ............................................................................................................... 22 Figure 8:FDA Process Diagram .................................................................................................................. 22 Figure 9: Relationship between Alpha and Time (Harl-Martin 2006) ........................................................ 33 Figure 10: Percent Cholesterol Level versus Dosage in Marmosets for a Period of 1 Week ..................... 35 Figure 11: Satisfaction versus Percent Cholesterol Level ........................................................................... 36 Figure 12: Number of People Suffering from High Serum Cholesterol Levels in the U.S......................... 37 Figure 13: Demand versus Price of New Drug ........................................................................................... 38 Figure 14: Demand versus Time with Different P1 .................................................................................... 39 Figure 15: Percent Demand versus Time .................................................................................................... 40 4 Figure 16: Equipment Prices for Scenarios 1, 2 and 3, 4 ............................................................................ 45 Figure 17: NPV versus Years of Project Including FDA Process............................................................... 46 Figure 18: NPV versus Different Price of New Drug ................................................................................. 46 Figure 19: Risk Curve based on Net Profit ................................................................................................. 48 Figure 20: Risk Curve based on NPV ......................................................................................................... 49 5 Abstract The objective of this project is to determine the feasibility of manufacturing and commercialization of a novel enzyme inhibitor of cholesterol synthesis. The goal is to propose a drug capable of lowering at least 50% of the total cholesterol level in patients dealing with high serum levels with the highest efficacy. This was done by analyzing the FDA and manufacturing processes, equipment pricing, manufacturing prices and determining highest demand for the drug, therefore, determining the best price for the drug. The suggested drug inhibits an enzyme